Good morning, everybody. I'm Stacy Lindborg, President and CEO of IMUNON, and I'm very grateful to welcome you to the 2026 R&D Day. It's great to see a full room here, and we have a really strong registration and online participation. We're excited by what we're going to share with you and the opportunity to spend real time thinking about frontline ovarian care treatment. We've got a wonderful set of speakers, very experienced and with unique perspective that I know they will impart to you. We, this morning, will be focusing a lot on the data that we've accumulated. We have a phase II trial that's completed with overall survival data, which is critical. Our product is built around IL-12, a cytokine that was tried by the industry for more than two decades and then was largely abandoned.
By the end of this session, my hope is that you will leave with three things. Number one, an insight into why IL-12 historically failed. Number two, why IMNN-001 is different, and number three, what the next few years will be and why OVATION 3 is a value-defining chapter for I MUNON . The problem, we'll start with the patient. We always have to remain focused on the patient. We have chosen to study newly diagnosed women with ovarian cancer. This is what we call frontline treatment. It follows in the same frontline treatment with maintenance therapy, but we are focusing on women who have just been diagnosed and are seeking the initial treatment, so they're treatment-naive. We know that the way it's been treated at its core hasn't changed for multiple decades. Platinum and taxane chemotherapy plus surgery have been the backbone of treatment. They have saved lives.
But we also know when we look to future patients, this really has plateaued in terms of the treatment paradigm. There have been many well-run trials with combination treatments, and they have failed to deliver overall survival benefits. Physicians will tell you they will use a drug that has small PFS improvement and no overall survival benefit. For example, bevacizumab, which is frequently used. This really tells you how much there is need and where the bar really should be as we reach the end of our phase III trial and we're seeking to be integrated into the frontline standard of care. Ovarian cancer remains one of the most deadly gynecologic malignancies. Women are diagnosed very late. Too many women are diagnosed in advanced stage.
Too many relapse, and too many never get the extra years that all of us take for granted as we have milestones and life that we want to see unfold. IL-12 is not a new idea. We're all aware of that. But we also know it's one of the most potent cytokines that exist and is a powerful weapon against cancer, if we want to use that term. It activates cytotoxic T-c ells and natural killer cells, and it works directly through interferon gamma. In pre-clinical models, the anti-tumor activity is profound, nothing short of profound. We've studied many different tumor types, and we're excited as we ultimately look at our first up, which is ovarian cancer.
We know that this is also the excitement and really the potential of IL-12 is why many large companies, including AstraZeneca and many others, went after IL-12, and they were approaching this with administering recombinant IL-12 systemically, so directly into the bloodstream. These programs did not fail for a lack of biology. They failed because they could not get to a therapeutic dosing window, and also because these, when delivered systemically, it produced dose-limiting toxicity. There was no therapeutic window. They had cytokine release syndrome and other immune-related injuries that closed the door, and the field, frankly, moved on. The field does what the field will do. You see a complication and a side effect that really is stopping development of an asset, and IL-12 effectively became a cautionary tale for products. I MUNON chose to not move on, and we've changed the delivery problem.
We found a way around the complications of before, and we developed a novel proprietary treatment. IMNN-001 is not a recombinant IL-12 injected into the bloodstream. It's administered as an IL-12-encoded DNA plasmid that's carried in our proprietary delivery system in a nanoparticle, and it's administered locally. Instead of systemically and going around the body, it's actually delivered directly where the cancer resides. It's designed to protect the DNA from degradation, allow it to go into the nucleus of cells, and allow those cells that are within each of these women's bodies to become factories that are naturally, through the immune system, producing IL-12, interferon gamma, and a whole cascade of effects. It drives sustained levels.
In our trials, you'll see we are giving them weekly infusions, up to 17 weekly doses, and yet you'll see that the data that we're presenting is out in the years, out to some women living and still in the trial being observed for more than five years. So sustained delivery of a local IL-12 at the tumor site, and using each woman's immune system to naturally fight the cancer. The hypothesis is simple: put the cytokine where the cancer is, not where the rest of the body has to absorb the cost. And we have been able to show in a 112-patient trial that was randomized against the standard of care, that we have been able to avoid these historic safety barriers and concerns. We're studying I MUNON in combination with the standard of care, which women are treated in neoadjuvant chemotherapy and then adjuvant chemotherapy with surgery.
The final overall survival data from the trial resulted in a median survival in the IMUNON arm of 45 months, and in the control arm of 30 months. So a 14.7-month improvement with IMUNON treatment. We saw with women who received PARP inhibitors in maintenance therapy, a 24-month improvement over the standard of care, so 56 months versus 41. Again, I can't emphasize this enough. The historic IL-12 safety barrier was overcome with our product. It did not exist in the trial. Our largest trial, 112 women, half on the experimental arm, no cytokine release syndrome, no serious immune-related adverse events. And while we've explored dosing, we actually never hit a dose-limiting toxicity. We're very confident with the dose that we're taking and used in phase II and we're replicating in phase III. And from an oncology standpoint, the IL-12 has been managed by design.
Put those results in context carefully, very carefully. If phase III is confirmed, if we've confirmed the phase II findings, IMNN-001 would be the first investigational therapy in this setting, in the frontline ovarian space, to deliver a clinically meaningful overall survival benefit in these women that are newly diagnosed. This is in combination with a standard of care that has been used for more than a couple of decades, and in a randomized, well-controlled trial. We have multiple randomized control trials. It would also be a first-in-class IL-12 DNA-mediated immunotherapy in any cancer, and it would be the first late-stage IL-12 program to pair a very favorable safety profile with the median overall survival that I've described. To our knowledge, no other investigational agent has produced an overall survival signal of this size in the frontline setting.
This is the opportunity, and I would even say it becomes the responsibility for us to see through, and it's why we are working incredibly hard with our partners that are on the frontline, to ensure that we're running a high-quality study. This is a pivotal trial with OS as the primary endpoint. We have two planned interim analyses. We have Fast Track designation and Orphan Drug designation, and the FDA aligned with our plans, which includes the protocol and the statistical analysis plan and all the accompanying documents that go with registration studies. We had an independent DMC, Data Monitoring Committee, recently that recommended the study continue without modification. As I end my concluding remarks, I want to really focus on where as a company we have to live, which is with the patient.
If OVATION 3 confirms what we've already seen, IMNN-001 holds a promise of giving women more time. Time to go to a wedding, time to spend time with grandchildren, and for many other memories. It's time that the current standard of care has not been able to provide and for a new generation. This is why the morning is built the way it is. We will have Dr. Faller starting. He is our Chief Medical Officer of IMUNON and will be focusing on IL-12 biology, why the field walked away, and how TheraPlas and intraperitoneal delivery changed the safety equation. We'll have Dr. Amir Jazaeri from UT MD Anderson Cancer Center talking about translational work and biomarker data, including preliminary findings from patients under his care in the MRD, Minimal Residual Disease, trial that's ongoing.
He'll report some early clinical findings, MRD status, circulating tumor DNA, and ultimately evidence that the tumor microenvironment is being remodeled. Then we'll have Dr. Premal Thaker from Washington University, who has treated women with IMNN-001 for more than 15 years. She has an immense set of experience with our product, our experimental product, but more broadly, across the field. She will share that experience and data from OVATION 2 and what the survival signal looks like from her perspective as a physician in the OR and also in the clinic. And then lastly, we'll hear from a woman who was treated with IMNN-001. I'll come back at the end and provide the investment thesis and the catalyst and what we're asking of you, but thank you for the opportunity to give these opening remarks, and I would say let's begin.
I'll introduce our first speaker, Dr. Douglas Faller. He's IMUNON's Chief Medical Officer. He's a medical oncologist and scientist. He has spent his career treating patients and stepping into the gap between patient need and providing drugs that you can give in the clinic. He will introduce the powerful potential of IL-12 from first principles. Why this cytokine the entire industry looked unbeatable from the bench, why systemic programs could not be delivered, and then he'll walk you through TheraPlas, the intraperitoneal delivery that we are administering our product through, and why historic IL-12 toxicities are not what we're seeing with IMNN-001. Douglas?
Thank you, Stacy. Stacy went through the agenda already, and we'll move right into Stacy also had this slide as part of her presentation and covered this. As Stacy said, what we're going to be focusing on for the next few minutes are the power of interleukin-12, the problems with its development, and how IMUNON has really completely overcome the barriers to harnessing interleukin-12 as a therapeutic. Also, as Stacy mentioned, this is really the first and only treatment in decades to demonstrate an impact on overall survival in newly diagnosed advanced ovarian cancer. There's been a long, long period of time in which people have tried to improve on the simple carboplatin/paclitaxel regimen that was developed 30 years ago. But all of the additions that have been tried have failed to demonstrate an improvement in survival.
IMNN-001 has the potential to transform the frontline standard of care for ovarian cancer patients. I'll emphasize again that this is frontline treatment. You may have heard about other drugs being developed in the second-line plus areas. There's been some advancement here. This is wonderful news for patients. But frontline is the opportunity to potentially cure patients, long survivals. Anything after frontline in many solid tumors is just giving patients more time, but diminishing returns. This therapy is not giving interleukin-12 protein, but rather causing interleukin-12 protein to be expressed by the immune cells. So a very different approach than what's been used in the past to try to use interleukin-12 as a therapeutic. So we're activating the immune system from within the immune system itself. It's a unique mechanism of action.
It's one of the few, if any, antitumor cytokines that stimulates both arms of the antitumor immune system, both the innate and the adaptive. We'll talk more about that in just a moment. But this is a two-pronged approach. Other cytokines that you're familiar with, like interleukin-2, which was discovered and developed around the same time, only stimulates the adaptive, the cytotoxic T- cells. Stimulating the innate arm of the immune system, NK cells, macrophages, monocytes, is an additional advantage of interleukin-12. Interleukin-12 is able to turn the tumor microenvironment from cold to hot. Ovarian cancer is one of the coldest immunological tumors by the time it's diagnosed. We'll talk about what cold to hot means. I'll also mention to you, very experienced investors and analysts, people have been talking about turning cold to hot as long as the tumor immune system has been being developed.
We're not just talking about it. I'll show you data that we do it in patients. Importantly, stimulating the immune system is not a one-shot deal. Once you stimulate it, the immune system can continue to recognize and kill tumor cells over years. Finally, we talked about local expression, local delivery. We're delivering interleukin-12 essentially, not the protein, but the gene, to the site of the tumor where the expression of interleukin-12 would be most important. We're not delivering it peripherally, so we're not seeing the kind of toxicities that have hampered its development, really more than hampered, blocked its development for two decades. Why interleukin-12? I mentioned already that do we have a pointer here? Maybe. I sort of have a pointer, but it doesn't work. That's fine. Interleukin-12 normally in the body plays a central role in developing antitumor activity. It's present at low levels generally.
It's made by monocytes, macrophages, and neutrophils, so myeloid cells down at the bottom of the slide. These produce interleukin-12 when they're stimulated by tumor or by some of the other agents that stimulate interleukin-12 pathogens. Interleukin-12 then does a number of things. I'll just mention before we move up to the top that one of the mechanisms of action of interleukin-12 is to stimulate the production of neutrophils and platelets. I mention this because cytotoxic therapies knock down platelets. They knock down neutrophils. That's the limiting side effect for most cytotoxic drugs. It's not just drugs like carboplatin and Taxol. ADCs, which have as part of their mechanism of action incorporated cytotoxic drugs into the molecule, these also cause suppression of neutrophils and platelets.
As a result, we can combine interleukin-12 with chemotherapy without exacerbating cytopenias, which is something that many other agents are not able to do. Interleukin-12, in turn, stimulates the production of interferon gamma. Interferon gamma is an incredibly potent anti-tumor agent. Does a number of things, and we'll talk about that on the next slide. But the fact that we can stimulate both innate immunity and acquired immunity really puts interleukin-12 and IMNN-001 in a unique spot in terms of therapeutics. So interferon gamma. Interferon gamma is an incredibly potent, as I said, cytokine. I took part in trying to develop it as a therapeutic many years ago. The toxicity of using it systemically is so great that there's no therapeutic window whatsoever. However, expressing it locally, which is what we do with IMNN-001, makes all the difference. What does interferon gamma do?
Now, interferon gamma is just one of the downstream effectors. There are other downstream effectors that interleukin-12 activates, including TNF alpha, which is a strong anti-tumor agent. But I'm just going to talk about the most potent of the downstream effectors of interleukin-12. Interferon has a direct effect on inhibiting metastasis, on increasing the dormancy of tumors, so slowing their growth. It causes tumor senescence, it inhibits angiogenesis, and it also, and very importantly, down-regulates the cold aspect of the ovarian cancer tumor cells. It reverses, really, the fact that the T regulatory cells, that myeloid suppressor cells, this entire suppressive microenvironment, interferon has the capacity to reverse that. Excuse me. Finally, it changes the cells around the tumor to, instead of a pro-tumor, tumor helpful phenotype to an anti-tumor phenotype. One example is macrophages.
There are multiple types of macrophages, but in ovarian cancer, the macrophage is an M2 phenotype. This macrophage actually supports the tumor. Dr. Jazaeri will also be talking about tumor-associated fibroblasts and stromal cells. What interferon gamma does is it can reverse the phenotype from M2 to M1, and M1 monocytes and macrophages are anti-tumor. This has all been developed in animal models, very convincing data, pleiotropic effects. When interleukin-12 was discovered in the early 1990s with the activity that was able to show in mice, it was rapidly tried to be developed by a number of pharmaceutical companies, and the results were, unfortunately, a great deal of toxicity. When trying to give the recombinant protein systemically, patients had serious major vital organ damage, hypotension, collection of fluids, to such an extent that two patients even perished from getting systemic interleukin-12.
Trials in the U.S. were halted, resumed, and then halted again because of the toxicity. At the time, this was called cytokine storm. Nowadays, we might refer to it as cytokine release syndrome. But it was really an insurmountable barrier. Subsequently, other people tried different ways of administering it up until about 2014. Lower doses, periodic dosing. None of these could develop a therapeutic window for the drug. Currently, there are a few early-stage programs, which I will mention a little bit later, which are trying to develop local delivery, for example, injecting the tumors directly. This is a fraught approach. As you can imagine, cancer and advanced cancer is not one tumor, and trying to inject multiple tumors is really a losing proposition in the long run.
What really changed for the entire area of interleukin-12 and delivery in ovarian cancer occurred with the OVATION 1 trial. This was IMNN-001 with chemotherapy, with standard of care chemotherapy, the kind of chemotherapy that every patient with newly diagnosed ovarian cancer gets. There were encouraging clinical responses with this really dose-ranging trial. There were complete responses. There were excellent surgical responses in the majority of patients. It looked very promising. OVATION 2, a randomized control trial, which you will hear more about from Dr. Thaker in a few minutes, gave us a very strong signal, a very encouraging signal, and really the first sign that we could improve overall survival meaningfully in frontline ovarian cancer. Lastly, we have OVATION 3, which is built on OVATION 2, which is currently underway and enrolling well.
Dr. Thaker will talk about OVATION 3 also. To lay out the problems, people are still working at early stages on trying to develop interleukin-12. Some of them are using intratumoral injection of either lipid nanoparticles containing interleukin-12 or interleukin-12 mRNA. But again, the intratumoral approach has the disadvantages I talked about earlier. People have been trying, especially at NCI, to link interleukin-12 to an antibody and then have the antibody direct interleukin-12 to the tumor site, in some cases focusing on tumor debris that the antibody recognizes. There are also viral vectors that have been used, engineered cells which express interleukin-12 to make them more active.
Viral vectors have the problem that you can usually not give them more than once because the immune reaction to them is such that the patient will generate antibodies, and giving the viral vector a second time, the vector's destroyed before any therapeutic effect occurs. The translational challenges from these platform approaches. We already mentioned that systemic recombinant interleukin-12 is just not viable. The therapeutic index is far too low. Intratumoral injection need accessible lesions, and very few advanced cancers are single tumors. There's also the issue of off-target expression, even with linking the interleukin-12 to an antibody. There's always off-target expression and toxicity. There are other repeat dose constraints with viral vectors, as I mentioned. How does IMNN-001 overcome this? We do regional delivery, which is exactly where the tumor is.
We're not using viruses, we're using plasmids, which do not generate an immune response against the plasmid. We're covering the peritoneal space. We're not trying to inject individual tumors. We're putting a liquid suspension of these nanoparticles into the peritoneum where they can reach all of the tumor within the peritoneal space. I'll mention here that the effects of the interleukin-12 exposure, not the interleukin-12, but the effects of stimulating the immune system reach far beyond the peritoneal space, however. I'll come back to that in a moment, but it's very important to realize we're delivering the drug systemically, but the immune anti-tumor effects are systemic. Thank you, Stacy. IMUNON is a regional, repeatable, non-viral approach for peritoneal ovarian cancer, but the effects extend far beyond. We get systemic anti-tumor activity. We're the only late-stage program working with IL-12. Is the intraperitoneal delivery an issue?
Is this a problem? Does this make the drug potentially less applicable for patients? In this situation, not at all, because gynecologic oncologists have been doing intraperitoneal chemotherapy administration for over 20 years. These physicians are experienced in the delivery of the drug. When I talk to physicians as we open new sites, they're very excited about having an intraperitoneal approach again, and there's even new excitement about intraperitoneal delivery of chemotherapy, with programs called HIPEC and things like that. This is a very well accepted and appreciated approach to delivering therapies. I'm just going to go up one level and mention that IMNN-001 is part of a platform. We can develop this platform to express other immune agents very easily because the plasmid is easily changed to put really any protein that you want to express the gene for that in the plasmid. Very simple construction.
The development and synthesis of the nanoparticles is also proprietary but straightforward, and in fact, we manufacture this drug ourselves. IMUNON does the drug manufacturing. This is a platform that IMNN-001 is just proof of principle for. We have many ideas about how to develop this further. We've talked about this, and this is just an example again of what we are hoping to achieve. We talked about the expression system. We talked about interferon being able to activate very potent anti-tumor responses, both arms of the immune system, but also inhibit the suppressive aspects of the immune system in the tumor and the tumor microenvironment. We've talked about this. We've talked about animal models. Let me show you that we can actually do this.
The first is we've designed this agent to deliver interleukin-12 locally, and let's just show you that in patients, we've been able to demonstrate that. In the top boxes on the left, interleukin-12 levels and right next to it, interferon gamma levels. The teal bars are ascites, and the darker blue or purple are the levels in blood. When we look across on the left side, different doses of IMNN-001 in patients sampled from the peritoneal fluid and the blood after treatment with the different doses, 36 ranging up to 100. We're able to show multifold, 25-fold induction of interleukin-12 and next to it, interferon gamma in the ascites, in the place where the tumor is. The blood levels barely change, often don't change at all.
Clearly, local delivery of interleukin-12, and this is why we see the safety profile that we've been talking about. Also, in OVATION 2, and in OVATION 1, we've been able to take tumor from patients at the time of diagnosis and then at the interval debulking surgery and look at the immune response to the tumor in those tissues. This is not a mouse model. This is actual what happens in patients when they get IMNN-001. We've presented some of the data shown on the right at a number of meetings recently, and we're going to be presenting at the Society for Immunotherapy of Cancer a month from now, the translational data, the biomarker data. I won't go through these because I'm running out of time, but I'll just mention that we're showing truly creating a hot tumor microenvironment.
We're increasing the recruitment of cytotoxic T- cells, myeloid dendritic cells, the M1 macrophages, the ones that I told you are anti-cancer in most of the paired samples in both the tumor and the stromal cells, the tumor microenvironment. We're able to show decreases in the immunosuppressive markers, exhausted T- cells, T regulatory cells, M2 macrophages. People have shown that these favorable ratios of anti-tumor activity to tumor suppressive activity are associated in patients with improved patient outcomes. What about safety? This is published data from the OVATION 2 study. Most of the serious treatment-emergent adverse events and the other treatment-emergent adverse events, in addition to the serious ones, were related to gastrointestinal and cytopenias. We'll talk about both of these. The cytopenias turned out to be a red herring. I mentioned earlier that if anything, interleukin-12 should be stimulating neutrophils and platelets.
It turns out that our participating investigators pointed out to us that the cytopenias were an artifact of the way in which we were looking at and sampling patients. We were seeing patients every week for the IMUNON arm, but we were seeing patients only every three weeks for the chemotherapy-only arm, and therefore, we were seeing in the IMUNON arm the chemotherapy-induced cytopenias. Cytopenias are not really an issue with respect to IMUNON treatment or addition to standard of care. Gastrointestinal. We've seen nausea and vomiting in some patients. This is manageable and also hard to dissociate in some cases with the chemotherapy that's being given at the same time that the IMUNON is being given. Our treatment-emergent adverse events of special interest are abdominal pain, excuse me, and cytokine release syndrome.
We have not seen cytokine release syndrome consistent with everything I've told you earlier about where we're getting expression of interleukin-12. Abdominal pain, though, is something that was more common in patients who were getting the infusion. We think that this is mechanical and not due to the drug, but nonetheless, pain is pain, discomfort is discomfort. Abdominal pain was the most common cause for us to reduce IMNN-001 doses in OVATION 2, but only 3% of patients discontinued treatment. However, we wanted to do better. In the course of OVATION 3, we instituted a prophylactic pain regimen so that ideally, women would not even experience discomfort the first time. They would already have medicines to prophylax against abdominal discomfort, and this has been very effective.
Abdominal pain has been a very minor issue in terms of numbers of patients affected in Dr. Jazaeri's MRD study in OVATION 2 and in OVATION 3. Safety, no cytokine release syndrome, no serious systemic toxicity, no immune-related adverse events. Most of the TEAEs were gastrointestinal. We have a very consistent safety profile across multiple studies and truly, we have overcome the historical safety and efficacy barriers associated with developing interleukin-12 as an immunotherapy. As Stacy mentioned, our independent safety review committees met in May for OVATION 3. There were no safety concerns. Continue the trial without modification. In Dr. Jazaeri's MRD study, the committee met very recently in August, a different independent committee. No safety concerns. Continue the trial. We believe that IMNN-001 is really defining the modern era of interleukin-12 in cancer immunotherapy. It's making it available to patients for the first time.
We've got a reliable system for expression of interleukin-12, a flexible and scaling manufacturing system. We've got a stable product, unlike recombinant proteins. These nanoparticles are extremely stable. We can induce the immune response. We've been able to show that in patients. We have direct access of the drug to the tumor microenvironment as well as the tumor, and we have very limited systemic exposure, potentially no systemic exposure. IMNN-001 has great potential in tumors beyond ovarian cancer, including gastric, pancreatic, colorectal, glioblastoma, mesothelioma. We have preclinical data for all of these, and I'm very pleased to say that we are actually in the process of starting trials in collaboration with the National Cancer Institute. They've asked to partner with us in developing IMNN-001 in the indications I just mentioned, newly diagnosed ovarian cancer with checkpoint inhibitors, colorectal cancer, pancreatic cancer, glioblastoma, and also not listed here, mesothelioma.
I'll conclude just by saying, I think you can sense my excitement about this therapeutic. This novelty, this ability to treat frontline patients to change the course of their disease, to enhance their lives, this is what drove me to join as Chief Medical Officer, IMUNON. I think you'll hear from our next speakers that we are really meaningfully affecting patients' lives and will continue to do so with OVATION 3. Thank you.
So we will hold questions and take them at the end. Thank you, Dr. Faller. It is my pleasure to introduce Dr. Amir Jazaeri. He is vice chair for clinical research and. Oh, gosh. These were Premal's slides. They have been. They will be pulled up. Let me finish my introduction while they are pulling up. Dr. Jazaeri does not want to ad-lib and give Premal's talk, although I am sure he would be very capable. Dr. Jazaeri is vice chair for clinical research and director of Gynecologic Cancer Immunotherapy Program at MD Anderson Cancer Center. He is the lead principal investigator for our ongoing phase II MRD study, and he is here because our confidence in IMNN-101, as Dr. Faller just evidenced, goes well beyond the overall survival curves in the clinical data.
He will show evidence the mechanism of action has been achieved and is being achieved by IMNN-101 and will take up the critical question of, is the product actually remodeling residual disease? Welcome.
Thank you. Thank you so much. It is indeed a pleasure to be part of the IMUNON Science Day. Before I get started with my talk, I just want to provide a little bit of context for our study, which is really complementary to a lot of other cool clinical and translational information you are going to get today. As you can see, this is a study that is jointly supported by IMUNON and Break Through Cancer. Break Through Cancer is a philanthropic organization that started about five years ago with the idea of using the COVID model of urgency to really attack the cancer problem. They decided to reach out to five premier cancer institutions, MD Anderson, Dana-Farber, Sloan Kettering, MIT, and Johns Hopkins University, to get investigators from these top-notch cancer institutions to really address the issue of cancer. They requested proposals about different projects.
One of the proposals that later became our project was: how do we deal with the problem of ovarian cancer minimal residual disease? What we mean by minimal residual disease in ovarian cancer is microscopic cancer cells that remain after frontline treatment. Many of you might know that ovarian cancer's frontline treatment is a combination of chemotherapy and surgery. But the problem with ovarian cancer traditional treatment has been that most patients' cancers come back. When we say cancer comes back, that is really a misnomer, right? Cancer does not really come back. It never leaves the body. It is this issue of cancer becoming undetectable, going under the radar, and that under-the-radar phase is what we refer to as MRD or minimal residual disease. But now we have become better at picking up the under-the-radar. We can do that two ways.
We can do it using surgery, so a second surgery where we go in there, do multiple biopsies, and identify cancer surgically that would be missed based on scans and blood-based tumor markers. There are a new class of tumor markers called circulating tumor DNA or ctDNA. So that's another way of capturing this clandestine portion of the cancer. We proposed this project, and the flagship aspect of our multi-institutional project was the IMUNON MRD study. The idea here was we wanted to take standard chemotherapy, but add to it the most cutting-edge, the most likely effective treatment possible. That, of course, is the IMUNON platform for multiple reasons. Not only that, as you heard, this platform has solved the issue of IL-12 being difficult to administer, so the deliverability issue, but also, as you heard, the platform is incredibly versatile.
The TheraPlas, you can imagine that there can be multiple immunologic sort of products that can be delivered through the same platform and with really very little risk because you've already shown that the delivery platform is safe and effective. So I just wanted to offer that little bit of background. What I'm going to share with you is our study, which is also ongoing, so this study has not completed, but I'm going to share with you some of the preliminary findings because I think they will complement and add to what you already heard from Dr. Faller. So the why of it, why do we want to do this? As you heard, a frontline treatment is the best chance to offer a cure. Patients who have recurrent disease are largely basically accepted to have incurable disease.
You heard about IL-12 boosting both innate and adaptive immunity, but the adaptive immunity is what gives you long-term protection against cancer. I sometimes use the example of you get chickenpox, and the chickenpox virus stays in your body, but your immune system can control it long-term, so it doesn't cause effects. Of course, as I mentioned, this platform also lends itself very well to additional future modifications of the immune system as we learn what makes this work and what are avenues where cancer cells might become resistant. So the better understanding of the mechanism of action is going to be fundamental to future development of this platform. So this is just a schema of our study, and I'll take you through it. On the left-hand side, you'll see that patients that are eligible for this trial are patients that have advanced stage disease.
In fact, they have a disease distribution and volume that makes them candidates for neoadjuvant chemotherapy. Neoadjuvant chemotherapy means that there's too much cancer to start with surgery, so we're going to start with chemotherapy to shrink the tumor, use surgery in the middle, and then in a sandwich manner, give additional chemotherapy afterwards. As you can see, this is also a randomized study. Patients undergo initial diagnostic laparoscopy, so we can document and sample areas of tumor before starting treatment. Then they're randomized to either neoadjuvant chemotherapy on the bottom. The control arm is neoadjuvant chemotherapy plus Avastin or bevacizumab for four cycles. The experimental arm, patients have an intraperitoneal port placed. This is the way we give IMNN-001 directly into the abdominal cavity, and they get the same treatment plus the weekly treatment with IMNN-001.
All patients are considered for interval surgery after four treatments. After surgery and recovery, all patients get adjuvant chemotherapy, so that's treatment after surgery. Again, the control arm gets the control treatment, experimental arm gets the IMNN-001. As I mentioned, we wanted to look specifically as accurately as possible to see who still has residual disease after treatment or not. One of the limitations of current clinical trials in this space is that we have to follow patients until recurrence. As you might imagine, that has a timeline of years. What if we could tell right after treatment whether there's still residual disease or not? One of the goals of this study is to see how does determination of minimal residual disease at the end of treatment correlate with long-term outcomes.
Obviously, the patients are still going to be followed for long-term outcomes. Many of you may be aware that there is a maintenance phase for most patients with ovarian cancer, and that's determined based on the molecular subtype of ovarian cancer. Roughly half of ovarian cancers are a molecular subtype that's called HRD positive or homologous recombination deficient. Those patients go on and get PARP inhibitors, and in this study, they get olaparib plus bevacizumab. Those that are HRD negative or homologous recombination proficient, then in the maintenance phase in the standard arm, are going to get just Avastin. That's the currently used maintenance for this patient population. But in the experimental arm, we had the opportunity to demonstrate safety of IMNN-001 in this maintenance setting for future studies where we may want to extend the administration.
In this setting, patients again get IMNN-001 intra-abdominally, but instead of once a week, they get it once every three weeks in conjunction with Avastin. The two things that stand out in this study is, one, that patients have determination of residual disease with a second surgery, so-called second-look laparoscopy. That's what SLL stands for. The second thing is that this study also adds a maintenance phase that may be important for future development. I'm going to share with you some of the clinical updates. This is just demographics. Again, it's a randomized trial, so it's always good to show the control and experimental arms are roughly the same. I won't go through this table, but it's enough to say that the populations are roughly equivalent in both arms. This is the outcomes.
These are swimmer plots where the green shows patients that are in the experimental arm, the blue shows the control arm. I think the key information is summarized in the boxes on the right side. If we look at MRD positivity rate in the control arm, you can see that six out of nine patients still had residual disease after finishing frontline treatment, so 66.7%. The MRD positivity rate in the experimental arm was numerically smaller. Only four out of nine patients that have made it to that second surgery had residual disease. Again, an improvement in residual tumor at that time point. Again, as I mentioned, another way of capturing this minimal residual disease is looking at tumor DNA in the bloodstream. That's called circulating tumor DNA.
And when we look at the rates of that circulating tumor DNA becoming undetectable, you can see that in the control arm, 62% of patients became undetectable, while in the experimental arm, 87.5% of patients became undetectable. Again, these are small numbers, but favoring the experimental arm. Then this is, again, some more clinical information. One of the things that I want to draw your attention to is chemotherapy response score. This is pathologists examining tissue that's removed at that middle surgery. Remember that middle surgery is performed after four cycles of neoadjuvant chemotherapy. They look at how much the tumor cells appear to be affected by the treatment. A chemotherapy response score of one means that the tumor cells are hardly affected. As you might imagine, two and three means that the chemo has had a greater effect on the tumor cells.
As you can see, again, in the experimental arm, there is a preferential effect by the chemo plus, of course, IMNN-001 in that arm. The second emerging clinical observation is if we look at, again, the second-look laparoscopy positivity rate I already went through in the previous slide. But also, if we look at just the regular way of looking at who doesn't have any disease, which is currently with a CAT scan and CA 125, you can see that of the patients that were NED or no evidence of disease, only five out of the nine patients in the control arm, but all nine of the nine patients on the experimental arm reached NED. Again, suggesting that a more favorable effect for the experimental arm. These are progression-free survival curves. Again, this is immature.
As you can see, the numbers are small, but you can see the trend is in favor of the green line, which is the experimental arm with medium recurrence-free survival of 26 months in the experimental arm and only 12 months in the control arm. I think another opportunity from our study is this ability to look at tumor at multiple time points so that diagnostic laparoscopy allows us to look at tumor before treatment starts. The interval surgery after four cycles allows us a middle view, and then those patients that are second-look positive or have MRD tell us what's going on in the cancer cells that are remaining after the end of chemotherapy phase. This is just a diagram. Again, as I mentioned, patients undergo screening and diagnostic laparoscopy in the beginning. They're randomized to experimental arm or control arm for the neoadjuvant phase.
They all undergo second-look or, sorry, interval cytoreductive surgery. That ICS is that interval surgery. All patients undergo second-look laparoscopy after adjuvant chemotherapy. I won't get too technical, but there are newer ways of looking at the cancer environment where we can look at individual cancer cells and look at what's going on inside the individual cancer cells. This is often referred to as spatial studies or spatial transcriptomics. We also performed single-cell RNA and TCR-seq that tells us about clonality of immune cells, and then whole genome sequencing to look at clonal evolution. This is just a plot of the different types of cells in the tumor microenvironment that we can detect using these cutting-edge translational methods.
You can see the tumor cells, the big cluster on the right side, but you can see various different types of immune cells that are able to be identified using these technologies. This is how we identify them. We identify these different cell types based on their gene expression signature so that the yellow bars are genes that are preferentially expressed. On the Y-axis, you can see the different types of immune cells. This is how we know different immune cells that are present in the tumor microenvironment. This graph shows looking at proportion of cells that change. The colors on the bottom is categories of patients in the experimental arm in the red colors and the control arm in the blue colors at the three different time points.
The diagnostic laparoscopy or DL is before any treatment, interval surgery is at the middle, and then second-look laparoscopy is at the end. You can see that in the experimental arm, there is a significant increase in macrophages, which is a type of immune cell that is part of the innate immunity. You heard Doug talk about how IMNN-001 stimulates innate immunity. Then importantly, we see immunosuppressive populations that are called myeloid cancer-associated fibroblasts, and you can see that their proportion goes down in the experimental arm compared to the control arm on the right-hand side. Here is really the crux of the matter. Here we are showing that only in the experimental arm, the macrophages are expressing the genes for IL-12A and B. That is what is programmed in that plasmid.
We are showing direct mechanism of action with expression of IL-12A and B in macrophages which are normally an immunosuppressive population. Douglas Faller mentioned turning a cold tumor into hot. This is showing you precisely how that happens, that we are taking a major immunosuppressive population and macrophages and also cancer-associated fibroblasts, and we are turning them into inflammatory cancer-associated fibroblasts. Of course, you see this only happening in the experimental arm and not in the control arm. This is just showing you visibly. Again, we are looking at all the different cells in the tumor microenvironment. The white shows you the tumor cells, the blue shows T- cells and B-c ells, and then various other immune subtypes are also shown. If we look at this and look at where is IL-12 being produced, this is taking the same topography.
If we go back, you can see the macrophages here and myeloid cells are shown in shades of green. If you focus on where the green areas are, these are samples from three different patients at the time of their interval cytoreductive surgery. Here, the peaks correlate with where the green is. Again, this is a different way of showing in the tumor microenvironment, we are actually showing the macrophages are expressing IL-12. Then another way to look at that is, again, looking at IL-12 in the surrounding radius of cells that are exposed to IL-12, you can see a much greater number of radius or spatial field associated with IL-12 in the patients that are on the experimental arm. Again, this is the graph of it, but visually, you can see IL-12 here shown in this heat map as areas that are red.
If we look at the red areas and we look at what is going on in terms of cell populations and then move away from the red area. If you have a bomb that goes off, you expect the cancer cells that are killed to be in the immediate vicinity, but as you go farther and farther away, there is going to be less effect. On the right-hand side, you can see the proportion of cells that are seen within the field, and then you see the radius as you go gradually farther and farther away. You see macrophages are concentrated because they are the cells that are picking up the IL-12. Then you can see, again, the cancer cells are less in the vicinity and get more as you get farther away. This just shows the same thing in a different way.
If we look at what is happening over time in the experimental arm and in the control arm with regards to immune cell clonality. One way to think about clonality is that if immunotherapy is working, then our immune cells are keying in on specific targets on the cancer cells. There should be less random immune cells. There should be more production of those cancer cells that are recognizing, sorry, those immune cells that are recognizing the cancer cells. The higher the clonality, the more specifically our immune cell is recognizing cancer. You can see that in the experimental arm, regardless of whether they were MRD positive or MRD negative, you see a much higher clonality compared to the control arm. Again, showing that not only is IL-12 being produced, but it is impacting the immune system on recognition and attacking the cancer cells.
Can you help me advance to the next slide? Okay, thank you. In summary, while preliminary, our data demonstrates lower MRD positive rates, higher chemotherapy response score, and lower NED positive rates, and better progression-free survival in patients that received IMNN-001. IMNN-001 may drive the expansion of macrophages and reduction in the immunosuppressive myeloid cancer-associated fibroblasts. Macrophages are the major cell population that pick up IL-12 as part of the platform and to a lesser extent, also cancer-associated fibroblasts. IMUNON treatment drives TCR clonal expansion, suggesting induction of anti-tumor immunity. In terms of future directions, of course, we plan to complete enrollment on the MRD study and to hopefully show the first abstract of the completed results in 2027.
There is integration of a lot of the translational stuff that I just touched upon, looking at both protein and RNA expression, and then also looking at how tumor evolution in the control arm and in the experimental arm differs. We also are interested in looking at the microbiome, the gut microbiome. We have samples collected in patients on both arms, and we look forward to analyzing those samples as well. I know we are going to wait for questions until the end, but happy to chat with anybody either during the Q&A or after. Thank you so much.
Thank you, Amir. I am delighted to welcome Dr. Premal Thaker to the podium. She is the David and Lynn Mutch Distinguished Professor at Washington University. She is Chief of Gynecologic Oncology and Director of Gynecologic Oncology Research at Washington University. She was the lead investigator for OVATION 2 and is also the lead investigator for OVATION 3. As I mentioned in my opening remarks, she has been associated with IMUNON development and has really had a very influential role in the development of IMNN-001 across the 15+ years that she has been involved. She is going to take you through her view into IMNN-001, our clinical data, and offering remarks that really impress upon why advancing phase III and getting the trial enrolled needs urgency. Welcome, Premal.
Well, thank you so much for having me. I am going to actually bring it back to the clinic, which is really why we are here. We are here talking about patients. It is great to show data about how we are changing that tumor microenvironment because it is very important for proof of principle. But when I am in the clinic every day, how am I going to translate this to a patient and how do I describe it to them? I have been involved. I do a lot of drug development, so this is obviously one that is very dear to my heart. I have been there for a long time, but I have developed lots of drugs in the platinum resistance space, platinum sensitive space.
I am very active in clinical trial development, but this is the first time we can really maybe affect a cure, which I think is a big word that we do not get to use often enough for our patients. Just to bring it back into perspective, about 21,000 patients will be diagnosed with ovarian cancer, and we will lose approximately 12,500 patients. We do have a five-year survival rate of about 51%, and it is pretty dismal because the fact is we diagnose these women way too late because we do not have a good screening test. We diagnose these women, they are stage 3, stage 4. As has been alluded to, they have disease that is widespread. They are very malnourished when they come to us. They have maybe been misdiagnosed even before they come to us. It becomes a real issue.
Because of that, we really do not use the word cure as often because the fact is we know that most of these women will recur, and how do we really change and break that paradigm? Only about 20% of our cases are found localized as a stage 1 or 2, and that is just usually by being very lucky because you went in for some other CAT scan for a kidney stone and found out that you had a mass, and you might have gotten diagnosed early. It really is important for us to try to say how do we break this sort of paradigm and improve this for our patients that sit in front of us every day. It is a very difficult disease because, as I said, we diagnose it late. We do not have a screening tool.
We actually have these patients that more and more are getting neoadjuvant chemotherapy. If you look over, there has been a huge paradigm shift because we know that more and more women get neoadjuvant treatment nowadays. It might be as high as 60% to 70% because we know that we cannot surgically go in and remove all this disease. We really have shifted from being like, "Oh, we are going to be surgeons and just cut it out," to knowing that we really need to be able to give them treatments to hopefully sort of chemically reduce the disease to have more successful outcomes. Recurrence is very common, as we have talked to, and really the way is for us not to have to keep saying to the women that you are going to get palliative treatment because you have recurred.
How do we really try, as I said, to keep breaking this cycle? We are in a desperate need because the joke in medical oncology is what you give patients who have gynecologic ovarian cancer is you give them Taxol/ carbo, because for 40 years we have not changed that paradigm. We really have added Avastin or bevacizumab, and we did that with only a progression-free survival difference of three months, but no overall survival benefit. Yes, it is something that we can add, but it is not really changing our upfront paradigm, which is when you talk to a patient or you really want to know what is the gold standard, is are you really changing overall survival? Not that incremental.
If I looked at any one of us, and you all are in the finance world, saying, "It is a quarter," you would not be like, "That is amazing.
I get an extra quarter of life." It is really something not meaningful to a patient. How did we end up doing this, and what has been so important is really we have been very thoughtful of how we have brought this drug to patients. Really, OVATION 2's schema was we wanted to build on the localized IL-12 safety. We wanted to say, can we actually change the tumor microenvironment? The MRD study has taken, of course, it a lot step further in the biology. But the initial sort of studies we are looking at, and it was in OVATION 2, it really was trying to say what we knew at that time, because remember, trials are always what we knew best at that time, was that surgery was our best option.
If we knew that we could get patients more to a no gross residual component at their time after chemotherapy, that we would be hopefully affecting their survival. How do we actually start helping the immune system learn how to control a disease? We actually are learning that in a lot of diseases, that sometimes giving it while the tumor is present can actually educate the immune system much better than actually after we have resected and then giving immunotherapy. We are learning that in quite a few diseases. It is pretty novel that in colon cancer, if you are mismatch repair deficient, you might get your immunotherapy up front with the cancer being there and not even need surgery potentially because they are disappearing.
This is a concept that makes a lot of sense and is also being seen in other disease sites as well, that we need to get the immune system involved earlier. We have had a lot of an eloquent talk about MRD and how we are seeing more ctDNA clearance, how the macrophages really and the peritoneum are taking up the IMNN-001. Really, we are asking these women to take this treatment up front. These are patients that we diagnose them, we ask them to take it up front. Very different than the phase III trials that you all talk about for maintenance, because in order to get a maintenance drug, you have to have responded. You have to have had either stable disease or a complete or partial response, really complete or partial response. These are women we do not know how they are going to respond.
We are taking them right from the get-go. It is a harder to treat population because when you look at those other phase IIIs, you do not ever see those women who were not eligible because they were not eligible for trial because they did not respond. Here we are giving these women intraperitoneal therapy. We are giving it to them weekly. If you talk to breast cancer patients, they get weekly treatments all the time. It is not something that is overly burdensome to a patient, and there is a finite date to be done with treatment. Yes, if they have an HRD signature, they could potentially go on to a maintenance treatment, but they actually, if they do not, they stop on this trial.
When you want to think about ringing the bell, being done, having a goal, setting a goal, you can actually time it out for yourself too.
Why am I so passionate about this? It is because really OVATION 2 gave us the first signal of an overall survival benefit. We have not seen that. We have tried so many different ways. We have tried different combinations of chemotherapy. We have tried different combinations, as I mentioned, with anti-angiogenics like bevacizumab, all with the hope that we would affect overall survival. We have never been able to do that. This trial is for all comers. We made a difference of 14.7 months with a cutoff in December of 2025. That is something I can go and talk to a patient very meaningful about because as Stacy Lindborg, she stole my line. It is another set of birthdays. It is another set of weddings. It is being a grandparent.
It is just another year of life, which is huge in a disease that we are trying to make it that they hopefully never recur.
If not, talking about that type of gain is really something substantial for patients. Additionally, when myself and Amir Jazaeri, we both trained together at MD Anderson, so we are compadres. We were always taught that patients who have a BRCA mutation or an HRD signature will always do better. Now we have also learned from our maintenance trials, these patients actually recur too. But you can see when you have that subset population, when you add IMNN-001 to the PARP inhibitor, they do significantly better as well. We are even making transformational changes for patients who are thought to do well, and we can make it even better. That is also important because patients recur, and we want to try to prevent that, breaking that cycle.
So this is the graph that you saw earlier with Dr. Faller, who did not get as much time to go through it, but it's really trying to just put into perspective. We keep talking about how we're trying to make this cold tumor into a hot tumor so that we really can affect it. And people always ask me all the time because they're like, "We've used checkpoint inhibitors," and we've actually had lots of patients take those medications in concurrent with chemotherapy. They've not been successful. Thousands of patients have been on those trials, and it's mainly because you're not affecting the immune system on both the innate and the adaptive portions and also affecting all the other cells. There's nothing that's a singularity about the immune system. We don't just say you're only T-c ells, you're only macrophages, you're only NK cells. You're everything. You're lymphocytes.
And that's what we're looking at, showing that we can really affect that portion of the immune system, which is a very much broader bomb, quote unquote, to help the immune system really attack and make the woman's own immune system augmented to do this. And in the area where the disease is located, intraperitoneally, that's where the disease is. So it's very important we're not getting those systemic side effects, which is also very critical so patients can tolerate this and get it very successfully. And we even shown proof of concept that the more you get, the better you do, because not every woman every week, they might miss a cycle for whatever reason. So we're actually very impressed at how much even with some patients who got fewer doses are still seeing robust responses.
So with the mitigation strategies of like giving for abdominal pain, we hope that we'll be able to give lessons learned in order to improve our administration as well, which we're doing much better on the OVATION 3 trial. As we made that amendment in OVATION 2, we also got much improved administration of IMNN-001. I think one of the other things everyone gets to see a forest plot, and I know the OVATION 2 trial is not statistically powered for all of this, but it's very consistent in that it's always favoring the IMNN-001 sort of factors that we look at. Patient overall survival. You're looking at progression-free survival. Were they HRD positive, not positive?
So this is very much telling to us that OVATION 3, if it can hit the same marks, which we very strongly feel it will based on this data, that we will be able to show that we can really move the needle and maybe make the first breakthrough in ovarian cancer. We don't have the side effects of cytokine release syndrome. For some of you who may or may not be aware of that's very severe. It's as if your body has like a sepsis, so it requires you to be in an intensive care unit. You have the neurological checks. You need intensive care. So it's not something that's minute because people ask about CAR T therapy, other therapies, and those have these adverse side effects.
And so trying to also think of a treatment that we can not only give not only in academia, but we'll be able to give broad spread into your rural areas, your community areas. That's also important. I love academia. That's where I am. But not every patient can come to us, nor do they have that sort of care team to take care of them. A lot of people are going to shy away from giving those therapies because they just can't do it. So this is a therapy that I also want you to realize can be widespread given, because we're not talking about something esoteric, which is a key thing. So why is this important to me as a physician? I think you hear me. The patients are the sickest of the sick.
We're taking them when we don't know how they're going to respond, and we're seeing responses. Then the translational components which really confirm what we saw pre-clinically, we're now seeing in our clinical specimens. We're seeing them durable, and if you look at a lot of immunotherapy, you see overall survival benefits because it takes a while for our immune system to be revved up and to give us those incremental gains. Then importantly, this is a treatment for all patients, not just the patient who's HRD. It's for every patient who walks in.
Because I said this yesterday, it's very hard for a patient to accept that their tumor microenvironment doesn't have the signature that they wanted in order to think ahead because all of these women are on blogs and talking with their social networks or care teams, and they know that if I have an HRD signature or I have a BRCA mutation, I'm going to get a PARP inhibitor, and that's going to maintain my response, and I'm going to do better. But think about the other flip of the coin, who comes in who does not have that. This is a way that we can overcome this. From a patient's perspective, what do they want? They want hope, and they want to know that there's going to be active treatment.
That is the reason there's people like myself and Dr. Jazaeri who keep pounding the pavement year after year trying to figure out newer treatments so we can honestly make a difference to those patients so we won't be just saying, "You're going to get Taxol/carbo and maybe bevacizumab." We'll be able to hopefully say, "You're going to get IMNN-001 with Taxol/carbo." Dr. Jazaeri's study gives us also the benefit that we can add bevacizumab if necessary. The treatment is time limited. I'm happy for my patients who can get on maintenance therapies, but there's a lot of them who don't also realize the side effects that they get from their maintenance therapies until they're really off the treatments that are oral.
The fatigue, the nausea, as well as we're not even talking about the financial toxicity to families because one of the parts of cancer treatment is also thinking about what are the ramifications after treatment. These women lose work. They may have to take extra time off. It affects families, affects their finances, and we're starting to appreciate that. I'm putting that in a perspective, because if you think about it from a patient's perspective, this all is in their head, what's going on, and how to get this to become a reality that they can overcome their disease. And quality of life is really important. In OVATION 3, we will be collecting that data. But talking to patients and having treated them, their quality of life is much improved, because the fact is they're living their life. And that is the key.
Because patients are willing to take side effects as long as they know they're going to get benefit at the end or benefit from the treatments they take. As I said, we've learned how to help them with the abdominal pain, with the nausea, trying to help them get through these medications, and also giving better education. I think a lot of it is once you educate patients and they know what to expect, they're much more able and capable to take the medications too. This is not uncommon. If we look at antibody drug conjugates, we're all on a learning curve. We all became now pulmonologists, ocular specialists, it's just a matter of learning. I'm going to take you through a case study of actually my own patient, who was diagnosed with stage 4 disease.
She's 45, so young kids, not even in college, just in grade school. She comes in, gets randomized, because she was on trial, to six doses of carboplatin and paclitaxel. She did the three cycles neoadjuvantly and three adjuvantly, and she ended up taking 15 weekly doses of IMNN-001, 88% dose intensity. She took eight in the pre-surgery and then nine afterwards. Then she had an R2 resection. So what does that mean is that we had to leave some disease behind. It was not the R0 that we always hope that we could remove everything. So that really would make you think, like, "Oh, she's not going to have as good a response." But she ended up having a good chemotherapy response score pathologically of two.
She had a complete response that she remained on for two years and normalized her CA 125 quickly, because that used to be one of the markers we used to utilize to say if you have an elimination of your CA 125 quickly, that you have a better response as well. She ended up on olaparib maintenance because she's a BRCA mutation carrier. She was able to maintain her response, but progressed at 34 months and then passed away at 70 months, which is much better than the curves that you actually typically see when a patient recurs. She got to get to see her kids graduate high school. She even saw one of them actually get married. So these are the differences that make, because we get to see these patients.
As a gynecologic oncologist, we take them through diagnosis and hopefully to cure. That is what we are here for today. We do take them through end of life as well. We get to know these women really well in and out. Even though we do not have a quality of life that was measured on OVATION 2, she did get quality and she got quantity. It is never enough, and that is what I tell every patient, and that is why we are here today to hopefully make that difference. What is OVATION 3? It is building really on OVATION 2. The schema is going to look very much the same. It is just a larger randomized trial. OVATION 2 had 112 patients. This is going to randomize 500 patients, stage 3B or higher. All of them have to get neoadjuvant chemotherapy. They will get their diagnostic laparoscopy.
They are randomized one-to-one to receive frontline chemotherapy versus frontline chemotherapy with IMNN-001, and then afterwards undergo an interval debulking and then get their adjuvant treatment. At the end of treatment visit, if they are HRD or BRCA mutated, they will end up on a PARP inhibitor. Really we are going for the gold standard. This is a trial that is looking at overall survival, and that is the actual FDA recommended gold standard. We rarely get it, so that is why we always are like surrogates of duration or response, progression free. Really, we are going for the gold standard because we really feel that based on OVATION 2, we will hit that mark. It is really important because we also have those interval looks at our data because we do feel that we will hit it earlier as well.
These are ways to try to get these treatments to patients as early and as safely as possible. What is really the importance is that we also are accruing quite well. We actually have activated quicker than a standard pharma trial. We are getting patients to enroll overall at a faster clip. We anticipate that we will complete enrollment in quarter one of 2029. We are looking at clinical as well as more importantly, biomarkers. We will have much more data to substantiate what we have presented today. Then we have the pre-planned interim analysis, which will also be very helpful because as I mentioned, we are hoping to get this to patients sooner. Why if this would become the next global standard of care, is that we would really be giving patients a huge benefit and opportunity to get a chance for a better tomorrow.
The mechanism of IL-12 Interferon gamma, I think we've talked about it all the time. It's really the first drug that has been able to prove that we can affect these critical cytokines, and we are changing the tumor environment. We all talk about it theoretically and hypothetically, but we really are doing it, as you've seen from the presentations that were eloquently ahead of me, and we're giving it without the systemic toxicities. We are able to give this, we're able to actually expand this to other disease sites. More importantly, I can say for sure that it has been a very consistent safety profile because I've done it in platinum-resistant ovarian cancer. I've done it in the early phase I all the way now to phase III. You can give it to your patients very safely. We've never seen this type of benefit in overall survival.
I think having that consistency, we have the opportunity to really change the standard of care, which is not something we can ever really say. This is really very exciting to me as a clinician and also more importantly to the patients that I serve. In closing, we're targeting ovarian cancer where it is in the intraperitoneal cavity. We're giving a frontline immune therapy that's effective. We're giving a way to give this repetitively to patients in order to change the trajectory of their clinical course. Ultimately, we want to transform our patients so that they are getting cutting-edge, newer therapies and longer lives. With that, I thank you.
Okay. I have the pleasure of introducing you to Terry. She is a woman who was diagnosed with late-stage ovarian cancer and was treated as part of our OVATION 1 study. She's chosen to tell you in her own words what her diagnosis and treatment was like, and she's joined by Dr. William Bradley, who's professor and vice chair of clinical research in the division of gynecologic oncology at the Medical College of Wisconsin. Dr. Bradley has been an investigator in OVATION 1, OVATION 2, and now OVATION 3 as well. He and Terry, unfortunately, were not able to be here in person but sat down recently to reflect on their relationship together across a 10-year span. If you'll play the record.
Interleukin-12 has been around for a long time. It's been used against a number of different cancers and has shown really excellent activity. The problem is that interleukin-12, when given intravenously, causes widespread systemic side effects that are essentially intolerable and very serious side effects in a subset of patients. The way this medication is given is intra-abdominally into the peritoneal cavity, which is essentially the sac that holds our bowels and the lining of our abdomen. This, in ovarian cancer, is where the cancer wants to grow. You're providing the level of therapy directly to the disease, and this is much more tolerated than it was intravenously and really has a higher level effect at the spaces in where the cancer tends to want to grow. Terry, we have known each other for a long time.
I confess, I do have some memories of meeting you, but they may not be as exquisitely clear as your memories are because you were going through something very different than I was at the time. Can you talk a little bit about the symptoms you had, the experiences you had in coming to a diagnosis that you had a serious disease that needed medical attention?
Sure. I first was having symptoms back in November of 2016. I remember that date because it was very close to Thanksgiving.
Sure.
My first symptom was that I had lower right quadrant pain. Being a physical therapist and being in the medical field, I looked my symptoms up. What I found was that it could be something to do with my bowels or that it could be ovarian cancer. Being that I was 58 at that time, I knew it wasn't bowel problems because I didn't have any symptoms that had to do with my bowels. My mind quickly went to ovarian cancer.
Okay.
I made an appointment with my primary care doctor, she was luckily able to get me in very quickly. That was just a little before Thanksgiving.
Sure.
She got me in actually that day. I was very lucky. That was a Friday. I had the ultrasound done, which is a very special type of ultrasound. With that, I got the results over the weekend.
Okay.
Being that I was on MyChart, which is the electronic charts at our facilities, I could read the results, and sure enough, there was something suspicious on my ovaries, both of them.
Okay. You probably knew what that meant.
Being medical, I knew what that meant, which was not good news. I was able to share that with my husband, which was very difficult. He is not medical at all. I said, "Honey, I think I might have ovarian cancer." I said, "I got to get an appointment as soon as possible." I didn't know how bad my ovarian cancer was, at what stage. I looked at all the oncologist gynecologists, and I really liked you.
Okay.
The description, and I waited till Monday, and I called for an appointment, and I was able to see you on Wednesday of that next week. I'm sure you all remember this because you're such a good doctor, and I thank you for that to this day. Because you are such a wonderful doctor. You saw me, you saw the results of the CAT scan, and you told me I had ovarian cancer, and it was on both my ovaries from the CAT scan. On Friday, my husband and I came back to see you on that Friday, and a change of plans happened, and I had some mets that had spread outside my lung and my liver.
You were, again, so good in explaining that. My husband, of course, was very shocked, and I just wanted to get everything done right away because you had to do what you had to do.
When we present treatment options to patients as physicians, just like any people, we have our biases, and I try to be very transparent about that, and I try to explain why I think one thing is more appropriate than another and that kind of thing. But things like clinical trials and experimental medications can be very intimidating when you already have an intimidating diagnosis. Can you talk to us a little bit about how you came to think about that, what your reaction to that was, and what information helped or clarified things for you?
Yes. When we came back and found out that I had spread of my cancer, not just in the local area, but also had spread, you said that, "I think we have to backstep a little bit," and said that surgery wasn't the first option. That we needed to go for chemotherapy, because we needed to try to shrink the cancer as much as we could first and then do surgery second. Our plan of action changed. In my head, I agreed that, yes, that sounded very rational, that that was going to be a better option.
Sure.
Then that's when you explained that you thought that trying to get into a clinical study could be an option, meaning that we do traditional chemotherapy and add a clinical study drug along with that. To kind of quarterback two types of chemotherapy with you, and that you knew of a clinical study that maybe I could participate in addition to the standard chemotherapy that's given for ovarian cancer.
Right.
I wanted everything and anything that could help me to survive, both for myself, mostly for my husband. I mentioned I was 58 at this time, but we had only been married 10 years. I wanted everything for him. I come from a very big family. I have four siblings, females and four brothers. My parents are alive, and I had 11 grandchildren at that time.
You weren't really intimidated by the idea of an extra medication. To you it seemed like-
No, I wanted everything.
The idea was.
The scary thing is that you said that you were going to try to get me into it because it kind of had closed. So you were going to try to get permission over the weekend for me to join this. You already had handy this big packet that seemed like 50 pages.
Yeah, sure.
William. You said, "Take this over the weekend, read it, and I hope by Monday I'll have news for you that I can put you in the study. That's what I prayed for over the weekend. You told me that next week that I could participate in the study, and I was blessed by that.
Great. I remember a couple of things just to clarify. It's been a long time since your diagnosis, which is wonderful, right? We love that you've had all this time, and no recurrences in that time, which is fabulous. At the time of your diagnosis, you were actually a stage 4 diagnosis. Then the survival numbers you were thinking about, although that may have been closer to true at the time of your diagnosis, they've gotten better.
This kind of thing is the reason I am biased towards these kind of things is because in my career, I want to see people with this diagnosis live longer and with fewer symptoms, and with more chance to have their productive lives that they want to live. Can you talk a little bit about barriers? That is one of the things we wanted to touch on is this is a weekly infusion. Most chemotherapy is given every three weeks. This is given weekly, so that is a little more frequent visits. You have to access a different MetaPort. It goes into the abdomen as opposed to the higher-up one that goes into the larger vein. That is a little different. Travel, time, things like that. Did those barriers seem challenging to you, and how did you overcome them? What did you think about all that?
I don't think it was a big barrier. I come from Cedarburg, which is about 35 minutes from where the main hospital is. We did okay with my husband driving all the time, and he came to every appointment with me. He was there at my side all the time, and he also came to checkups when you and I had to do checkups during the treatment time and also after when we had to come for checkups for labs all the time and CAT scans for checkups. He came for that, but I don't believe there was any really big barrier for that.
Okay.
No, I don't think there's any problems.
Okay. All right. One other thing that people who are on treatment have to deal with is that's a very large focus of your life while that's ongoing, right? I tell patients it's almost like you've been assigned a job that you didn't ask for, right?
You're coming back and forth, you're checking labs, you're seeing doctors, you're here, there, infusion, that takes time, et cetera. How long after all that was done, and so people get very focused on that, how long after that began to wrap up did you start to feel more like, "I'm back to where I was before. I'm more of a normal person. This is who I am"?
That's a very interesting question. I think because I had such good support from family and especially my husband, I started this in December after I had the port put in. That was a minor kind of surgery, having that done. We started in December. I think after I had chemo, I had surgery, and then I had chemo again. I think by May, which was at the end of the second chemo session, I felt that I was a little more physically able to do things for myself and not having to feel tired. I never really felt sick.
Yeah.
I didn't have problems because they give you medicine so that you don't vomit.
Yep.
I had my energy back by May.
That is really remarkable. That is great.
That was not a long time.
Okay.
Yeah, it was more of being tired.
Mm-hmm. I told you earlier that I have a bias towards clinical trials because I think that this is the way we get better outcomes for our patients, and I've seen it in my career, so seeing is believing for me. I guess the question I have is, for you, can you talk a little bit about what you think the participation in this study gave you, beyond what you got with standard of care chemotherapy?
It gave me a miracle. I think that's my best answer for that.
Good.
Every time I see you at the year marking, which May 23rd is a very important date for me because that is my milestone of a year and then two years, and now May 23rd, 2026, I have been nine years cancer-free. I hug you each time on that date that when I see you that is closest to that May 23rd. If I did not have that clinical trial drug, the GEN-1, I would not be here.
Because it is a drug that made me sitting here today. So thank you.
Oh, gosh.
Thank you, Dr. Faller, and everybody else that works on GEN-1. So that is my answer.
Okay. I'd say that's pretty compelling. Talk a little bit about what you do with your life. I remember talking to you and Mike many times about what you guys are up to and what you do, but share a little bit of that.
I know one of the things was, what is our interests and hobbies? My interests are my grandchildren. I have 11 grandchildren and when I started the study, I had 11 grandchildren, but now I have three great-grandchildren. I have nieces and nephews. I married Mike late in my life. We've been married 20 years now. You've seen that. They're my life. I have 13 nieces and nephews, and I have great nephews and nieces now, too, since when I studied the drug. So they are my life.
When I approach a patient and talk to them about treatment, and I talk to them about clinical trials, there is a lot of different motivations that I see. One is certainly, I hope that I get a good response, I get better outcome, and I think that is a very appropriate goal and hope, right? That is what I hope for them, too. There is also some patients have kind of an altruistic point of view of, this is a big deal. I am going through this, and I am trying to help the next person, the next woman in this case, who is going to go through this. Can you talk a little bit about motivations to participate in a clinical trial? I know you said some of them already, but what motivated you?
I have to say that I wanted everything I possibly could do to help me. I really did not want that as a selfish thing for me. I wanted it because I really wanted myself to get better for my husband.
Sure.
I was blessed to have grandchildren. I come from a big family. I love family. When I told my grandchildren about this, they came over that night, and they sat down with me in the living room, and they said, "Grandma, you can't die. We do special things, like we have a zoo trip every summer." I'm the one that does that. They said, "Will we be able to go to the zoo? You can't die." I said, "I'm not going to die." To say that could've been a lie. I didn't think it was because I was positive that this clinical drug and the cure I was going to get from you was going to happen. So I had to tell them, "I'm not going to die. That's my motivation.
One of the things I do in this job, taking care of our patients, is deal with bad news, right? It's never a pleasant part of my job, and sometimes my trainees will say things like, "How can you do that?" The only answer I can really think that makes any sense is, because we're trying to do our absolute best. As long as we can do that, we can at least say, "I'm terribly sorry that this happened to you," or "that this outcome occurred, but we did everything we could." The wins, they're really important for the patient, but they're really important for the doctors, too, because we get to remind ourselves that actually things do work out for people, and that we are getting better at this, and this is one of the ways we do that.
Thanks for sharing, and thanks for participating. I can recall when the data was presented that the overall survival looked like it was something greater than a year to ultimately 14 months. The reason I recall that is because it seemed so impressive to me. We don't get studies frequently that show something like a 1+ year increase in overall survival that often. That really stood out. I'm very, very hopeful that that turns into a meaningful, statistically significant outcome for our patients. When I've talked to my patients with ovarian cancer who've been fortunate to survive for longer periods of time, they do often talk about a year, having another year, having another year, and that rings pretty clearly to me why somebody would think about that, to hopefully be able to say this is potentially another year for you is very appealing.
Neoadjuvant chemotherapy is commonly used to fight ovarian cancer. It's one of the first decisions we make with our patients as we're starting to figure out a treatment plan for them. The addition of IMNN-001 offers a chance for a longer life. The phase II study did show an increase in overall survival that would be what I would consider highly significant, and we're hoping that the phase III study shows something similar or even better. What I counsel my patients is that women, when I started my career, were living more than five years with this diagnosis less than half the time. Now they're living more than five years with this diagnosis more than half the time. The reason for that is better therapies. This is potentially one of those better therapies that could have a major impact on life expectancy and longevity with a devastating disease.
Thank you, Dr. Bradley and Terry. It's awfully difficult to get up and talk after that. The story brightens our world and I think gives us the hope that we're looking for. Let me take this back to the investment case that you have heard. This is obviously about people. It's about improving lives, but there is a very meaningful investment opportunity here. If I can recap what you've heard. The frontline standard of care has essentially remained frozen for 3 to 4 decades. You've heard why systemic IL-12 could not be delivered and how IMNN-001 has overcome that. You've seen a safety profile that is easily managed and that we can then deliver the kinds of effects that we're observing in the clinic. You've heard the translational signals and the observed biomarker data that's consistent with our mechanism, a colder microenvironment turning hotter.
You've heard lower MRD rates, higher circulating tumor clearance, and early evidence that IMUNON may be able to be given even in a maintenance setting down the path. We're studying that now in the MRD study. We also know from that trial that as we get to the real world, we know starting out that it can be given safely with combination with bevacizumab. You've heard from descriptions from our surgeons that have been treating these women and what it's like for them and directly from Terry to receive this product. At the end of the day, a 14.7-month overall survival improvement received with this product in our largest and our most recent clinical trial. You've heard from a patient of what it means to be cancer-free, in her words, and the opportunity that she has to live life. Here's the thesis plainly stated.
IMUNON is developing a first-in-class immunotherapy based on IL-12, a potent cytokine. In the randomized phase II trial, we've seen clinical effects and biomarker data that has not been seen previously. The confirmatory trial, the phase III trial, is open. It's enrolling. We're exceeding our forecast and our assumptions from a site perspective. If phase III is able to replicate these findings, we will have what we believe is going to be a change to the standard of care. IMNN-001 has Fast Track designation and Orphan Drug designation in the U.S. We also have Orphan Drug status in Europe. We haven't spent a lot of time talking about it. Douglas mentioned this briefly, but our manufacturing story is also an incredible bright spot.
Our plasmid plus the nanoparticle that is delivered, that really is this novel proprietary delivery, we expect to have incredibly attractive margins at the commercial scale. We're producing the core active pharmaceutical ingredients in-house, and we're able to track and are preparing readily for the years to come, which will be, we hope, the commercial setting. The platform, as we've referenced, is not only ovarian cancer. TheraPlas has an opportunity to be encoded with other proteins. As we learn and continue to expand in science, and we learn from our partners in academia, we have an opportunity to certainly turn our sights to other cancers. With the recently announced partnership and the CRADA grant through National Cancer Institute, we expect to be able to accelerate that. We're very excited. What comes next is really going to be about execution.
We have a new leadership team that is here. Douglas attested to the reason he joined IMUNON. It is the reason it was very easy for me to accept the role of CEO and President. We have an incredible leadership team that is extremely well-prepared for the task at hand, which is going to be execution of this trial. We follow the trial design. This is a confirmatory trial, so it follows phase II with some enhancements that really just give us more confidence as we enter, and we think about the pricing and reimbursement discussions that we would have in the future. As Premal noted, we expected fast enrollment. We did not expect to exceed. At a site level, we set a target which is far above what we've observed in larger trials from the past in the frontline space.
Our target was 0.3 patients per site per month. We are actually observing 0.5 patients per site per month, and it is an average across the trial. We are doing incredibly well, and we think it really is a testament to the effects that we have been able to uncover with a very thoughtfully laid out clinical development plan. Premal referenced treating patients in the recurrent setting. Actually, the two trials that we have going are our seventh and eighth clinical trials in ovarian cancer. Four of them were in later lines. We decided with advisors and through multiple sets of advisory guidance that we would be well-served to go after the frontline. It was a bold move, and I think we are obviously very pleased that we did that.
Our data monitoring committee will continue to meet across both of these trials, and we are extremely pleased that we continue to see the safety profile that we expect because of the design, which was very intentional to avoid the systemic challenges. With that, what we have before us is to continue to activate sites at a pace that allows us to keep with the enrollment that I have committed to. We have publicly advised that we would have the 500-patient trial enrolled in Q1 of 2029. We are working hard. We have phenomenal sites. The quality of our data, really the ability to deliver clear signals ultimately comes from the product, but it comes from the clinicians that are ensuring that all of the detailed records that are required to get a registration will follow.
We are working to make sure our supply is strong and that we can raise capital to really ensure that the trial continues at a pace, perhaps even accelerate, which is really important. Let me just be direct and clear from a capital standpoint, since predominantly we are speaking to investors and the investment community. We are a clinical-stage company with no revenue stream. Therefore, this really becomes a funding business. At our heart, we are scientists. We want to advance this transformational therapy, but we do need to keep the company funded. As we have disclosed in the past, we had a financing in June that brought in additional capital. We had a financing last December. But to complete the trial, we do need to raise additional capital, and we are working on that right now.
The objective, of course, is to keep pace and have far enough frontline with our cash to really be able to accelerate. We have commented before in earnings calls that leadership has taken a meaningful portion of our compensation. Actually, not just leadership. Many of our employees have also volunteered to do this in equity instead of cash compensation. This is not a slogan. This is really how we are aligning our burn rate with the timeline of the trial, and we are ensuring that we are really leveraging the capital that we have, that we steward on behalf of our shareholders as effectively as we possibly can. Here is what I am asking. I know we will have clinicians viewing this in the future.
Help us enroll the right patients, help us do so quickly to get this trial approved, hopefully the drug approved and the trial completed, and to do so cleanly, because we know that every month that we wait is another month that the field is waiting for a new treatment that they can bring to the forefront. If you're an investor or potential partner, the data that you've heard this morning, my ask is that you'll diligence it. We have manuscripts here, our primary publication in gynecologic oncology from phase II. We have other publications that are here.
Dig in, look at the safety data, look at the data that's been released across other trials, the translational and biomarker data, and then decide if you believe from all that you've heard, that if a first-in-class IL-12 with a randomized clinical study in the phase III setting, if we confirm this overall survival benefit is priced like the value that we believe will come and with the risk that we think we've quantified. We did not come here to claim that we are finished. In fact, we came here because the biology is working. We've shown you evidence of this, and that the safety barrier that I think has been looming across many people as they've heard about IL-12 over time, that it has been overcome.
I guess in closing, really confirming that this is the job that we're signing up for and that we are very ready for. I want to thank everybody for your time. We've gotten a couple of questions online that I'll pull up, and we will provide microphones so the webcast people can hear questions. We'll start with questions in the room.
Hi, Emily Bodnar from H.C. Wainwright. Thanks for hosting this event, and really impactful to hear the different results you've had. Two questions from me maybe. You mentioned the prophylactic regimen in OVATION 3 to lower rates of abdominal pain. Can you mention what specifically you're using in that regimen and also the extent of reduction in abdominal pain you're expecting from that based on what you've seen in the patients you've used it in so far? Then secondly, if you could talk a bit more about the NCI partnership and what the terms of that look like and the plans for colorectal and pancreatic development. Thank you.
Sure. I will answer the clinical question. What we realized, and it is very well known, that there is somewhat of a distension effect because you are putting this medication into the abdomen directly. We give them a narcotic, such as oxycodone, which they take, or if it is IV dilaudid, and then also give them an anxiolytic, because the fact is a lot of it is anticipatory once you do it, if they have had pain. We are trying to eliminate that. We saw the reduction go down by over 50%. Probably about 20%-30% of our patients still have some discomfort, but they are able to go home and take oxycodone at home for about 24 or 48 hours and then it self-resolves.
As I also mentioned, education has been a key for us to let the patients know that this is an anticipated. Just like when people hear chemotherapy, they anticipate they may have nausea and vomiting, and we want to be very proactive.
Could I just add to that? We have been tracking dose intensity, meaning the intended dose versus the dose the patient receives for IMUNON. In both the MRD study and in OVATION 3 so far, we are about 90% of the intended dose. Abdominal discomfort is not limiting our ability to give the drug.
Can you talk about the NCI?
Oh, certainly. The opportunity with NCI is one that is extremely exciting to us. NCI selects a few novel and very promising drug candidates every year for a partnership with them. In the course of the partnership, we decide with NCI what indications we are interested in pursuing, usually ones that the company itself is not pursuing directly, so additional indications. We have worked with them to develop the indications that I mentioned to you, and they may have already, but very shortly if not, going to be issuing requests for applications for clinical trials using our drug in these indications. We will work with them to decide which trials we like. They provide the large majority of financial support for these studies, which is also very important for us.
Thank you. They also operationalize the trials, so it allows us to remain focused on our singular goal, which is our phase III program. It should advance other indications and allow us to then pick up and be in hopefully a later clinical line. Yes. There is a microphone behind you.
This is Rosie Abbott from Point Capital Markets. Thank you for having us. My question is for Dr. Amir On the MRD data. Once you look at the cell at microscopic level and then you also perform the ctDNA assays, what additional biomarkers do you need to be 100% sure this person will not have a disease come back or for how long? Based on that, what is the future treatment plan for that patient in terms of immunotherapy, the regular duty, the doses, frequency or no treatment at all?
Yeah. Thank you for that question. Oh, sorry. These surrogate biomarkers of efficacy, both surgical MRD and ctDNA MRD and clearance, have to be tied to standard outcomes such as progression-free and overall survival. Our study is designed to accomplish that and show proof of principle that maybe someday in the future that early time point can predict what would be the eventual outcome. From a practical standpoint, patients that have e valuation for MRD after finishing that main phase of chemotherapy are still going to undergo maintenance therapy. We don't stop at that point, regardless of the results of whether they're MRD positive or negative, because we feel that at this point, there isn't sufficient data to act on that information. It's prognostic rather than causing an intervention.
Every patient, whether they're MRD positive or negative in our trial, are going to go on to the maintenance phase, and they get the appropriate maintenance therapy. If they're HRD positive, they get a PARP inhibitor plus Bev. If they're HRD negative, they either get Bev in the control arm, or they get Bev plus IMNN-001 in the experimental arm.
Hi, Stacy. Graham Powis from Brookline.
Hi, Graham.
Can you discuss in more detail what you think has caused this terrific and unexpected faster pace of enrollment, the 0.5 versus 0.3? Maybe dig just a little deeper on what's causing that.
I think that it really is due to the data. Premal should follow me, but I think that we anticipated. We were advised by the CROs that we were interviewing. We did a proper RFP, went out to contract research organizations that would be able to come alongside and really help us with a broad trial. They advised us to actually go after 0.2 patients per site per month. We believed that as the clinical team that were on site, that they would have data they could share from OVATION 2 that really was differentiated, that we might see a higher rate of women that were saying yes to the clinical trial. It's a personal decision. Obviously, there's a lot involved as you're making these decisions, but we believe that evidence would be something that we didn't have in OVATION 2.
As we ultimately looked at our own experience, how we would set those targets. But, Premal.
Just to add to that, I think part of it is also patients like the concept of immunotherapy. They see it all the time. They don't understand it like you've gotten told today about innate and adaptive. They see Keytruda, Opdivo, everything, immunotherapy changing the world. So patients want it because they understand the concept of what the immune system does. I think putting it in combination with chemo is very attractive for patients now, especially on top of it, we have the data that shows a large trial that shows a huge benefit. I think we can with much more confidence, always having a patient go on a phase III trial is a lot easier of a conversation than when it's a phase I like Terry did, because that's really the unknown, right? We don't know if the dose is right.
We don't know if it's going to work. But now we're at a phase III, so I think it's a much easier way to get patients to enroll. Also, patients are savvy. They are looking for trials, and they want to live. I think they're also seeking us out, too.
Can I just add one thing? The one other aspect that we've focused on extensively is to make sure that enrollment onto our trial does not delay in any way the patient's ability to get therapy, because that's paramount in the physician's mind and in the patient's mind. We've actually made a few changes in the course of OVATION 3 already that have made it very simple for the patient to get enrolled, to start treatment, and nothing about the enrollment process, the screening process, delays the ability of the patient to start the treatment that she needs.
Hi, [Min Wong from Acorn Publishers]. Thanks for having me, and excellent presentation. I guess a few on the MRD study. You're now having that added to the neoadjuvant setting. Is that typical in your practice? And that was on OVATION 2? Maybe explain that a little bit.
Yeah. As you heard, addition of bevacizumab to standard chemotherapy has some PFS improvement of three months. It's a little bit underwhelming. At the same time, we're so limited by what else we can offer patients. There's some retrospective studies that suggest, especially in patients with stage 4 disease or larger volume disease, addition of bevacizumab might have some incremental benefits. For our study, we decided everybody would get bevacizumab. Also, I think there is biological rationale for why inhibiting the VEGF pathway, which bevacizumab accomplishes, can be complementary and synergistic with activating the immune system, because VEGF is also a very potent immunosuppressive molecule. There's sort of rationale for that. The second part of your question was what's the situation with OVATION?
Sorry. I guess another sort of thing regarding the data on positivity at second laparoscopy scan versus the no evidence of disease.
Yeah.
There's a discrepancy there maybe.
Yeah.
Can you explain how you have lower positivity at second laparoscopy, but 100% no evidence of disease?
Yeah. No evidence of disease is based on current clinically used assessment, which is usually a radiologic scan and a CA 125 tumor marker. Obviously, if you go a level beyond what's currently available, if you look with surgery, we've shown that surgery can pick up minimal residual disease a lot more sensitively than current clinical methods. It is not surprising that if you look with surgery, the numbers are going to be a little bit different. We wanted to offer both because while MRD is an exploratory endpoint in our study and is pushing the boundaries, most patients with ovarian cancer, their disease assessment is by current clinical standards, which are imaging and CA 125.
Just another on your translational data. It was mostly macrophages that express IL-12.
Yes.
I guess given that it was given through LNPs, there should be no discrepancy in pickup of various cells. How do you explain?
Well, right. We don't know that, right? If you think about it's not surprising. Macrophages, they clean up. They're the immune cells that eat other cells and pick up debris. I think what we're seeing is that the macrophages are picking up the nanoparticles, they're expressing the IL-12, and then influencing other immune cells in the microenvironment. So that part to me makes sense with what we know about macrophage biology and prior translational data.
Could I continue with a few more? Just on your PFS curve, I know it crossed at the end. Your treatment arm came down relative to control arm. That's not typical for, I guess, IO curves in general. I know it's small numbers, but maybe can you just comment on that?
Yeah. I would just say the numbers are very little, and the end of Kaplan-Meier curves become very unstable when you're talking about small number because of all the patients that are censored. I presented that data because we wanted to be very transparent with whatever data's available, but I would be very cautious about over-interpreting Kaplan-Meier curves with only nine patients in each arm.
Okay. Can I ask a few more just on OVATION 2? For Dr. Thaker. I guess, likewise, the OS curve doesn't really resemble a typical IO curve because I would expect a larger separation to tail towards the end of the OS curves. But yours came a little bit closer together, converged a little bit. If you can just comment on that.
Yeah. I think, to Amir's point, even with the trial being the way it was, the OS is going to have that because there's lots of subsequent therapies. A lot of patients do get censored at the end as well, so it's partly from that. What I think is really distinct to what you see from our curves is the numbers also at the end get very small when you look at those OS as well. That's part of, I think, what happened as well.
Have you guys followed patients just to analyze the post-surgical treatment options between the two arms just to make sure there wasn't any imbalances?
Yeah, so there were no imbalances in terms of that all the patients got to surgery, all of them. That's in the paper where you can look and see that they all were very balanced in terms of their resections, and there actually were better R0 resections, even though the case study I presented of my own did not have an R0. It also shows that even though we try really hard, it can't. You can see the complete responses in terms of also the pathologic responses were better in the experimental arm. In the experimental arm, we had more stage 4 patients and less of the patients who had an HRD signature. So, that's also part of it. It wasn't completely balanced, but remember it wasn't stratified for that either as well.
Got it. Then just lastly, did you look at the breakup between platinum-sensitive patients between the two arms?
Platinum sensitive doesn't really apply to this. When someone recurs, ultimately every platinum-sensitive patient becomes a platinum-resistant because this is really looking at upfront. All the patients when they pass ultimately become platinum resistant, unless something.
I guess after surgery or after having.
In terms of how many patients? We didn't really look at progression-free survival too, in a sense. We did not look at that. In this trial, which is powered OVATION 3, we can look at a lot more of those because it was being powered to actually have a much better statistical analysis than we could. We didn't look at that specifically because if we then also break it down by PARPs, who's on PARPs, because we know patients who are on PARP maintenance do worse if they do recur, even if they're technically platinum sensitive. There's less now nuances. We're using platinum sensitive and resistant. That's another definition that we probably should get away from. We still are burdened with that just like we are with 40 years of Taxol/ carbo.
Okay. Thank you.
Yeah. One point I would just add to that, if you look at with IMNN-001, one of the advantages, Premal, you referenced this, is really how short the treatment period is. Ultimately, when you're looking at those survival curves, the ones she presented, there was a light blue shading. The treatment period is actually happening in that first six to seven months. The curves that we're showing are demonstrating that the immune activation is sustainable, right? Ultimately when we think about where we may go from here, there may be an opportunity to study maintenance. Then your sites actually in terms of the length of time that you would expect and would want to be looking for an effect may advance. We're talking about a relatively short treatment, especially when you think about the time frames of IOs, immune checkpoint inhibitors.
Their treatment periods are much longer. Just a point of clarification. I know we're getting long on time. I'll just answer two quick questions from online. There was a question, have we received any interest from non-U.S. pharma that might result in
Some kind of non-dilutive partnerships. I have commented at our earnings that we have continued to receive interest and have diligence ongoing, but we cannot comment more than that. Then I would like to close with a question we got online for Premal and Amir. There was a question specifically to the clinicians, which is very appropriate given the question: What makes you believe it can be a cure? There is a potential.
Yeah. I think there has been a lot of negative phase III randomized studies in ovarian cancer. I think what makes OVATION 3 set apart for me is OVATION 2. It is very rare that we have a program that deliberately tests a novel therapy before getting to a frontline setting, probably because a lot of frontline phase III trials are done with large pharma companies where maybe being frugal or the funding is not as much of a problem. I think the fact that OVATION 2 data exist and are so promising makes me really think that we are going to see cures in OVATION 3.
The other thing was something that Douglas touched upon, but I wanted to further highlight, that in OVATION 2, the way blood counts were being checked each week was creating an artificial bias against the experimental arm because blood counts were being checked in the middle of chemo cycle. We would expect them to be low from the chemo. Then treatment with IMUNON was being held based on that. So one of the discussions that we had with the IMUNON management team when we were considering the MRD trial and later OVATION 3 was, "Hey, we are inadvertently underdosing the patients on the experimental arm." Despite that, OVATION 2 showed the results that you guys saw. So I am 100% sure that OVATION 3 is going to have much greater dose intensity.
I think if despite inadvertently underdosing, we saw benefits, I think that is another thing that gives me confidence that in OVATION 3, we are going to see long-term benefits that eventually we are going to interpret as cures.
I completely agree with Amir on that. I think also one thing to point out, Terry, who was on OVATION 1, only would have received IMUNON with her upfront chemotherapy and neoadjuvant, and subsequently would have had surgery and not gotten IMUNON. We actually only gave it upfront, and they got nothing in the adjuvant. It is even more impressive. It just lets you know a little bit more about the durability. To Amir's point about dose intensity, we should see improvement in OVATION 3, but we see these responses in the immune system happen quite quickly with the administration. I think that also has made me very confident all these years because you could also say I am either a glutton for punishment or I am someone who is a real believer.
I am a real believer because we have also done the translational components, because a lot of trials done with big pharma does not do the why not or why does it work. Here we have persistently done it from OVATION 1, 2. We have gotten samples. We have looked. We have tried to ensure safety, make sure it is not systemic, looking to make sure we make that changes in the macrophages, the T- cells, changing that we are not just claiming we are making from cold to hot. We really are showing our data. That is why we present it at SITC.
This is data which is telling us our drug is hitting what we want, and I think that is going to make a big difference because we are all scientists here and believe really that the science should guide how we should be treating patients, and we are changing the science.
Thank you. I want to thank everybody for coming, for staying through this discussion, the Q&A. Great questions. We will make sure that the questions we got online, you also have an opportunity if you want to drop additional questions on the last slide that had our email, and we will make sure we get back to you with answers. Really, thank you for the time. We look forward to continuing the conversation with you. Have a great day.