Agenus Inc. ($AGEN)

Good afternoon, everyone, and thank you for joining us. I'm Stefanie Nacar, Chief Communications Officer at Agenus and welcome to our March stakeholder webcast. Today's discussion comes at an important moment for oncology and for patients whose cancers have historically remained outside the reach of an immunotherapy. And on this last day of Colorectal Cancer Awareness Month, we continue to acknowledge that CRC is one of the clearest examples of this. Recent published data from the American Cancer Society showed that colorectal cancer is now the leading cause of cancer-related death in people under 50 in the United States with mortality in younger adults continuing to worsen. And for the vast majority of metastatic colorectal cancer patients, those with microsatellite stable or MSS disease, conventional immunotherapy has historically offered limited benefit. And that gap, Agenus is focused on closing. Our goal is to extend the reach of immunotherapy to patients who have historically been left behind, particularly these MSS tumors, which account for approximately 95% of metastatic colorectal cancer and a substantial portion of solid tumors more broadly. These tumors are often described as cold. More simply, they our tumors the immune system has not effectively recognized or engaged. Our strategy is to change that. Today's webcast will show how that strategy is advancing across 3 fronts: clinical development, responsible patient access, and the operational readiness required to bring these therapies forward. You'll hear how those fronts are beginning to converge, expanding our global access through a program such as France's AAC program advancing the Phase III BATTMAN trial and continuing to build a clinical dataset across multiple tumor types. Because in oncology, real progress is not defined by a single headline. It is defined by more reproducible clinical activity, durable benefit and the ability to extend that benefit to more patients over time, while considering their quality of living. Before we begin, a brief reminder that today's discussion includes forward-looking statements, please refer to our SEC filings for additional details on our website. So as I mentioned, today's program will walk through the progress we're seeing from access and real-world experience to clinical execution to commercial and operational readiness. Following these discussions, Agenus leadership, including Dr. Steven O'Day, our Chief Medical Officer; and Dr. Robin Taylor, our Chief Commercial Officer, who will join Garo for a live Q&A. Questions may be submitted at any time during the webcast by using the QR code on the screen or by visiting slido.com and entering the event code showed below. With that, I'm pleased to introduce our Founder, Chairman and CEO, Dr. Garo Armen. Garo?

Thank you very much, Stefanie, and thank you, everyone, for joining again today. We're going to repeat some of these points that Stefanie made because they're very important. Let me begin with a simple point. The need here is not hypothetical. And butt valve's ability to help patients is not an abstract idea anymore. Practicing oncologists are seeing these patients are asking for it, and requests are now coming from all over the world, literally all over the world. As we all know from recent published data, colorectal cancer, as Stefanie said, is now the leading cause of cancer-related deaths in adults under 50. Now what's worse is that those under the age of 50 are often diagnosed with late-stage disease, advanced disease. It used to be that colorectal cancer got caught early because of colonoscopy and other diagnostic techniques, but now that has changed. People talk about the magic of recent advances made for certain types of colorectal cancer. But what's often getting left out is the fact that this magic benefit is only in a small fragment of the patients. Of course, it's very important what we've accomplished with immunotherapy even in the 3% to 5% patients that are called MSI-high disease. But the overwhelming majority of metastatic colorectal cancer, which is known as MSS disease, microsatellite stable disease, where conventional immunotherapy has not shown any benefit. So far, most CRC patients treatment is still in that 95% plus group is dominated by cytotoxic therapy. With all of its handicaps toxicity, and without a possibility of a cure. Now at Agenus, we are changing that reality. For decades, our conviction has been that the immune system when properly engaged, can do what conventional approaches often cannot. That is why our focus is not on one tumor at a time, but rather our focus is on the immune system itself, how to activate it, how to sustain that activation and how to disarm the cancer's defenses. This is also very important. That's where the combination of botensilimab, BOT; and balstilimab, BAL, comes into question. So for many years, we've been considering that cancers other than melanoma and in some cases, renal cell carcinoma have been beyond the reach of immunotherapy. Now Dr. O'Day is an expert in this because when we started the company 30 years ago, we were told repeatedly that immunotherapy only works in melanoma, and that's a very small market. And now we know that with the advent of PD-1s and other immunotherapy techniques, that's no longer the case. So immunotherapy's reach has widened, but not wide enough. So when you begin to see durable activity in tumors, long described as immunologically cold, as Stefanie said, you're not looking at a small incremental step. You're looking at the possibility of expanding immunotherapy to patients who have historically been excluded from this benefit, with the possibility of a cure for some. And we also know that the earlier we treat the cancer, the greater the possible outcomes. For example, when you look at our neoadjuvant data, what you see is something remarkable. Within 6 to 8 weeks, with just BOT/BAL in so-called immunologically cold tumors and even in the hot ones, tumors literally melt away. And that is something that we've never seen with immunotherapy, particularly in cold tumors. And importantly, we are seeing this across multiple cancers. Our BOT/BAL program now includes more than 1,200 patients treated across 9 tumor types. And across those studies, the continuous emergence of data is not merely response rates but the durability of these responses. And Dr. O'Day points this out repeatedly because responses can be transient. But when responses become durable, then you basically can live with your disease for the long time or the long term and you could be cured. So these types of outcomes have been historically very hard to achieve, particularly in cold tumors. And of course, this matters scientifically. It matters clinically. And above all, it matters for the patients the most. It also reinforces a central idea so-called cold tumors, which represent, as we talked about, the great majority of cancers are not beyond the reach of immune control. They have simply not been engaged by the right immune mechanism, which is what we specialize in, and we are changing that reality. So with all this momentum, 2026 is an important year for us, but most importantly, for the patients. An important year for patients because our access is expanding, an important year for us because we are streamlining that access, prioritizing regulatory filings in the U.S. and Europe and moving with urgency on commercial product readiness, which is critically important, by the way, for approval for both BOT and BAL. And when you see the remarkable effect of BOT/BAL in patients, it would be heartless not to make access a high priority for patients. The broader role of immunotherapy is expanding. But the more important question is whether the patient population benefiting from immunotherapy expands with it. And this is what our mission is. That is our highest priority now. That is the opportunity in front of us, and that is exactly what Agenus is built to pursue. Now to build on that, you're going to hear from our colleagues, and I'd like to turn this back to Stefanie, who will be speaking with our Chief Medical Officer, Dr. O'Day, and also other members of our senior team, and how those data are shaping our development strategy, starting immediately. Stefanie?

Great. Thank you so much for that, Garo. And Steven -- Dr. O'Day, it's a pleasure to have you here with us and me getting the opportunity to have this one-on-one dialogue. And we've really built this session today because we've received a tremendous number of questions, both through this forum in past webcast, but then just in other forums. So hopefully, this will shed some light on some questions that we've been receiving. But let's start off a little bit to talk about that clinical progress with BOT/BAL. So to start off, Garo was just talking about, in general terms, the really broad data set that we have for BOT/BAL. As a clinician and from a clinical perspective, what stands out to you most about the data set thus far?

So thanks, Stefanie, and it's great to have the opportunity to sort of weigh in here as the Chief Medical Officer of Agenus. I think Garo really set this up beautifully. And as background, I want the audience to know, I've spent 30 years in the clinic prior to joining Agenus at the forefront of the checkpoint revolution in melanoma. And we took in refractory disease, patients that were destined to die in 6 to 12 months, almost uniformly. And with targeting not the tumor, but the immune system by unleashing first -- the first checkpoint CTLA-4 and then the second checkpoint, PD-1 and then in combination, we took advanced melanoma refractory patients with brain, lung, liver mets with 6 months to live. And with ipilimumab CTLA-4 alone, we cured 1 in 4 patients and with the combination, half of the patients. I got to watch this extraordinary paradigm-shifting revolution of immunotherapy. What's more, this was relatively short exposures of immunotherapy in a very advanced disease setting and the patients who benefited were treatment-free and long-term survivors and eventually, we know cure. So that's the setting I saw. Unfortunately, as we move these drugs out into, as Garo described, cold or poorly immunogenic tumors, we did not see the same immune recognition. And this was the fundamental limitation of CTLA-4 and PD-1 first generation. I became involved with the Scientific Advisory Board at Agenus, and I saw the next-generation CTLA-4 botensilimab and its mutational Fc engineering, the promise to unleash these T cells in a more potent way against cold or poorly immunogenic tumors. I was the primary investigator on the Phase I first-in-human trials, and I started to see very similar patterns to melanoma, but in tumor types that had no business responding, MS stable colorectal, refractory ovarian cancer, sarcomas, and this really prompted me to want to join Agenus and really drive this forward. So I've been in the clinic with melanoma with first generation. I've been in the clinic with botensilimab and balstilimab in this next gen, and I've watched the paradigm moving where it's never been before. So to get back to your original question, what is the BOT/BAL data showing us? We've treated over 1,200 patients across a number of tumor settings, as Garo has mentioned. What are we seeing? And why does it impress me? Well, what really stands out is the consistency and reproducibility of our clinical results. In oncology, particularly in immunotherapy, isolated exceptional responses can occur in a data set. However, when meaningful clinical activity repeats across multiple data sets across multiple tumor types and matures with time into more durable benefit, confidence in the benefit of the therapeutic intervention is significantly heightened. And that's why I am in reviewing this data to date. With BOT/BAL, we are seeing consistent, meaningful clinical activity in tumors that have historically been resistant to checkpoint blockade. Importantly, we see this activity translating into long-term survival, including treatment-free survival, a hallmark of effective immunotherapy and a hallmark of the melanoma IO revolution. This is highly unusual for these heavily pretreated populations of poorly immunogenic tumors. That combination, the breadth of our data, the consistency of our data, the durability with flattening of OS curves over time, it's reproducibly is what makes these data sets compelling.

Thank you so much for that, Steven. And thank you, too, for just sharing a little bit about your history because I think it's so relevant and to share the context of what never thought was possible in melanoma and now setting the stage for hope for additional tumors as we move forward. So you talked a lot about durability. Can you maybe just share and expand upon that a little bit more about what you're seeing in terms of this long-term outcomes in that regard?

So durability with checkpoint inhibitors, particularly CTLA-4 as a hallmark feature. And why is that? Less so with PD-1 except in very highly immunogenic tumors. But CTLA-4, the hallmark is durability of response and long-term survival plateaus. And this is because CTLA-4s, when they're working, either in hot tumors historically or now in colder tumors based on botensilimab's engineering are causing an expansion of T cell repertoire through the Fc engineering of botensilimab. This tightens the synapse between the antigen-presenting cell and the T cell, this critical synapse that actually drives T cell recognition of tumors. So tumors that are more hidden to the immune system, which is the vast majority of these cold solid tumors, get away with not being recognized. But by making the Fc-enhanced portion synapse sticky with botensilimab's engineering, it's forcing the T cell to spend time to recognize tumors that are poorly immunogenic. And once they're recognized and they expand their T cell repertoire, you're able to get durable responses, long-term disease stability and long-term survival in some of these patients without additional treatment. And that's what we've really seen in this. So it's a one-two punch. But the foundation is not the PD-1. The foundation to cold tumor recognition is a CTLA-4 that expands the T cell repertoire with memory and potency. And then the PD-1s are like pouring gasoline on the fire and drive these T cells and prevent them from exhausting. You can't eradicate cold tumors with PD-1s. They simply are not the fuel. CTLA-4 and botensilimab is providing the fuel to cold tumors and PD-1 is driving it further. It is a one-two punch and the combination is essential.

Thank you, Steven. So you elegantly explained that much better than I did in the opening about what makes a cold tumor cold. So essentially, as I've heard you describe before, it's this one-two punch, it's really that botensilimab is priming and amplifying right, the immune system and creating that memory and teaching it while as you explained, balstilimab really helps sustain the response, and that's why we actually see the durability that many other combinations are not seeing. Is that a correct way to paraphrase that?

That's exactly right. And I think really the next generation, and you see CTLA-4s now being resurrected as a target because they're validated targets in first generation. And as we expand their use and modify them to be more potent in expanding T cell repertoires, the field has a validated target that will address the unmet need. And we are the leaders of that at Agenus with the extensive now clinical data that we've really developed with BOT and BAL across disease settings, tumor types, essentially a tumor-agnostic mechanism of targeting the immune system, not the cancer.

Okay. Wonderful. So in talking then about mechanistically, and you just shared a little bit about multiple tumors. So we've seen data now across various settings, including in colorectal cancer. So in the neoadjuvant setting, even earlier in the metastatic and then also in the refractory late-line setting as well as in multiple other tumor types beyond colorectal cancer as both you and Garo had mentioned. How important is this cross-tumor consistency that we're seeing when you think about BOT/BAL as a program?

Well, I think it's critical because it's directed to the immune system not the cancer. So the fact that we have sort of a tumor-agnostic mechanism. Now certain tumor types clearly may benefit better than others even in an immune-directed approach. But the fact that we're seeing remarkable consistency in our pan solid tumor data of over 400 patients that we presented at ESMO at an oral plenary session this year, the consistency was remarkable. And this included MS stable colorectal cancer, ovarian cancer, hepatocellular cancer, non-small cell lung cancer and sarcomas, among others. But the consistency in this refractory setting of seeing deep durable responses in approximately 20% of patients with prolonged stable disease and most importantly, survival plateaus emerging after 2 years and approximately 40% of patients alive at 2 years. This is really groundbreaking because it's pan tumor. In this large database, we also saw responses in liver mets and non-liver mets in patients who had failed IO as a first line of therapy and who were naive to prior IO therapies. Again, consistency across tumor types and disease settings.

Fantastic. So when you think about the data set, we have over 1,200 patients treated either alone or in combination with BOT/BAL. But from a regulatory perspective and a maturity perspective, we have the most data, right, in colorectal cancer. So can you share with us in that context how the Phase III BATTMAN study and that trial is essentially the next step to advancing to getting this potentially approved and to getting it to patients. So how does the BATTMAN study build on what you've observed so far? And how does that play in?

So I think to set up the BATTMAN study, the work that we've done in the last 5 years, both in the Phase I setting with a large expanded cohort of MS stable non-liver met population as well as the Phase II setting global trial, we've shown that we have demonstrated contribution of components, single-agent activity, and dose selection, which has been aligned now with regulatory bodies. This is obviously a huge amount of important regulatory work that sets up a registrational trial. And we've now really opened the BATTMAN trial, and this is obviously the next logical step. It is critical that we design and test this in a randomized Phase III setting with survival as the signal, and that's what the BATTMAN trial do. It focuses on refractory MS stable colorectal population, both the liver met and non-liver met populations, and it's powered to address both. We think that there's clearly a benefit in the non-liver met population. We also feel strongly that there is a benefit in the liver met population based on our pan tumor data as well as our limited data to date. So we're going to look at the broad refractory MS colon patient population that has failed all available therapy. Obviously, that's the subgroup in the Phase I and Phase II trial that are producing 20% response rates and durable survival plateaus and median survivals of approximately 20 to 21 months. So that is the setting that's been derisked for the BATTMAN trial and it's being compared in a global Phase III trial to the best supportive care.

Great. Thank you, Steven. Not to get too far ahead, but we did have a question that was submitted in advance asking about why are we confident about including the patients with liver metastases as well as the non-liver metastases patients. You just touched upon that briefly, but maybe can you go in a little bit deeper about why we did decide to include them in the BATTMAN study and how the study is structured to ensure either overall or a subset of patients from a successful trial perspective.

Yes. So when we did our initial Phase I trial, we obviously started to see a stronger signal in terms of objective responses in the nonactive liver mets, meaning population that either had treated liver mets or never liver mets. We did treat a small group of active liver mets. These were advanced patients in a Phase I trial with heavy burden of disease. We did see disease stabilization, some tumor shrinkage, but they didn't meet the RECIST criteria response, although the median survival of that group outperformed historical controls. So -- and then across more broadly, our 400-patient solid tumor program, we're clearly seeing RECIST responses and deep durable responses in active liver patients. So yes, liver met patients have more challenges with IO, but we think there is effect there. And in the CCTG large previous CTLA-4 -- first-generation CTLA-4 PD-1 trial, despite having no objective responses, they essentially had a trend in survival even in that small randomized Phase II trial. For those reasons, we think that all patients with metastatic colorectal cancer that have failed therapy should be -- have the opportunity to see the benefit of BOT/BAL in a survival analysis.

Thank you for that extra clarification, Steven, very helpful. So now if we look beyond colorectal cancer, how are you thinking about expanding into other tumor types or earlier treatment settings given all the data that we've gathered thus far?

Yes. Well, I want to reassure people, we are absolutely focused on the data we've collected in colorectal cancer in the refractory disease setting and driving the BATTMAN global Phase III trial to completion and hopefully successful registration. But as you know, from the data that we've presented over recent years, we have broad signals in other solid tumors in the refractory setting. But as Garo mentioned earlier, the future of the next generation of IO is both a next-generation of IO is both -- a next-generation of CTLA-4 that does what first generation didn't, which is to drive T cell priming and memory and deep responses in cold tumors combined with PD-1. And we're really -- and the earlier the disease setting, the better. And this is the melanoma paradigm, again, that I want to refer to. In melanoma, we started in the very late-stage, end-stage melanoma setting. We moved to first-line metastatic setting with the checkpoint drugs. And the real progress in recent years has been to watch the neoadjuvant setting explode in melanoma with curative therapy in almost 2/3 of patients with large primary nodal disease. And that's because having an intact primary tumor is the perfect reservoir to educate and expand the T cell repertoire. Now you have to have an active CTLA-4 in colder tumors. We have that in botensilimab. You have to have an active PD-1 that drives these expanded tumors. We have that in balstilimab. But we also have very important data in both a U.S. study and Italian multicenter trial, the NEST and UNICORN trial, showing that just a very limited 6 to 8 weeks of 1 dose of BOT and 2 to 3 doses of BAL followed by surgery results in complete or near-complete responses in approximately 40% of patients in 4 to 8 weeks. So this data is compelling. We hope that it will be published in the near future. And this will drive us to look for opportunities for a derisked Phase III randomized trial in the colon cancer setting. Why am I enthusiastic about that being derisked? It's because these pathologic responses, which are approximately 40% in the data that we have to date in a cold tumor have translated historically in hot tumors to very consistent and robust EFS data. And in our data sets, both the Italian and U.S. studies, we show deep pathologic responses. We show clearing of ctDNA. And most importantly, we have not seen recurrences to date in the data reported to date in terms of follow-up, in terms of events, free relapses. So all of this is aligning to a very powerful ability to impact and potentially deescalate therapy as we go. And going forward, we obviously have other tumor types we're going to continue to update across our solid tumor program as well as melanoma, which we'll be updating at conferences this year. So a lot of additional data in addition to the neoadjuvant data.

So that's exciting. So a lot of exciting data that set the foundation in 2025, and it sounds like without giving too many specifics, a lot of exciting potential data thus to come in 2026. So with that, thank you so much, Steven. This has been a really engaging conversation and a lot of insight and background about why we're so feel positive about the potential impact that and could make for patients moving forward. So with what we're seeing clinically, it's now beginning to translate into real-world interest from physicians seeking access to patients pursuing the treatment through international pathways. So to build on everything that Steven just walked us through, we are originally going to have Kamal, our Head of Medical Affairs, walk us through more what this looks like in practice with some more specificity around the named patient programs and the French AAC. He unfortunately is out on medical. He's ill today. So Garo is going to be jumping in to walk through some of the details about these programs. So to bring Garo back in, maybe Garo, you could start off in explaining how the paid named patient program actually works.

Just first off, patient access historically has been in the context of either clinical trials or we had a very robust compassionate use program. And clinical trials obviously are now limited to Phase III trials that are meant for registration with the exception of several ISTs that are mostly sponsored by institutions, but those are small trials. And the compassionate use program, we had to terminate those sadly. Why? Because there was an explosion of requests for compassionate use. And as the explosion of requests occurred, it became untenable for us to deal with the cost of doing that. And the cost was both administrative costs, mostly external costs that we hired companies to do that with as well as the product costs. So volumes drove us to basically eliminate that program. And with the grace of the French government, we had the AAC program that was administered in France. And that is a program where [indiscernible] who meet the criteria for colon cancer, for sarcoma and for ovarian cancer have access to BOT/BAL with the full reimbursement by the French government. But in addition to that, we also instituted a paid named-patient program. And the paid named-patient program can be administered in countries that allow it. And those include, for example, Britain, U.K., Switzerland, Brazil, Argentina and several others. And what those programs allow patients to do is if the doctors request BOT/BAL and they're willing to pay out of pocket for the cost of BOT/BAL, then they have the opportunity to be treated with BOT/BAL. And we're seeing now both programs, the AAC program growing in numbers as well as the paid named-patient program growing numbers. Now I just want to make sure that the world understands we're not promoting anything here. It is strictly based on requests that come in. And those requests come in from physicians, word of mouth or knowledge as well as patients.

Great. Thank you, Garo. So just to kind of then summarize because there could be some confusion, right? There is the French AAC program that has -- is being reimbursed by the government, but also in countries that allow outside of France, the named-patient program allows individual patients to be treated, again, across multiple tumor types as well as the French program is covering both the metastatic MSS late-stage colorectal cancer as well as certain sarcomas and platinum-resistant ovarian cancer. So there are 2 different programs, but they offer patients different pathways still while the development is ongoing to receive access of BOT/BAL, which has been initiated by the physicians themselves. So you touched upon this a little bit just now, but can you share maybe a little bit more because we've had a lot of questions about the global interest and what that looks like to date and what that tells us?

So what's interesting is that we're getting a substantial number of inquiries from as we've stated before, 30 different countries, 270 inquiries. And this is through the end of March, which is basically today. And this is happening because sadly, patients are desperate for treatments, desperate. And even patients who are not desperate for treatments would, in some cases, prefer chemo-free options. And that's what, of course, BOT/BAL offers. It's a chemo-free option. And so the demand is growing. There's no question about it. We will qualify -- I mean, quantify this on our next earnings call in terms of percentages, not in terms of numbers because we don't want people to calculate the cost of the product. there are sensitivities associated with that. And there's also competitive concerns associated with that. But what's interesting to me is that physicians from the U.S. are calling us and saying, we have XYZ patient, and she or he would like to be treated with BOT/BAL, where can we do it? And so we provide the referrals, but we don't tell the physician or the patient to be treated with BOT/BAL because that would be promotion. And that is not the intent of either the French AAC program nor the out-of-pocket paid named-patient program. So we're very encouraged with the trend that is developing. And what's also important is that up until about a month ago, we did not really have a formalized effort in medical education. So typically, as you know, companies that are doing clinical trials have a medical education department. But because of our previous budget cuts, we had pretty much eliminated that and Dr. O'Day and some of his colleagues were providing medical education. But in the last month, we have formalized our efforts to put into place a medical education department as well as medical affairs. And the importance of this will be not just educating patients and doctors on the data that's been published. And as you know, we have published extensively in peer-reviewed journals, and we have also presented extensively at the major conferences. So with all of that, we are delighted that we have a number of professionals in place now who can educate people. And that is going to be a very important part of our undertaking. And the same department, the medical education and medical affairs department will also be in charge of collecting real-world data from the experiences that we have with patients under both the AAC program as well as the named patient program. So that collection, both from a regulatory perspective as well as an educational perspective will be a very important part of our undertaking going forward.

That's great. Thank you so much for that, Garo. And I think one of the third element that we've spoken about a bit too is not just on the education and certainly the real-world experience and that data helps in so many different ways, but particularly ensuring patient safety and that physicians that may be new to BOT/BAL get experience but understand how to dose it, how to manage any potential side effects and making sure that the patients receive the best outcome possible and understanding how to do that appropriately. So I know that the team has been fielding a lot of patient safety-related questions so that they can ensure that the patients are at the forefront and retain the best experience possible. So as we think about just a little bit more in closing, you mentioned some of this, Garo, about beyond access and the clinical insights and the real-world data how should we be thinking about the broader impact of these programs and really what that potentially means for patients now helping to receive access to these treatments in addition to the real-world experience that physicians are receiving?

So certainly, for French citizens or residents, the French government is underwriting the cost of treatment. And that's a very, very important thing to do. And French government actually and the French regulatory system has been among the most sophisticated in the world when it comes to oncology as well as when it comes to early adoption of immunological treatments for oncology. So that's one piece of it. Now with the paid named-patient program, I think given the fact that patients will constitute a wider group of people or patients that may have different stages of disease or may have even different cancers, that kind of data is going to augment the phenomenal data collection that Dr. O'Day and his team have engaged in, in the last years. And I think the collection of that is going to have very, very important implications for us from a regulatory perspective because the totality of the data, I mean, for example, when we had our Berlin pan-tumor presentation, at that time, the presentation was in over 400 patients across 9 different tumor types. And what was remarkable about it is that there was a narrow band of activity threshold for patients. For example, if you looked at survival at 2 years across all of these indications, it was somewhere between 39% and 41%, which is remarkable, which substantiates the point that I made earlier that we're not going after a specific cancer. We are really training the immune system to fight cancer. That is the key to all of this. And so this broader activity is going to be something that doctors are taking notice of. And there are patients, by the way, not insignificant numbers of patients that when they hear about the attributes of immunotherapy and the well-known shortcomings of chemotherapy and other toxic treatments. They go to their physicians and they ask them, immunotherapy is available for XYZ, why can't we have access to it. And so these are very important questions that both the regulatory authorities and the medical community need to wrestle with because after all, it is not just the standard of care that dictates how patients should be treated. There's also a patient preference issue. And it's between the patient and the physician that they need to make these decisions. So we're very, very, very optimistic and also really fulfilled by the fact that at least through these programs that we offer, paid named-patient program as well as the French AAC program, at least patients and physicians have some say.

So with that, we're going to actually welcome back Steven O'Day and Robin Taylor for our live Q&A.

Thank you so much to everyone that has joined us today and engaged. We've had a tremendous number of questions that have been submitted, so I'm going to try to paraphrase questions for our leadership here. So if you don't hear your specific question, it's only because we're trying to manage over the 30 questions that have been submitted. So with that, there's a lot of questions related to regulatory path and our approval strategy and potential endpoints and data. So Steven, I'm going to ask this question to you first, I think you can jump in here, so can you walk me through what's the most realistic regulatory path for BOT/BAL is across U.S. and/or Europe? And if there's an opportunity in for an earlier submission for a conditional use of approval?

Sure. So obviously, the main focus is the data we've generated in the Phase I and II trial, the contribution component, the selected dose and the Phase III registration BATTMAN trial that has been reviewed by FDA and EMA regulatory bodies as potentially registration-supportive. So that is obviously our main focus of a regulatory pathway. Having said that, we continue to watch this Phase I and Phase II blended data mature. We continue to see an occasional late response that's durable and the survival plateaus continuing to evolve. And we are looking at the patient population within this group that has failed all standard therapies. And we look forward to continuing to interact with U.S. and European regulatory authorities in the coming months about this evolving, maturing single-arm data with the hope that it could be considered as a more accelerated pathway, knowing that we have a supportive Phase III trial that is actively accruing patients and generating the data that will be critical to full approval. I would just add that, obviously, the other pathway that is of great interest to us is the neoadjuvant setting in the colorectal space, colon cancer, in particular, based on our Phase II data in the U.S. and Europe. And we're actively reviewing that data and moving forward with planning to a pivotal registration potential trial with traditional EFS as an endpoint going forward. We think that will have tremendous potential to impact, as Garo said, the large group of locally advanced colon cancer patients, which includes young patients that are diagnosed and require surgery and chemotherapy that can be debilitating. And despite the best surgery and chemotherapy in these high-risk locally advanced colon cancers, 25% to 30% will eventually recur and most of those will die with metastatic disease. So if we could impact that by curing them earlier with better immune drugs and deescalating eventually chemotherapy in patients who may not need it, that would be a tremendous arc to the story from late to early stage in colon cancer.

Thank you so much for that, Steven. And I'm actually going to skip ahead a little bit because we did have a lot of questions about the neoadjuvant setting as well as what data do we have that has caused us to be confident about the BATTMAN study, you already addressed all of those. So I'm going to actually jump ahead. We did have another question about the access programs and I'm going to turn it over to Robin to answer. So what are we seeing in terms of real-world interest and the utilization across the access program? And how is that clinical development and how we think about future commercialization? I know Garo touched upon this a little bit, but maybe if you could provide a perspective of your thoughts for the future and commercialization.

Thank you, Stefanie. So one thing I think to look at is that we have 2 different types of programs. One is the named-patient program. And the people who express interest in that come from both a mix of patients and physicians. In order for a patient to actually receive BOT and BAL through the named-patient program, they need a physician who will send in the request, but we do get a lot of requests actually from patients who we can then help them understand the pathway. The French AAC program in terms of the paid access has only been open really for -- opened in the last quarter of last year. And in that quarter, we saw a lot of interest, but there was also building awareness about the program because the access program had already been open. Colorectal cancer was approved through ANSM as an access program. Subsequently, ovarian cancer and sarcoma were also added. And so all of those are now available in France for physicians to request access for their patients. We saw actually $3.2 million in realized revenues in the fourth quarter of last year across both the named-patient program and the French AAC. And we're seeing an increase in the interest in France, I think, probably as physicians speak to each other and there's greater awareness about the program. In terms of how this impacts us for the commercial side, there are 2 things. One is that physicians are getting broader experience with BOT and BAL. And we have our medical affairs organization on the ground in France now to be able to help physicians understand the best way to manage patients, ensure that they're being safely managed. And that's really important because as we transition at some point to commercial access for BOT and BAL, the more physicians who have already used BOT and BAL and understand how to treat patients appropriately, that will make things a lot easier for a commercial launch. So it's really a unique program in France that the French government recognizes that this early access is a way to actually benefit patients not only before the drug is approved, but also afterwards because physicians who have more experience are also going to be able to treat patients more appropriately in the -- as Garo mentioned, the real-world data from this program will also be helpful, both for regulators, but I also think for the discussions that we have with payers, having that real-world data really demonstrates that the BOT and BAL are performing as has been seen in a clinical trial.

You mentioned it a little bit,Rob, and there's a follow up question. How should we be thinking about the economic profile, if you will, about BOT/BAL today through the access programs and how that translates into future commercial opportunity? I know we're not -- it's different when you have a full sales force promoting the product but what is this foundation maybe telling you from a commercial perspective?

Well, I think the first thing it tells us is that there is already awareness of the data with BOT and BAL that is driving this interest in -- for French physicians for the named-patient program, we do see there's a lot of awareness. So awareness is always important in the commercial launch. Secondly, I think the question might also be getting at the economics in terms of things like pricing. And our pricing for BOT and BAL is at a point where we anticipate that this would be reasonable for our commercial pricing. We want to make sure that we're not undercutting our future potential pricing on the commercial side, but come in with something that is recognizing the value that BOT and BAL delivers in terms of the full benefit, everything that we're seeing in the clinical trials and how that translates into long-term benefit.

That's fantastic. So maybe just to switch gears a little bit, I'm going to come back to you again Robin, to give others a little bit of a break. There's been a lot of questions about the competitive landscape and positioning, if you will. And how do you view the competitive landscape in MSS colorectal cancer and other immunologically cold tumors, right, and what differentiates BOT/BAL as we move forward? And I think Steven shared a lot of it what we think is differentiating and the large dataset that we have but perhaps from a commercial perspective, as it's just maybe is a little bit of a different lens that you could share to that?

Yes. Well, there's 2 elements to this. One is the competitive landscape or the options that patients have in late-line colorectal cancer. And in that setting, there are already 3 approved drugs in the late-line colorectal cancer setting. There may be more coming. If you think about it from a patient benefit perspective, the more options there are, the better. And then is where does BOT/BAL fit into that. Our initial indication with the BATTMAN study is in this late-line setting after patients have exhausted available therapies. How that's used in the real world, this is where once the drug hits the market, physicians will start to figure out where does this fit in their treatment paradigm. Secondly, as Steven talked about, we have data now in the very early disease setting. So in the neoadjuvant setting, we're seeing really encouraging data with BOT and BAL. And that we hope is going to lead to a registrational study in that early disease setting where really there have been no significant advances in colon cancer for essentially the last 20 years. The last drug approved in the adjuvant setting for Stage 3 colon cancer in not MSI-high is essentially oxaliplatin or Eloxatin. And so we think that there's a really tremendous opportunity to be able to improve on event-free survival, overall survival in that setting. And that would be a real game changer for these patients and certainly would be a situation where we don't see any real competition at the moment for BOT and BAL in that setting. The second part of the question is really around other immunotherapies, other CTLA-4s that are in development. We have a tremendous advantage with BOT and BAL in that this is a very unique molecule. It was designed, as Steven described, with -- to be engineered to improve T cell priming and activation and generate T cell memory. Those modifications are fairly unique to botensilimab. So there are other immunotherapies that are looking at different ways of modifying CTLA-4 or other types of constructs, but they are distinct from what we've seen with botensilimab. And so not only do we have the advantage right now of having a bigger data set so that we've been able to see the effect of botensilimab across multiple cold tumors, but we also believe that we have a molecule that we're going to be able to advance not only in colorectal cancer, but ideally be able to take across to other cold tumors where we've seen significant data.

Great. Thank you so much for that, Robin. So with that I think we have one last question for Garo. I think we're almost top of the hour. And so Garo, this question just came in a little bit late, just later in the day today after we started the call. And it's something that you've been talking about internally as well. And the question actually is related to, we had so much strong data that's been presented over the course of 2025. We have spoken a lot about potential milestones or catalysts. What's ahead for us in 2026 and the execution that we're focused on delivering? However, the market doesn't seem to be responding to the value that we believe that we have in BOT and BAL and what that could offer to patients in colorectal cancer and potentially in the future beyond. What is your thinking and why do you think that's the case?

Well, let me just address this with some of the facts. And the facts are, as you stated, Stefanie, there is a disconnect between the progress we're making, and this is real tangible progress with patients and the value the market assigns to Agenus. Now of course, part of that disconnect is simple. Taking BOT/BAL all the way to approval, which we're getting closer and closer to, we believe, scaling it. By the way, we have done most of the scaling already. And by scaling it, I'm talking about significant quantities of commercial-grade product. We've done really a phenomenal job of advancing that and commercialization, which I'm hoping that will not require very much based on the demand that we're seeing or the requests that we're seeing from physicians and patients. Of course, to be competitive, you need to have a bit of a commercialization effort. But all of these things require capital as well as getting through the details of the clinical trials. So that's a real reality for us, and we don't hide from it, but we're working on solutions to it. We've already taken major steps to do exactly that, strengthening the company, expanding reimbursed and paid access is a part of that, advancing our Phase III trial, pursuing the regulatory paths that can move BOT/BAL much closer to patients and commercial reality quicker. I think that's very important. So this is not a story of promise without a plan. It's a story of proof and discipline to carry out the proof across the finish line. Now we've had a very challenging period. I mean it is a miracle that we've gone through, persisted through this challenging period while maintaining the integrity of making sure that BOT/BAL is made available to patients expeditiously while making sure that our GMP production for both BOT and BAL, commercial-grade production is not compromised. And yes, of course, our shareholders matter in this process, not as spectators, but also as owners. We want to have our owners who understand the magnitude of what is being built here and who recognize that lasting value is created when clinical impact, regulatory progress, access, manufacturing readiness, and capital discipline come altogether. And we've done some very creative financings in the last couple of years to be able to meet our challenges. We're not quite there yet in terms of the magnitude of capital that's going to be required, but we have actively pursuing programs. We have been, to do -- to make sure that, that gap closes as soon as possible. So we're not going to let a temporary valuation disconnect define Agenus. We're going to close the gap with the data and execution and the results that market can no longer -- we don't want the market to have an excuse to ignore these important advancements. So that's what I think about it.

Thank you for that very transparent response. And thank you to both Steven and Robin for joining in the live Q&A and for everybody that submitted questions. We're going to close the Q&A session for now but for any questions that we did not have an opportunity to answer, we will be sure to carry forward into future webcast. With that, Garo, I'll just turn it back to you for any type of closing remarks that you'd like to make before we close the official call today.

By the way, I apologize for the fact that Stefanie's broadcast quality voice is crackling because of some technical glitch that is not ours. I assure you but it is the system that's providing this for us. But even with that glitch, Stefanie, you came across very clearly. So what you've heard today is not a collection of separate updates. I hope not. It is one story coming together that is the clinical data, physician interest, patient access, operational readiness. I mean, these are not trivial feats to be able to pull off. Those are no longer separate work streams. They are reinforcing one another, and that's what we're doing. This is why 2026 matters to us. This is a year where we have to execute on all of these fronts. And what do I mean by that is the patient access program, the French AAC, reimbursed AAC, and paid named patient program. We have to execute on at least one filing in a major geography, at least that. And you may say, well, didn't you fail in your previous filings? We haven't. We haven't, not on BOT/BAL. What we've done is a very rigid FDA opining across a virtual meeting that we should not go for accelerated approval. Well, since then, we have collected a significant amount of additional data. The data has matured, and it's been, as Dr. O'Day says repeatedly, we know that data is durable. In other words, the responses have not only gotten better, but some stable disease patients that were not yet that official -- across the official response threshold. Now they've become responders after 2 years. I mean that speaks to the immunology's power in controlling cancer and controlling tumors. And execution on the regulatory engagement, of course, requires both urgency and discipline. And execution on the broader strategy to extend immunotherapy into cancers and patients that have historically been left outside of its reach. As access programs expand within the proper regulatory framework, which we're doing, we're also beginning to see early pre-commercial income in certain settings like the AAC and named-patient program. That is not a story, but it is a sign that physician-led demand is translating into real-world requirements and use. We do not see this as a single milestone story. We see it as the building of a durable foundation because success is not defined by one readout or one indication. Success for us is defined by whether more patients live longer and live better because the immune system was finally engaged in the right way. And certainly, I'm delighted that we have the right tools. And in fact, we have tools beyond BOT/BAL that we have put on the shelf for now. And as soon as we have the plenty fullness of resources, we will bring them back because each one of these programs and each one of these leads have a very sound reason why these molecules were designed and why they were taken into the clinic. And we have taken at least 5 other molecules into the clinic. But as I said, they have been put on the shelf for now. So that remains our standard, and that remains our focus. And let me close with this. We're not here to participate at the margin of immuno-oncology, as Dr. O'Day indicated and Dr. Robin Taylor, who is one of the world's greatest experts on CRC. We are here to change what is possible for patients who have been left out for too long. That is the work that we're doing. That is the opportunity. And that is exactly what Agenus intends to do. With all the obstacles we've encountered, we continue to pursue this mission and our expectation is that we will deal with these obstacles very expeditiously in the next 6 to 12 months. So with that, thank you very much, everybody, and our team and our participants, and thank you, Stefanie.