Agenus Inc Q2 FY2025 Earnings Call

Good afternoon. My name is Stefanie Nacar, and I'm the Chief Communications Officer here at Agenus. Welcome to our webcast where we'll be discussing topics related to patient care, their experiences, their needs, and the work that's required to bring new options to those impacted by cancer, specifically colorectal cancer. Before we begin, a quick reminder that today's discussion includes forward-looking statements. These are subject to risks and uncertainties that could make actual results different. Please be sure to check our website for our SEC filings. Joining us today are distinguished leaders from industry and medicine, each bringing deep expertise and a shared commitment to advancing patient care. From Agenus, we will be joined by our host for today, Dr. Garo Armen, our Chairman and CEO; as well as Dr. Richard Goldberg, our Chief Development Officer; and Jennifer Buell, Chairman, Executive Counsel at Agenus and President and CEO of MiNK Therapeutics will be joining us. We'll also have members of our executive team join us for our question-and-answer session, Robin Taylor, our Chief Commercial Officer; as well as Dr. Steven O'Day, our Chief Medical Officer. I'm also excited to share that we'll have external thought leaders, Dr. Nicholas DeVito, the Assistant Professor of Medical Oncology at Duke University; as well as Dr. Chris O'Callaghan, the Senior Investigator from the Canadian Cancer Trials Group. For the agenda, we'll specifically be discussing the growing colorectal cancer crisis, the spotlight on emerging data from the BOT/BAL immunotherapy program, and hear firsthand perspectives from leading clinicians. We'll also examine the systemic regulatory challenges that continue to delay access to potentially life-extending treatments. And finally, we'll answer your questions. So we invite you to stay engaged and be part of the conversation. Please submit your questions either via text at (510) 323-5188 or e-mail ask@agenusbio.com. And with that, I'll turn it over to Garo to start our webcast for today. Garo?

Thank you, Stefanie, and hello to everyone: patients, advocates, investors, and truth seekers. I'm Garo Armen. Today, we will address what truly matters, especially to cancer patients. We are here because colorectal cancer is not just another illness; it represents a crisis with nearly 900,000 deaths annually across the globe. In the U.S., it is expected to become the leading cancer cause of death for individuals under 50 by 2030. That is approaching quickly and it is shocking. For metastatic patients who have not responded to first and second line treatments, existing approved drugs offer only 6 to 11 months of survival. These figures are not just statistics; they represent lives, broken families, and lost futures. The system is failing these individuals. The current approach is bogged down by bureaucracy and favors medications that extend life by only weeks. In contrast, BAL has demonstrated that some patients can live for up to 4 years without disease, enjoying life with quality, and without the burdens of toxic chemotherapy or invasive surgeries in some instances. Let’s recognize who this disease impacts: younger adults, including children. We received a compassionate use request for an 8-year-old child with metastatic colon cancer, which was unprecedented and unfortunately denied due to bureaucratic reasons. Consider this: An 8-year-old! Look around us—people in their 20s, 30s, and 40s who should be building careers and families are instead facing chemoradiation treatments, surgeries, colostomy bags, infertility, and financial ruin. Now, I would like to share a story that millions have witnessed. Andy, please play the video of Tanner. Wow, this was Tanner Martin, who died in June at the age of 30. Millions followed his plight online, brutal treatments, endless suffering, as you saw, and now a wife and a daughter left behind. That's the potential of delays. Chadwick Boseman, James Van Der Beek, famous names, yes, but they are just the tip of the iceberg. This disease is everywhere. You can see it. You read it in papers all the time. So common that they lowered the screening age from 50 to 45; still not enough. CRC is exploding as we speak. Why don't we drop the screening age to 40 or 35 or even 20? Would that be enough to end the current epidemic of CRC? Because we lack effective treatments today, effective chemo-free treatments, people will still be suffering with no viable solution, no matter how early diagnosis is. At Agenus, we don't settle for a few more months. We have our eyes on much bigger outcomes. We have the fortitude to fight for cures, patients alive for years, and living better, and ultimately, all patients cured. Ultimately, we're not quite there yet. No more bags, no more infertility, no more mutilating surgeries, no more toxic treatments that rob patients of their quality of life. Patients don't live on bureaucratic time. They live on cancer time. We need all recognizable facts that move this to the highest sense of urgency. Now here is the other side of the story. What happens when we unleash the immune system? Andy, if you could please pull the breakthrough IO therapy slide. When strictly regulatory-minded people may call these slides anecdotes, let's be clear that these are not anecdotes; these are real people, real patients. We know some of them. These are real families. We have treated over 1,200 patients across colorectal, breast sarcoma, lung melanoma, and ovarian cancers. These outcomes are simply representative patients—the ones that you see on these slides. To be clear, not all patients respond, and most side effects are transient and they don't last. As we go from late-stage patients that have failed everything, where the response rates are 20% plus or minus, we move to earlier-stage patients like Stage III cancers, and responses go up dramatically, as you see in these pictures. The outcomes are black and white, and they're not anecdotes, as I said; they are real patients. Take a look—1 dose of BOT and 2 doses of BAL. The tumor is gone in 7 weeks, and the patient kept their quality of life. That's not chemotherapy. That's the immune system doing its job. It is the miracle of the immune system, an absolute miracle. That's why we built BOT/BAL with that in mind. That's why we're here to show what happens when you prime and unleash the immune system. And today, you'll hear from people who know this fight inside out—advocates, physicians, patients, and my colleagues at Agenus who push the science forward every day. One last point before I hand it off. If you keep the current paradigm, we're not punishing companies like Agenus; we're punishing patients, and that should never be the role of any health care system. The good news is that we now have an FDA commissioner in Dr. Makary, who has laid out a reformist agenda. We hope to work with him and with his colleagues and reform-minded people at the FDA and outside of the FDA to align regulatory science with medical science. We have an opportunity today to do the right thing for patients because the truth is, science has moved so fast and regulation has kept poorly pace with the rapidly moving science. That gap is costing lives, and that's a very sad thing, as you saw with Tanner's video and Tanner's plight. So now let me introduce Dr. Richard Goldberg. Let me bring you in, Richard. You've treated thousands of colorectal patients over the years. You know the toll of this disease and how it really punishes patients and our limited options. So my first question to you is: What's the real cost to patients of waiting on bureaucracy while therapies like BOT/BAL are sitting right in front of us?

Thanks, Garo. So over my 40 years in practice, just like the epidemiologists who track trends in cancer incidents, I've seen the heartbreaking rise in the number of young people like Tanner with colorectal cancer. I've also observed and contributed to the standard of care changes that we've seen in colorectal cancer. When I began, we had one drug. We then went to multiple chemotherapy drugs. We then developed targeted therapies that apply to some patients with colorectal cancer. And most recently, the immuno-oncology revolution has changed the lay of the land and the treatment of colon cancer. Today's immuno-oncology or IO effects can be seen in patients with immunologically hot tumors. In the colorectal cancer population, this is about 5% to 15% of all patients. For the other 85% to 95% of patients—those with cold tumors—immunotherapies have been ineffective to date, and no approaches have yet been FDA approved. There's a clear unmet need here. Patients are clamoring for an IO approach that will bring the benefits seen in the few CRC cases with hot tumors to the majority of cases with cold tumors, and that's what Agenus is trying to do with BOT/BAL.

Thank you. So Richard, if you look at the current landscape, we talked about younger and younger people coming down with this disease. And I know I'm asking you a question, which is impossible to answer. But why do you think this is? Why do you think we're seeing an explosion of CRC in the young people today?

Well, the answer to that question is the subject of intensive research, but we really don't know. We think that it may be childhood exposures to potential risk factors like high fat, low fiber diets; it may be things we are breathing in the air or drinking in the water. But we really don't know. The advances that we're making in colorectal cancer apply to all patients, fortunately, whether they're young or old. Therefore, the research that we're doing can help to combat this epidemic.

And if you look at the composition of responses that we have seen, first of all, your decision to become our Chief Development Officer, that was a big leap for you, of course. What was the tipping point of that decision? Because I know that before you joined us, you immersed yourself with a lot of data, you cut it in all ways, and what happened that really tipped you off to something that is worthwhile pursuing here?

Well, for one thing, I joined the Board of a colorectal cancer advocacy group called Fight Colorectal Cancer and had the opportunity to interact with patients differently, not as their doctor, but as their advocate. That made it clear to me the unmet need we're seeing for those 85% of patients with cold tumors. Then I had the opportunity to evaluate many of the new drugs and technologies that are in development across the spectrum of the biomedical community. I had the opportunity to see what was happening not just with BOT/BAL, but with other companies who are advancing other drugs. The most promising combination in my mind was what I was seeing with BOT/BAL. When I got inside the company and had the opportunity to look under the hood, my conviction that this is a strong combination that will ultimately save lives—not just for colorectal cancer patients but for many kinds of cancer patients—was solidified. I made the decision to put away my fly rod and go back to work.

Well, we're delighted to have you with us because I cannot envision an expert in the field that has seen it all, has done drug development and can objectively evaluate the plight of the patients and the benefit that our combination BOT/BAL is bringing to them. But on another note, if you look at, for example, the field that we're in, it's confusing because as more scientific developments take hold, confusion really spreads more. We have hot cancers and cold cancers. Within the label of hot and cold cancers, we have cancers like colorectal cancer that are largely cold. But there's a segment of them that behave differently—for example, we call it MSI-high, which are some of the so-called hotter versions of colorectal cancer. Unfortunately, it affects only about 5% of colorectal cancer patients. Then we have the MSS patients, which is what BOT/BAL is going after. There has been confusion about MSI-high because we've seen drugs like PD-1 drugs or PD-L1s that have shown very high efficacy—up to 100%. In fact, you remarked in a conversation we had yesterday about how these drugs are changing the treatment paradigm. How do you extrapolate from that, simplify some of these definitions, and show what BOT/BAL is doing in a portion of the cancers that are not being touched by the first-generation IO products?

Well, so BOT is not just another drug targeting CTLA-4. It's been engineered for deeper immune activation and also to avoid side effects. So it's a second-generation CTLA-4. We've studied it across more than 1,200 patients with 9 different tumor types, including colorectal cancer. Recently, we updated our data from our Phase I study of 123 patients with MSS colorectal cancer. These are late-stage patients. They've either had 3 lines of therapy or 4 lines of therapy. In the cases of those with 4 lines of therapy, there's nothing more to do other than best supportive care. Despite that, in this patient population, we're seeing a 42% 2-year survival rate, which is really unprecedented, seeing a median overall survival—and the data is still maturing—of 21 months. This is way more than the 10 to 14 months that has been the best case reported in the current standard of care regimens. We are also seeing manageable and largely reversible side effects in contrast to the profiles that we see with many chemotherapy regimens. Many of these patients, even though they are years past getting oxaliplatin, still have the sensory neuropathy, which is the scourge of treatment with that drug. It saves lives in some cases; it extends lives in others, but patients are always reminded of it if they have that side effect of neuropathy. Even though we are going for approval first in late-line therapy, the application that seems even more exciting to me is the application in early-stage cancers. When you give a medical treatment before surgery, we call that neoadjuvant therapy. We have 3 studies, the NEST, UNICORN, and NEOASIS studies, where we're treating early-stage cancers—not just early-stage colon and rectal cancers but many different kinds of cancers, including breast cancer—and we're seeing that in patients with robust immune systems that haven't been damaged by exposure to cytotoxic drugs, the responses are even more dramatic. Just like you saw in that patient's colonoscopy, where the colon cancer disappeared with just 3 treatments. The preliminary data that we're seeing with BOT/BAL, everywhere we look, it's active. We hope that it will translate into lives saved.

On that note, Rich, if we look at the landscape, you remarked about the broader activity of BOT/BAL. Given that we've treated over 1,200 patients, we have a pretty good sense of the toxicity profile and the transient nature of some of the toxicities that we're seeing. Jumping ahead, because you've worked in a regulatory environment most of your career, what would be the risk of allowing BOT/BAL access by patients and doctors on a wider scale, more notably in a commercial setting, quicker rather than later? As you remarked, if we conduct randomized trials for every single indication, patients will wait a long time for access, wide access. Why do you think there is this hang-up? How do you think the regulatory system can evolve so that the precedent-setting blockages are not going to be the drivers of future decision-making?

That's a complicated question. Even when there are early indications of dramatic tumor shrinkage, such as we're seeing with BOT/BAL, the regulatory environment is such that the FDA still requires proponents of new approaches to perform large Phase III trials with hundreds of patients, and randomize patients between a new therapy and the standard of care. Given the efficacy signals and the toxicity differences that we're seeing with the new IO approaches, patients considering these studies often hesitate before accepting randomization. Today, they hope for more time, for moderate time off treatment, for meaningful extension of their life expectancies, and they even dare to hope that they can be cured. Our ambitions and their hopes to accomplish this with IO regimens without the side effects of traditional chemotherapy-based regimens is why BOT/BAL was developed and why we're moving forward with those drugs. When we had our last meeting with the FDA 2 months ago, they told us that we had to do a Phase III trial. Fortunately, as you'll hear from our colleagues from the Canadian Clinical Trials Group, they approached us with an idea for a Phase III trial that the FDA accepted as necessary to show the efficacy of our drugs in the late-line setting. When we met with them, we presented the strong activity signals that we presented at many international meetings. We informed the FDA team about the high level of enthusiasm among both oncologists and patients with experience using BOT/BAL and their desire to get the combination into the clinics as soon as possible. Since then, we and our academic collaborators keep asking ourselves why the FDA isn't open to accelerating the approval, allowing us to save lives that will be lost in the interim. Science is moving fast; regulatory processes need to keep pace with the science. We believe regulators must reflect upon and update the approval process.

Thank you. Now, let's go to Dr. DeVito. Dr. DeVito, your background as an immunologist turned oncologist is fascinating because that's not the usual progression that we see. How has this impacted your research and shaped the way you think about treatments and your patients?

That's a great question. I came into oncology from a background of immunology and an interest in cancer vaccines, which are obviously limited by immunosuppressive mechanisms that compromise their efficacy and have led to a lot of unfortunate failures. I have always viewed the mere existence of a cancer inside someone's body as an immune failure, as immune surveillance that didn't happen. When you reframe oncology like that and come into this with that mindset, you think about ways that you could alleviate immune suppression and develop immune elimination of tumors rather than treating them almost like an infection with antibiotics—like antibiotics with chemotherapy or playing whack-a-mole with targeted therapies that inevitably lead to resistance, where you get these nice durable responses and tolerable therapies. I think there's a real appeal to patients as well with immunotherapy; this is what I've always seen in clinic. It is really resting back control by saying this is my immune system attacking the cancer; this isn't just me surviving chemotherapy or something like that. I have found a lot of fulfillment in coming into this field as an immunologist and feel that it aligns really well with what patients want.

And so you embarked on a very courageous—and I should say unorthodox—trial because the standard way of thinking is that you have a standard of care; no matter how poorly that standard of care is performing, you need to use that as the first line of therapy before you can try something else. As we adhere to that practice, patients are getting sicker and sicker, and the more sick they get, the more difficult treatment becomes for them. Can you tell us a little bit about your trial? We don't want to jeopardize your ability to publish and present the data, but perhaps you can give some representative examples of patients as to why they decided to enroll in this trial.

Happy to do it. This is referring to BBOpCo, or botensilimab and balstilimab optimization in colorectal cancer. It is a first-line trial in microsatellite stable colorectal cancer patients without liver, bone, or brain metastasis, which we believe may be immunosuppressive sites we still need to learn more about until we can overcome in the first line. But it's first-line BOT/BAL, no chemotherapy, in Stage IV MSS CRC. We've almost completely recruited the trial in a year, which I think explains what the patient desire is, and it speaks for itself. This trial came purely from a place of empathy. I thought about what I would want if I was diagnosed with Stage IV colon cancer. I work on cars; I play music; I have 2 young boys, like I'm active. I don't want neuropathy from oxaliplatin, and I don't want cytopenias from irinotecan. I wouldn't want any of those things. I would want at least a shot at immunotherapy to see if it was going to work and lead to a durable response. That's exactly what one of our patients, who's 30 years old, came in with lung metastasis after not getting scans for a Stage II colon cancer because he was told that he didn't need them, but he really felt uncomfortable with that. He came to see us at Duke, and we started him on the trial, and he's done amazingly well. He says that I'm a celebrity in his house apparently because I came up with this trial, but it aligns exactly with what he wanted. At the time, he was the only one working, and he needed to be there for his family. He's tolerated everything incredibly well. The side effects of BOT/BAL, I think, are so much more manageable once oncologists wrap their minds around them and say, 'Okay, we're just trying to prevent autoimmunity and trying to educate patients and educate providers so we can act early.' In this trial, we give patients steroids that they take home. If they develop diarrhea due to immune-mediated diarrhea and colitis, they start the steroids, come in, and receive infliximab or another biologic, and we can turn them around. That is a lot different than oxaliplatin reactions, which can lead to a terrible infusion reaction or delays in chemotherapy with irinotecan while it's infusing. So a lot of these things are very different with BOT/BAL. And this is why this trial was developed. We hope that by giving BOT/BAL in the first line, we can transform this disease into something where patients have more options, and they have a shot at avoiding chemotherapy entirely, just like patients with melanoma and patients with microsatellite unstable colorectal cancers too. Moreover, it's fascinating to look back in 5 to 10 years; we might discover that MSS CRC looks just like MSI CRC, with immunotherapy actually working much better if given first. If you look at some of the crossover arms like the IPI/NIVO trials, patients who got chemotherapy first then crossed over to IPI/NIVO still did worse. They still didn't have as high of a response rate. Immunotherapy early is better before there's tumor immune evolution in response to chemotherapy and resistance to chemotherapy, and before patients are getting absolutely obliterated by some of these side effects from chemotherapy that accumulate over time. Unlike BOT/BAL, where you're managing the side effects upfront, this is something with chemotherapy that just builds. If you try to do things like FOLFOX reintroduction, you raise your risk of oxaliplatin infusion reactions. It's vital to me that patients have this option. If they have it as early as possible, especially in a disease setting like Stage IV CRC, which we know is typically incurable, maybe it could change.

So what you're basically saying in very simple terms is, why not use the best option for the patient first? If that fails, you can use some of the nasty things like chemotherapy later, which is, by the way, what Mike—Dr. Atkins—advocated at last year's SITC meeting because he said exactly what you're saying: It doesn't make sense to keep the best to last.

Use your most durable, tolerable therapy first, and let's get people into long-term remissions and spare them the toxicity of other regimens. That's exactly right, and it's exactly what Mike Atkins did with the DREAMseq trial in BRAF-mutant melanoma. You have patients that respond much longer and do much better. There's a 20% difference in overall survival if you give immunotherapy first. You can give targeted therapy first and vice versa. So completely agree.

And yet another provocative question for you as I did with Dr. Goldberg. Despite all of this, patients are being held back from being exposed to drugs that could be the best option for them. Richard Goldberg said that the FDA requirement today is randomized trials with 4-, 5-, or 6-year readouts. Of course, we're trying to change that. When we talk to Chris, we'll touch upon how we're going to do that. But how do we—I mean, if you were the FDA commissioner today, how would you practically change this archaic paradigm that is based on precedence from an old generation of drugs rather than embracing new innovative drugs? How would you do that?

Why are we so wed to the mustard gas, I guess, is my phrase; chemotherapy, in my eyes, is the horse that got us to the car. Now we need to get in the car and drive. The car is obviously immunotherapy here, so let's get going. Let's hit the gas. We need to have an open mind. There are patients who present with colorectal cancer that are asymptomatic. They have a period of time where they could try certain drugs, and the risk of a tumor pressing on something or causing them a problem is not that great. I believe there is a patient population you can select for to try promising agents like botensilimab out as first line, obviously, under consent and a protocol. We're sending BOT/BAL, scan at 6 weeks, monitor circulating tumor DNA, etc. We monitor patient symptoms, and we can rescue with chemotherapy and add it on if we need to, opening the window. It gives us a foothold, that first rung on the ladder, helping us understand who is responding first line and avoiding chemotherapy entirely. Doing that in a population that's enriched for patients that have responded in later lines might change the outlook.

So when you came up with this idea of trying BOT/BAL as a first-line therapy in metastatic colorectal cancer, can you walk us through some of the challenges you encountered at your institution, at the FDA? How did you resolve them?

Yes, it was incredibly difficult. I know you've heard the story, but I'll repeat it for everyone on the call. In the 2022 SITC hot topic session, I saw the BOT/BAL data and leapt out of my seat, thinking, 'Why am I the only one standing up and looking around?' I was a man on an island, and I didn't really understand why people weren't as excited about the data as I was. I immediately wrote the trial, crafting it on the plane home. The knee-jerk response from almost everybody, with a few select people, was, 'That's a really good idea, and you'll never pull it off.' The idea was that we develop drugs late line and slowly work them back into the first line, combining them with chemotherapy, not administering them by themselves. That doesn't make sense. FOLFOX has been given for 50 years, which brings us the most dangerous phrase in the English language: that's the way we've always done it. That has been a real barrier, and I had to keep pounding the pavement, saying, 'I guarantee this is something that patients would sign up for and would be interested in.' I received no internal funding. There's little funding for investigator-initiated trials, which is a different issue about how we need to allow physician scientists like myself to run these trials. It languished for about 1.5 years. We were extremely fortunate because I kept applying for different opportunities, various grants, and Gateway—Clinical Trial Research Foundation—ultimately funded us and was enthusiastic. They said, 'We whittled this down to 32 trials, and yours was the clear winner.' They've been extremely involved since, with patient advocates saying this is what patients really prefer: an option toward immunotherapy. We hit the heartbreak of the FDA after that. We were essentially told we must scan these patients at 6 weeks or we cannot proceed with this trial. This raised trial costs tremendously, doubling our diagnostic costs. That was difficult when all our money comes from a foundation; we needed to contribute internal Duke funding, which was tough. We do have an amazing GI oncology research group, 9 physicians, and a great research team who were behind us, saying, 'Let's get this done.' The entire trial of 15 patients is executing quickly and at a low cost. Recruitment is speedy; this is testament to patient demand.

Well, that's terrific. So I’m going to switch to Chris O'Callaghan, and then we'll come back with some questions for everybody. Of course, we have questions from the audience. Chris, you were exposed to BOT/BAL maybe about 2 years ago. You've been after us to do a trial. Can you recount what drew you to us? You have done a lot of trials, and your business is not just generating revenues—you're also funded by government entities. But you wanted this trial for a reason. Can you let us into your mindset?

Sure, Garo. It's a pleasure to be here and to speak on behalf of the trial we've proposed. I'm a member of the Canadian Cancer Trials Group, which has been in existence for 45 years. Importantly, we have done colorectal cancer trials in an international collaborative environment for 25 years. We are different; we are on the back end of where Dr. DeVito was. I applaud him and think it is exciting that he's taking immunotherapy to the front. However, there are patients who exhaust all available therapies and are still looking for options who are otherwise fit and ready to continue treatment. We've done a Phase II trial in which we took 2 agents that targeted similar receptors as BOT and BAL combined. Our feeling was that in the microsatellite stable population or the cold tumor population, there was still a possibility we could overcome that coldness, through synergy with different approaches to stimulating the immune system. The trial was positive, and we were pleased. Serendipitously, we became aware of your work with BOT and BAL, and frankly, the results look more impressive. We were looking for an opportunity to continue our work and demonstrate proof of principle in a Phase III study, which is why we approached Agenus. We are excited as we embark on our CO33—or BATTMAN trial.

When you discussed the trial, I suspect the reason it worked but wasn't blowing you away is because the molecule didn't have the turbocharging capabilities that BOT brings to the party?

That is certainly our hope based on what we're seeing with the results you are producing. Our Phase I and Phase II studies look indeed to outstrip what we saw in our combination trial. It's a great position to be in; we think there’s been a proof of concept for our trial, demonstrating that immunotherapy can work. Now the question is whether we can show that it works even better with the best immunotherapies available.

A couple of days ago, we were talking about logistical steps towards enrolling patients. We finalized our agreement with you, and we are now ready to enroll patients. What is happening? Why are people excited about this?

The first thing I should say is that we are putting together an international collaboration. In Canada, we have experience collaborating with groups around the world, notably in Australia, New Zealand, and France. We have put together an international team around this subject and are excited about it. Canada will lead the way, and I'm delighted to let you know that we have submitted our clinical trial application to Health Canada already. Health Canada will require a 30-day review period, after which we will be centrally activated and ready to go. The enthusiasm for this trial is such that at least 2 of our lead investigators in major provinces in Canada got their ethics submissions in within 6 days of our submission to Health Canada; that is unprecedented. It reflects investigator enthusiasm to trial these agents.

When we discuss enrollment timelines, one thing that attracted us to work with you was not just your team but your ability to work with centers in Canada, France, and Australia to quickly enroll patients. The quicker you enroll trials, the more profitable they are, plus subsidies that are also available to you. With that, what can you say about enrollment timelines?

Let me tell you that in our CO26 trial, we enrolled 180 patients over 10 months. Month-on-month, our accrual was better. In the final month, we enrolled 39 patients from Canada alone, which is a reflection of an unmet need, a patient desire to benefit from immunotherapy and investigators' willingness, and belief in using immunotherapy. If we can put 39 or 40 patients on in Canada, tripling that with Australia, New Zealand, and France, our target is averaging over the life of the trial 60 patients a month. That means we could potentially recruit 834 patients efficiently.

Thank you for that. It's a privilege to work with like-minded experts, both internal and external like you, Dr. DeVito, our very own Dr. Goldberg, and Dr. O'Day. Our Chief Commercial Officer is with us; Robin Taylor has extensive knowledge of CRC from previous experience. This is a fantastic opportunity for patients because we want to get to the finish line as soon as possible. We will also explore more expeditious ways forward, possibly pressuring systems to accept our accelerated approval application when that decision is made. We have faced some resistance, but we can talk about that separately. Now, let me switch gears and go to Dr. Jennifer Buell. We began as an immunotherapy company a long time ago, 31 years. It's not for the faint-hearted, no pun intended due to your Irish heritage. As we expanded our immunotherapy armamentarium, we transitioned to cell therapies. Going from molecules to cell therapies is getting into a more intelligent system. Invariant NKT cells are the most intelligent cells of all the immune system. Can you give us a flavor about the synergy in cancer and the capabilities of these cells beyond cancer?

I'm happy to. What a perfect segue. Following chemotherapy, the immune system does become somewhat incompetent. It struggles to do its job. We identified certain cell types that do the job much better; that is what led us to develop MiNK Therapeutics. Invariant natural killer T cells, as mentioned, are rare cells, and they're one of the most highly conserved cells in immunity. They've been identified for the longest time, but they are the rarest—making up less than 0.1% of circulating lymphocytes, as they're highly potent. They act like first responders. These can kill dangerous cells directly while waking up the immune system to fight back. The immune system has 2 main branches: innate immunity that provides rapid defense and adaptive immunity, which mounts a more specific and long-lasting defense. Most immune cells specialize in one branch, but the uniqueness of iNKT cells is their ability to bridge both branches. They respond quickly and can influence adaptive memory—important for durable immunity against cancer or infections. MiNK is currently one of the most clinically advanced companies developing iNKT cells. Unlike T cells or NK cells, they operate through a common receptor, meaning their delivery can happen without rejection. They can infiltrate tumors and reprogram the microenvironment. They are resistant to graft-versus-host disease, which leads to our work with the government with nondilutive grant financing to advance in various disease settings.

Why is the government interested now as opposed to 10 or 20 years ago? I might add that 20 years ago, we were contacted due to the potential of QS-21 as a biodefense agent. What is happening that is generating interest now?

In 2020, we launched the cells in clinical trials at the same time the pandemic began. Early discussions showed that these cells prolonged survival in influenza and pneumonia models and restored immune function. The FDA cleared us to start a clinical trial based on our preclinical data. We published this in Nature Communications. What we saw in our clinical trial indicated that we could extend patient survival in the ICU from primary infections and prevent secondary infections—those infections that cause high death rates in the ICU. We are demonstrating that we can help patients combat infections they are facing, while preventing secondary infections. We've shown that administering the cells prevents significant complications in infected patients. This work has drawn interest from clinicians and government agencies, particularly related to preparedness for infectious threats. Our iNKT cells could be pivotal for future defense against pathogens; they could be large players in the current and novel infectious threats.

I know there are other logistical advantages in terms of storage and transport of these cells. We're eager to learn about those developments. The government could become a major stakeholder in this progress. We're delighted about the synergies between iNKT cells in cancer patients and stand-alone opportunities outside of cancer. We're also very pleased to be a major stakeholder; Agenus owns about 48% of MiNK. We want to leverage that as we also believe it is beneficial for both companies. Thank you. We are progressing beyond 5:05 with our time, so we can choose to show Jennifer's video—a touching video that speaks to Dr. Nick DeVito's point about life with chemotherapy versus life with immunotherapy. Andy, can we roll that video? With that note, it is our moral responsibility to work collaboratively, particularly with the new leadership in Washington, in health agencies, the FDA, with Dr. Makary, to ensure patients have access to their best treatment options as quickly as possible. Waiting 4 or 5 years for randomized trial readout before patients have access to drugs like BOT and BAL is unacceptable—for us and for patients. In closing, I want to thank all participants on this call for your time. I want to thank our internal and external experts for your insights. I'd also like to thank our collaborators, many of whom are on this call, and all our colleagues in every division of the company. They have worked hard and remain dedicated to our mission. Thank you to the entire Agenus team for making this possible. We are getting closer to our endgame here, and I believe our external environment, including the regulatory environment, is moving in the right direction. This will be a significant advantage for a company dedicated to ensuring that patients receive meaningful benefits—not just days and weeks of extension but transformative lives for every family involved.

Great. Thank you very much, Garo. Thank you all for your continued engagement throughout the webcast today; it's been fantastic. We've had a number of questions already come in. If you didn’t miss the beginning of the call, you can submit questions either via text or email. Please text (510) 323-5188 or email ask@agenusbio.com. So let me get started with that. Some questions, Garo, are about the status of the Zydus collaboration. Thank you for addressing the state of that transaction and the next steps there. We have questions related to the Phase III study. Chris, can you share some additional resources that CCTG provides the partnership, and what does the monetary commitment look like to execute the study?

The CCTG has a history of executing clinical trials. We are capable of doing everything from Phase I to Phase III. We research various types of cancers. We are renowned for our excellence and our ability to get those trials completed. For a large Phase III trial like the one we proposed, it requires an international effort. Thankfully, we've cultivated long-standing collaborations with groups around the world, specifically the Australasian Gastrointestinal Trials Group in Australia and New Zealand. Bringing together our organizations ensures that we can get this study done in a timely manner. In terms of financial support for the organization, the Canadian Cancer Trials Group is funded by a major program grant from the Canadian Cancer Society. We leverage funding from various sources including academic grants and unrestricted pharma support. Financially, this works out to about 10:1.

Do you see any gating steps in initiating the Phase III study this year? Can you share some of the study design, including the control arm?

The trial will target patients who have undergone the full trajectory of available treatments for their colorectal cancer, progressively becoming resistant to available therapies. These patients who are fit are looking for options given best supportive care measures typically. The study will enroll patients with microsatellite stable disease—cold tumors. Randomization will mean half of patients receive BOT and BAL, according to the same treatment regimens used in Phase I and II trials. The other 50% will proceed with best supportive care, which is appropriate in this context. The trial will recruit 834 patients, and we project this will take about 20 to 24 months. After that, there will be follow-up for data maturity and subsequent analysis. We are confident, cautiously optimistic that it will support registration of BOT and BAL internationally.

Why has the study been delayed by approximately 18 months since the completion of Phase II?

At last year's FDA meeting, the FDA insisted on a 3-arm trial. Even though we brought in experts, it took the FDA about a year with additional data to agree that a 3-arm trial was not necessary, leading to a delay of at least a year. At this year’s meeting, they consented to a 2-arm trial, recognizing the contributions of the components—not probing any further. It was a favorable change, and we are delighted with that outcome.

We’ve been receiving many questions about our neoadjuvant strategy. Steven, can you share what else we are doing in the neoadjuvant setting? Are there additional investigator-sponsored trials planned or upcoming data reads?

Rich Goldberg has elevated our understanding of GI cancers from a clinical and regulatory perspective. What's clear is there is a late-line setting across multiple solid tumors with patients having deep durable responses which take brave trials to move early, just like we did in melanoma. The neoadjuvant space is significant; it serves as the education center for T cells for better memory and higher tumor eradication. We're seeing BOT/BAL performance in neoadjuvant settings become more prominent now with ongoing studies like NEST in colorectal cancer, the Italian study with colorectal cancer, and Myriam Chalabi's work across multiple solid tumors. Those data are consistent and support dramatically early responses.

Are we doing anything specific to identify patients with MSS disease?

This is the holy grail: MSS disease. In warm or hot tumors, we have some suboptimal markers to enrich for IO responses. For cold tumors, we struggle much more. We’re working internally and through external collaborations to find several ways to deeply enrich MSS stable tumors so more patients can benefit.

With ESMO upcoming, can you summarize upcoming presentations and expected data?

We are excited about ESMO and will present data in the refractory setting across multiple tumor types. When IO therapy works, we know what good looks like—20% of patients represents a game-changing outcome. More data will emerge from neoadjuvant settings in the coming year.

Garo, there are questions regarding some additional financing and partnerships, especially given the rate at which things evolve in D.C. Did the announced tariffs affect our cost of goods with the Zydus deal or Phase III development? Where do you see this impacting or not impacting at all?

The impact is positive. If there are tariffs on countries like India, things they'll ship to the U.S. will have those tariffs. With Zydus purchasing this facility, they can produce biomolecules in the U.S. facility not subject to tariffs. This is an advantage for us and for our collaboration with Zydus. Yes, Zydus was the first step. We are engaged in multiple discussions with one in particular that will result in significant cash infusion into the company. We haven't released details, but the acquisition will keep rights to BOT/BAL in valuable territories including the U.S., Europe, Japan, and South America. Thank you all for your time. I want to thank all our participants for their insights, especially our external experts—your knowledge is invaluable. Thanks to our collaborators and colleagues in all divisions of the company who have worked hard to make this possible. We're getting closer to our end goal, and our external regulatory environment seems to be moving in the right direction. Ultimately, we are dedicated to ensuring patients receive meaningful benefits that transform not just their lives, but their family's lives as well.