Agenus - Earnings Call - Q2 2025

Transcript

Stephanie Fagan (Chief Communications Officer)

Good afternoon. My name is Stephanie Fagan, 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 shared commitment to advancing patient care. From Agenus, we will be joined with 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 and Executive Council 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 from emerging data from 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 email [email protected]. And with that, I'll turn it over to Garo to start our webcast for today. Garo?

Garo H. Armen (Chairman and CEO)

Thank you, Stephanie, and hello to all of you: patients, advocates, investors, truth seekers. I'm Garo Armen. At today's stakeholder briefing, we will cut through the noise and talk about what really matters to everyone, particularly to cancer patients. Why are we here? Because colorectal cancer is not just another disease. It's a crisis. Close to 900,000 deaths a year worldwide. In the U.S., it's on track to be the number one cancer killer for people under 50 by 2030. That's around the corner, and that's insane. For metastatic patients who have failed first and second line, today's approved drugs give you 6-11 months. That's it.6-11 months. These aren't numbers. They're lives, families broken, futures stolen. And here's the truth: the system is failing them. The current paradigm clings to paperwork. It rewards drugs that give weeks.

BOT/BAL is showing patients alive for as long as 4 years with no disease, living their lives with quality intact, without toxic chemo, without mutilating surgeries in some cases. Let's talk about who this disease is hitting: younger adults, even children. We had a compassionate use request for an eight-year-old child with metastatic colon cancer that was unheard of. It was denied because of bureaucracy. Think about that. An eight-year-old, and look around us: 20s, 30s, 40s, people with careers, young families with kids of their own. Instead of raising families, they're thrown into chemo radiation, surgeries, colostomy bags, infertility, bankruptcies. Now I want to show you a story millions have seen. Andy, please play the video of Tanner.

Hey, it's me, Tanner. If you're watching this, I am dead.

Finishing making that chemo.

So Tanner's home now and still getting chemo.

Nicholas DeVito (Assistant Professor of Medical Oncology)

Hello.

Come visit me.

This is my future home.

Chris O'Callaghan (Senior Investigator)

You guys, life was awesome. I really enjoyed it while I was here. Hopefully, I believe there's something after this, and I'm excited to meet those people. And hopefully, we're hanging out now and making fun of all you nerds.

Garo H. Armen (Chairman and CEO)

Wow. This was Tanner Martin, who died in June at the age of 30. Millions followed his fight 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're 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 - 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 today, people will still be suffering with no viable solution, no matter how early the 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's 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 make all 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 who have treated over 1,200 patients with breast, colorectal, breast,sarcoma, lung,melanoma, 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, but we go to earlier-stage patients like stage three cancers, 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. One dose of bot and two doses of bal. Tumor is gone in seven weeks, and the patient kept her or his quality of life. That's not chemo. That's the immune system doing its job.

It is a miracle of the immune system, an absolute miracle. That's why we built BOT/BAL. That's 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 this 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 healthcare 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 with pace of rapidly moving science. And 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 a therapy like BOT/BAL is sitting right in front of us?

Richard Goldberg (Chief Development Officer)

Thanks, Garo. So over my 40 years in practice, just like the epidemiologists who track trends in cancer incidence, I've seen the heartbreaking rise in the number of young people like Tanner with colorectal cancer. I've also both 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 in 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%-15% of all patients.

For the other 85%-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 the hot tumors to the majority of cases with the cold tumors, and that's what Agenus is trying to do with BOT/BAL.

Garo H. Armen (Chairman and CEO)

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 young people today?

Richard Goldberg (Chief Development Officer)

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 things like high-fat, low-fiber diets. It may be things we're breathing in the air or drinking in the water, but we really don't know. And the advances that we're making in colorectal cancer apply to all patients, fortunately, whether they're young and old. And therefore, the research that we're doing can help to combat this epidemic.

Garo H. Armen (Chairman and CEO)

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. What happened that really tipped you off to something that is worthwhile pursuing here?

Richard Goldberg (Chief Development Officer)

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 clear to me the unmet need we're seeing for those 85% of patients with cold tumors. I had the opportunity to evaluate many of the new drugs and technologies that are in development across the spectrum of the biomedical community and had an opportunity to see what was happening, not just with BOT/BAL, but with other companies who were advancing other drugs. The most promising combination in my mind was what I was seeing with BOT/BAL.

When I got inside the company, had an opportunity to look under the hood, my conviction that this is a strong combination that will ultimately save lives, not just of colorectal cancer patients, but of many kinds of cancer patients. I made the decision to put away my fly rod and go back to work.

Garo H. Armen (Chairman and CEO)

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, on another note, if you look at, for example, the field that we're in, and it's confusing because as more scientific developments take hold, confusion really spreads more. We have hot cancers and cold cancers. And 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-H, which is some of the so-called hotter versions of colorectal cancer. But unfortunately, it affects only about 5% of the colorectal cancer patients.

And then we have the MSS patients, which is what Bot/Bal is going after. Now, there's been confusion about MSI-high because we've seen drugs like PD-1 drugs or PD-1s that have shown very high efficacy, as much as 100%. And in fact, you were remarking in a different conversation that we had yesterday about how these drugs are changing the paradigm, the treatment paradigm. And so 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?

Richard Goldberg (Chief Development Officer)

BOT is not just another drug targeting CTLA4. It's been engineered for deeper immune activation and also to avoid side effects. It's a second-generation CTLA4. We've studied it, as you mentioned, across more than 1,200 patients with nine 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 three lines of therapy or four lines of therapy. In the cases of those with four 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% two-year survival rate, which is really unprecedented. We're seeing a median overall survival, and the data are still maturing, of 21 months.

And this is way more than the 10 - 14 months that has been the best case reported in the current standard of care regimens. And then we also are 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're years past getting oxaliplatin, still have the sensory neuropathy that's the scourge of treatment with that drug. It saves lives in some cases. It extends lives in others, but you're always reminded of it if you have that side effect of neuropathy. And even though we're going for approval first in late-line therapy, the application that seems even more exciting to me is the application in early-stage cancers. So when you give medical treatment before surgery, we call that neoadjuvant therapy.

We have three studies, the NASCENT, Unicorn, and Neo-ACIS 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. 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 three treatments. The preliminary data that we're seeing with BOT/BAL, everywhere we look, it's active. We hope that that will really translate into lives saved.

Garo H. Armen (Chairman and CEO)

So on that note, Rich, if we look at the landscape, and you remarked about the broader activity of BOT/BAL. And given the fact that we've treated over 1,200 patients, we had a pretty good sense of the toxicity profile and the transient nature of some of the toxicities that we've seen. And jumping ahead, because you've worked in a regulatory environment pretty much all 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 because, as you remarked, if we do randomized trials in every single indication, patients will wait a long time for access, wide access. So why do you think there's this hang-up?

Why also do you think, or how do you think, rather, can the regulatory system evolve so that the precedent-setting blockages are not going to be the drivers of future decision-making?

Richard Goldberg (Chief Development Officer)

That's a complicated question. Even when there are early indications of dramatic tumor shrinkage, such as we're seeing with Bottbell, the regulatory environment is such that the FDA still requires proponents of new approaches to perform large phase III trials with hundreds of patients that 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 more 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 hope to accomplish this with IO regimens without the side effects of traditional chemotherapy-based regimens is why Bottbell were 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 you had to do a phase III trial. And fortunately, as you'll hear from our colleagues from the Canadian Cancer Trials Group, they had approached us with an idea for a study 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 did present 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 Bottbell 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 move at the same pace as the science. We believe that the regulators need to reflect upon and update the approval process.

Garo H. Armen (Chairman and CEO)

Thank you. And we'll come back to you. But on this very important note, let's go to Dr. DeVito. Dr. DeVito, your background as an immunologist turned oncologist is fascinating because it'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, just to start?

Nicholas DeVito (Assistant Professor of Medical Oncology)

That's a great question. So as Garo mentioned, I came into oncology from a background of immunology and an interest of cancer vaccines, which are obviously limited by immunosuppressive mechanisms that compromise their efficacy and have led to a lot of unfortunate failures. But I have viewed the mere existence of a cancer inside someone's body as an immune failure, as immune surveillance that didn't happen. I think when you reframe oncology like that and you come into this with that kind of mindset, you start to 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, 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, is what I've always seen in clinic. It is really wresting back control by saying, "This is my immune system attacking the cancer. This isn't me surviving chemotherapy or something like that." I think that that's extremely meaningful to people. 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.

Garo H. Armen (Chairman and CEO)

And so you embarked on a very courageous, I should say, unorthodox trial because the way of thinking about things 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. And of course, as we adhere to that practice, patients are getting sicker and sicker and sicker. And the more sick they get, the more difficult treatment becomes for them. So can you tell us a little bit about your trial? And 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.

Nicholas DeVito (Assistant Professor of Medical Oncology)

That'd be lovely.

Garo H. Armen (Chairman and CEO)

Yeah. Thank you.

Nicholas DeVito (Assistant Professor of Medical Oncology)

Yeah. So this is referring to BB-ACCO, or botensilimab and balstilimab optimization in colorectal cancer. And it was a first-line trial in microsatellite stable colorectal cancer patients without liver bone or brain metastasis, which we believe to be immunosuppressive sites that we still need to learn more about so we can overcome in the first line. But it's first-line BOT/BAL, no chemotherapy, in stage four 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. So that's sort of one metric that I would put out there is that we're going to be able to present that data, hopefully, early next year, which I'm very excited about. But this trial came purely from a place of empathy. I thought about what I would want if I was diagnosed with stage four colon cancer.

I work on cars. I play music. I have two young boys. I'm active. I don't want neuropathy from oxaliplatin. 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, and that's exactly what one of our patients, who's 30 years old, came in with lung metastasis after not getting scans for stage two 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 trial, and he's done amazingly well. He says that I'm a celebrity in his house, apparently, because they came up with this trial, but it really aligns with exactly what he wanted.

He's like, "Let my immune system get a shot before I have to go down this road of FOLFOX and getting side effects that could derail all of my family plans and all the things that I'm normally doing in my day-to-day job. I'm the only one that's working right now. I need to be there for my family." And he's done great, and he's tolerated everything really, really well. And really, the side effects to BOT/BAL, I think, are so much more manageable once oncologists wrap their minds around them and they say, "Okay, we're just trying to prevent autoimmunity and trying to educate patients and educate providers so we can act early." And that's what we do in this trial. We give patients steroids that they take home.

If they develop diarrhea due to immune-mediated diarrhea and colitis, then they start the steroids, and they come in and get infliximab or another biologic, and we can turn them around. That's a lot different than Oxaliplatin reactions that end up in people in the hospital or where we have to do desensitization because it randomly at the ninth dose or something, it can happen anytime, leads to a terrible infusion reaction, or some of the other things like diarrhea during chemotherapy with Irinotecan while it's infusing can even happen, so a lot of these things are very different with BOT/BAL. And so that's 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 that they have a shot at avoiding chemotherapy entirely, like patients with melanoma and patients with microsatellite unstable colorectal cancers do. Moreover, one thing that I think is really fascinating here, and I think I hope that when we look back on this in 5-10 years, Garo, that we say, "Look, MSS-CRC, it's looking just like MSI-CRC, where if you give the immunotherapy first, it works much better." If you look at some of the crossover arms in the Ipi/Nivo trials, the patients who got chemotherapy first and crossed over to Ipi/Nivo still did worse. They still didn't have as high of a response rate.

So immunotherapy early is better before there's tumor evolution and response to chemotherapy and resistance to chemotherapy, and before patients are getting absolutely obliterated by some of these side effects from chemotherapy that just accumulate over time. Unlike BOT/BAL, where you're dealing with the side effects upfront, you're able to manage them. This is something with chemotherapy that just builds and builds. They just get worse as you go further along. And if you try to do things like FOLFOX reintroduction, you raise your risk of oxaliplatin infusion reactions. So it's very important to me that patients have this option and that they have it as early as possible, especially in a disease setting like stage four CRC, which we know is typically incurable. That may change.

In a population that's enriched for those that we've seen respond in later lines, like those with lung mets or peritoneal mets only lacking liver metastasis.

Garo H. Armen (Chairman and CEO)

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

Nicholas DeVito (Assistant Professor of Medical Oncology)

Use your most durable, tolerable therapy first, and let's get people into long-term remissions and spare them the toxicity of other regimens. And that's exactly right. That'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 and if you give targeted therapy first. So right on the nose, completely agree.

Garo H. Armen (Chairman and CEO)

Yet, another provocative question for you, as I did with Dr. Goldberg. In spite of all of this, patients are being held back from being exposed to drugs that could be the best option for them. Of course, Rich Goldberg said that the requirement today is randomized trials that have four, five, six-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. How do we, I mean, if you were the FDA commissioner today, how would you practically change this archaic paradigm that really is based on precedents, based on an old generation of drugs, rather than embracing new innovative drugs? How would you do that?

Nicholas DeVito (Assistant Professor of Medical Oncology)

Yeah. Why are we so wed to the mustard gas? I guess it's the phrase that I always say. Chemotherapy, in my eyes, is the horse that got us to the car, and now we need to get in the car and drive, and the car is obviously immunotherapy here. Let's get going. Let's hit the gas, and the way we do that is we have 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 think that there is a patient population that you can select for to try highly promising agents like botensilimab in first line, obviously under a consent and a protocol and with a plan like what we have for BD-ACCO, which is where we give BOT/BAL, we scan at six weeks, we monitor circulating tumor DNA, etc. We monitor patient symptoms, and we can rescue with chemotherapy and add it on if we need to. What that does is it opens up the window. It gives us a foothold. It gives us that first rung on the ladder and helps us say, "Okay, who's responding first line and can really, really avoid chemotherapy entirely? And what are the resistance mechanisms in the absence of chemotherapy and other variables?" Thinking from a very basic scientific standpoint, we want clean outcomes here. We want clear answers.

So if we want to learn our biomarkers, they're not going to be in the third and fourth line necessarily. They're probably going to be in the first line where there's less patient and tumor heterogeneity. There's more similarity between the diseases. So if we can define those biomarkers by giving effective therapies first line, and we can kind of open that door up a little bit, we're only going to increase it from there. And chemotherapy will start to become something that is really just like salvage when everything else has failed and we know we still have more work to do on the research side.

Garo H. Armen (Chairman and CEO)

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, and how did you resolve?

Nicholas DeVito (Assistant Professor of Medical Oncology)

Yeah. It was incredibly difficult. I mean, I know you've heard this story, but I'll repeat for everybody on the call that in the 2022 SITC hot topic session, I saw the BOT/BAL data and leaped out of my seat and was like, "Why am I the only one standing up and looking around? I was just this man on an island, and I didn't really understand why people weren't as excited about the data as I was." I'm like, "Just get it first. Give people a shot at it." I immediately wrote the trial after that, on the plane home, just started crafting it. The knee-jerk response from almost everybody, with a few select people, was like, "That's a really good idea, and you'll never pull it off. It just won't happen." We develop drugs late line, and then they slowly move back into the first line.

You combine them with chemotherapy. You don't mess with the stuff where you're giving it by itself. That doesn't make sense. FOLFOX has been given for 50 years, which brings on, of course, the most dangerous phrase in the English language, which is, "That's the way we've always done it." So that being said, this stick-to-it-ness of, "That's the way we've always done it," was a real barrier. And I had to kind of keep pounding the pavement and saying, "I guarantee this is something that patients would sign up for and that they would be interested in." So I received no internal funding.

There's really not a lot of funding for investigator-initiated trials, which is a totally different issue for a different day about how we need to do more of that and let, hopefully, some physician scientists like myself and others who are out there seeing patients, but also in the lab and understanding how we get from one side to the other, let us run some of these trials and come up with these innovative ideas and appeal to our patients. And it really didn't happen. It kind of languished for about a year and a half. And we were extremely fortunate because I kept trying to apply for different opportunities and finding different grants and everything else. And Gateway for Cancer Research ended up funding us.

And they were enthusiastic beyond my wildest dreams, really, because they said, "We whittled this down to 32 trials, and yours was the clear winner. This is what we will fund." They've been extremely involved since then. They have patient advocates as well who have said that this is what patients really would prefer is to at least have an option towards immunotherapy. And then we hit the heartbreak of the FDA after that, where we were essentially told that you must scan these patients at six weeks or you cannot proceed with this trial. This raises trial costs tremendously. It doubled our diagnostic costs. And that was difficult when all of our money comes from a foundation. And then we had to put some internal Duke money towards that, which was not easy.

Frankly, we have an amazing GI oncology research group, nine physicians and a great research team who really were all behind us and said, "Let's get this done. Let's get this over the finish line. You got it this far. You got $250,000 from Gateway. Let's go." And that's what happened. And the entire trial of 15 patients is being executed at a pretty low cost, I think. And it's happening very fast. And again, recruiting as many patients as we have, as fast as we have, that is a testament to the demand. There's nothing I can say that beats that. So it has been a long and difficult road, but it's 100% worth it. I would do it 10 times over again, even if it took twice as long.

Garo H. Armen (Chairman and CEO)

Gateway is happy so far.

Nicholas DeVito (Assistant Professor of Medical Oncology)

They're thrilled. They just invited me to a gala to speak, and they're saying, "We want to get some of the patients from the trial involved and giving their stories." So stay involved with looking at Gateway's website. You'll see things about BD-ACCO start to pop up over time. And I think you'll see at least two or three of our patient stories show up on there, including the 30-year-old with lung metastasis that I mentioned before.

Garo H. Armen (Chairman and CEO)

Wow. That's terrific, so I'm going to switch to Chris O'Callaghan and then we'll come back with some questions for everybody as well. And of course, we have questions from the audience. Chris, you were exposed to BOT/BAL maybe about 2 years ago. And you have been, after us, a trial. Now, if you can sort of go back and recount, what was it that drew you to us? Because you've done a lot of trials, and your business is not just to generate revenues because you're getting funded by also some government entities. But you wanted this trial for a reason. And if we can get into your head and tell us that, then I have a couple of additional questions for you.

Chris O'Callaghan (Senior Investigator)

Sure, Garo. It's a pleasure to be here and to speak on behalf of the trial that we've proposed. I'm a member of the Canadian Cancer Trials Group, as you know, and the group has been in existence for 45 years, but more importantly, related to this particular subject, we've been doing colorectal cancer trials in an international collaborative environment for 25 years, and we're a little bit different. We're on the back end of where Dr. DeVito was. I applaud him. I think it's incredibly exciting that his trial is taking immunotherapy to the front, but we also have to remember that there are patients who exhaust all available therapies out there and are still looking for options who are otherwise fit and ready to continue to take more treatment, and that's where we focused on.

And we've done a number of trials in that patient population of colorectal cancer patients who are at the end of their ropes and have exhausted all other lines of therapy. And one of those trials in the early days of the immuno-oncology revolution was a study in which we took two agents that targeted similar receptors as bot and bal, and we combined them. And our feeling was that in the microsatellite stable population or the cold tumor population, as you've noted, that there was still a possibility that we could overcome that coldness, if you will, by synergy with different approaches to stimulating the immune system. And that trial was a phase II trial. It was positive. And I have to admit that I was a little bit surprised at the time. It was a bit of a Hail Mary pass for us.

The trial came out positive for overall survival, for quality of life benefit. We were excited by that. Serendipitously, we became aware of your work with bot and bal around that time. Quite frankly, your results look even more impressive for those agents. We were looking for an opportunity to continue our work and to demonstrate proof of principle in a phase III study where we could answer the question definitively that dual IO therapy works in these patients. That's the reason we approached Agenus. We are very excited as we embark on opening up our CO.33 or BOT/BAL trial.

Garo H. Armen (Chairman and CEO)

When you talked about the other trial, Chris, I suspect the reason that it worked, but it wasn't blown you away, is it because the molecule didn't have the turbocharging capabilities that Bot perhaps brings to the party?

Chris O'Callaghan (Senior Investigator)

I think that is our—that is certainly our hope on the basis of what we're seeing with the results that you are producing. The phase I and phase II studies that you have done really outstrip the results that we saw in our combination trial. I think that it's one of these really great positions where we think that there's been a proof of concept for our trial that has demonstrated that immunotherapy can work. The question is, if we use the best immunotherapies that we can get our hands on, can we show that that works even better?

Garo H. Armen (Chairman and CEO)

Thank you. Now, a couple of days ago when we were talking, you mentioned we were talking about logistical steps towards enrolling patients. Of course, we have finalized our agreement with you, and we are now ready to go, so to speak, to enroll patients. And you told me, because I always push, as you're well aware, and the push is, "Since we've got everything in order, why don't we enroll patients tomorrow?" And of course, I know that is not possible, but why not? But you gave me a couple of pieces of news that reflected the level of enthusiasm and engagement by the participating centers and physicians. If you can talk about that, what is happening? Why are the people excited about this? And then another follow-up question for you after that.

Chris O'Callaghan (Senior Investigator)

Sure. So the first thing I should say to you is that we're putting together an international collaboration. Ourselves in Canada, we have experience and decades, quite frankly, of history in collaborating with other groups like ourselves around the world, most notably in Australia, New Zealand, and France. And so when we came to you, we had put together this triumvirate, if you will, of three regions around the world that want to enroll patients. That said, Canada will lead the way. We will be the first off the mark. And I'm delighted to let you know that we have submitted our clinical trial application to our regulatory authority, Health Canada, already. Health Canada will require a 30-day review period, after which we will be what we call centrally activated and ready to go.

But notably, the enthusiasm around this trial is such that at least two of our lead investigators in provinces, the major provinces in Canada, in Ontario and British Columbia, got their ethics submissions in within six days of our submission to Health Canada. That is utterly unprecedented, and like Dr. DeVito said, it's a clear reflection of investigator enthusiasm to trial these agents.

Garo H. Armen (Chairman and CEO)

So when we go through with this, we've talked about enrollment timelines. And of course, one of the attractive aspects of working with you was not just your team, but your ability to work with the centers in Canada, France, Australia, and bring on patients very quickly and do this. Of course, the quicker you enroll trials, the more economic the costs are, plus the subsidies that are also available to you. So with all of that and with the initial signals that you're getting, what can you say about enrollment timelines?

Chris O'Callaghan (Senior Investigator)

Let me tell you that the trial that I mentioned to you previously, which we call our CO26 trial, the phase II trial, we enrolled 180 patients over 10 months. Month on month, our accrual was better. In the final month of that trial, we enrolled 39 patients from Canada only, which I think was, again, as Dr. DeVito had noted, it was a real reflection of an unmet need, a patient desire to attempt to benefit from immunotherapy, and investigators' willingness and belief in the use of immunotherapy.

So if you think that we can put 39 or 40 patients a month on in Canada, our population base of about 35-40 million, and we triple that or more than triple that by engaging Australia, New Zealand, and France, I think our legitimately conservative target is that we average over the life of the trial 60 patients a month, and so in the context of an 834-patient sample size, that is a pretty expeditiously recruiting trial.

Garo H. Armen (Chairman and CEO)

Thank you. Thank you for that. And it's really a privilege to work with like-minded internal experts and external experts like you and Dr. DeVito and, of course, our very own Dr. Goldberg, Dr. O'Day, and our Chief Commercial Officer, who is here as well, Robin Taylor, who might as well be a physician. He's a scientist, but he knows the field of CRC inside out based on his previous experience at Genentech and Seagen. So it's really a wonderful outcome for patients because we want to get to the finish line as soon as possible. But more importantly, we will also explore the more expeditious ways forward, meaning potentially pressuring the system to accept our accelerated approval application when that decision is made.

And of course, we know we've hit some resistance on that in the past year, although that resistance seemed to be a bit more moderate when we encountered the FDA this year. But we can talk about that separately. Now, let me switch gears a little bit and go to Dr. Jennifer Buell. And if we can bring Jennifer Buell here. As you know, we started as an immunotherapy company a long time ago. That is for the audience to know. It's been 31 years. And as the Irish say, this is not for the faint-hearted. And no pun intended because you're Irish, Dr. Buell, not by birth, but by heritage.

But if you look at what we've done, how we expanded our immunotherapy armamentarium, because I say to people like the military system, it's silly to expect that a single agent or a single pathway is going to get the job done because the immune system is like the military fighting an enemy. In this particular case, the enemy is cancer. And some time ago, we expanded our efforts to cell therapies. And as you go from molecules to cell therapies, I always say, and sometimes you'll ridicule the fact that you're getting into a more and more intelligent system. Cells are more intelligent than molecules. And of course, our own invariant NKT cells are the most intelligent cells of all of the immune system. And so we did this, and we segregated the companies because the manufacturing model is different, of course, going from molecules to cells.

And we did it also because there are synergies between cell therapy and our molecules that constitute the immuno-oncology armamentarium. And then you also took the concept to another level by getting into an engagement with the government and government's interest in all of this. So if you can give us a flavor about the synergy in cancer and also the capabilities of these cells beyond cancer.

Jennifer Buell (CEO)

I'm so happy to. And what a perfect segue, given what you just heard from Dr. DeVito and Chris. The immune system, as we observed, following chemotherapy, does become somewhat incompetent. It's unable to actually do its job. And what we identified early on is that there are certain cell types that actually do the job far better than other cell types. And that's what brought out MiNK, MiNK Therapeutics. So the invariant natural killer T cells, as you've mentioned, they're rare cells. They're one of the most highly conserved cells in immunity historically. They've been around, identified for the longest period of time. But they are the rarest. They make up less than essentially 0.1% of your circulating lymphocytes. And that's because they're so potent. They act like first responders. These are, on one hand, they can kill dangerous cells directly.

And on the other, they're waking up the immune system to fight back. So your immune system has two major branches for those who aren't immunologists. And that's innate immunity, which provides broad and rapid defense, as well as adaptive immunity, which we came to know far better during a pandemic. That part of your immune system mounts a bit slower, but it's highly specific, and it's somewhat long-lasting directly against a particular threat. So most immune cells specialize in one branch or the other, innate or adaptive immunity. The uniqueness of iNKT cells is that they actually are unusual because they bridge both arms of immunity, both innate and adaptive. And they're really unique in doing so. So they respond quickly, like innate cells. They release cytokines, different chemicals that effectively can operate within minutes. They can kill or lyse cancer cells. They can also clear infections.

At the same time, they influence adaptive immunity, like T cells that you hear so much about or B cells, shaping the memory. That long-term memory response is what is necessary for long-term durable anti-cancer or anti-tumor immunity or anti-infectious immunity, so these make iNKTs really powerful coordinators, as you've mentioned. They are intelligent. What we've seen is data in cancer, which I'll speak to in just a moment, as well as in severe inflammatory or infectious diseases, including pulmonary diseases, and that's where the immune system is really disorganized, so MiNK, as an entity, launched as an independent company in 2021, and it does work together with Agenus as well as independently. It's one of the most clinically advanced companies developing iNKT cells.

So unlike T cells, which you hear about, or NK cells, which you also hear more about, iNKT cells operate through a very specific, essentially, it's called a glycolipid antigen. I don't want to be too technical, but it's an antigen that's really common in all of us. So we could deliver these cells. I could take them from me and give them to you. You won't reject them. It's essentially an invariant T cell receptor. So the cells recognize this antigen. It enables the cells in cancer to essentially infiltrate tumors and reprogram the microenvironment. And it's essentially this dual mechanism that directly kills, plus the orchestration, to modulate different cells and immunity. Now, these are naturally resistant to graft-versus-host disease.

And that's another area where we are working with the government as well as with an institution with non-dilutive grant financing to advance these cells in these disease settings.

Garo H. Armen (Chairman and CEO)

Thank you for that. And so why is the government specifically now, as opposed to 10 years ago? Although I might add, 20 years ago, when 9/11 happened, we were relatively an unknown quantity as a company at the time. But we had an agent called QS-21, which we still have with a new means of producing it in large quantities. And we were contacted by the government because they considered QS-21 as a potentially a biodefense agent because then the country came under attack. And the concern was that we may next encounter things like anthrax and other means. So what is happening right now that is generating interest, particularly now?

Jennifer Buell (CEO)

I'll tell you. When we launched the cells in clinical trials, we effectively started in 2020. And it was at the time when the pandemic was really just becoming identified in February of 2020 in the United States. And it very quickly overwhelmed the ICUs. We talked to the FDA about the preclinical data we had that showed that these cells actually prolonged survival in influenza and pneumonia models and actually restored immune function and improved oxygenation in the lungs by repairing cells within the lungs. So the agency cleared our ability to start a clinical trial. We did so. We published these data in Nature Communications, and they're really quite exciting for us and part of the reason why they can, we believe, that they can be very important, particularly in protecting our nation from different infectious threats.

So what we showed is that in our clinical trial now published, that when you administer just a single dose of about a billion iNKT cells, they very quickly reset the immune system. They help the body fight opportunistic or resistant infections, and they protect against secondary infections. And patients in the ICU, they're intubated, undergoing procedures, blood draws. They're vulnerable to infections. They're quite sick. And in that setting, we've shown not only that we can clear primary infections and restore oxygenation to the lungs, getting patients off of ventilators very quickly, we've shown that we can also prevent secondary infections. And those secondary infections are generally what causes the high death rate in patients in the ICU.

There were two opportunities for us in those settings that showed that not only can we help patients immediately with the threat that they're dealing with and the pathogens that they're exposed to and fighting, but also we can prevent secondary infections. That was really illuminating for us. When we think about the types of threats that we demonstrated in our clinical trial, we saw that patients who had either recovered from COVID or were infected with COVID, we could address that complication not only in patients that were on mechanical ventilation, but also those patients who are on the most severe form of life support called VV ECMO. We could administer the cells, and they do not clog the oxygenator, which is a problem with other immune cell types.

So they're really broadly active, and they can be broadly used in an ICU setting on top of steroids. That is of great interest, not only as we face our annual threats of influenza and pneumonia in our country, but also as we contemplate preparedness for other threats that may be imposed upon us or biowarfare. We have shown and will be publishing relatively soon some very important data on the effect of the iNKT cells in atypical pneumonia. And these are pneumonias that are generally caused by fungal infections. And those are of high concern for potential biologic threats. So we have been talking certainly with clinicians who are quite interested, but also with government agencies who would like to see these cells advancing relatively quickly.

Again, Garo, I think it's important to note that these cells can be delivered without HLA matching, which is unique, as well as no lymphodepletion. Typically, when you're administering a cell therapy, the cells could be rejected if you don't administer high doses of chemotherapy to deplete a patient's immune system. And in those settings, you're killing the actual cells that you need. And the way that we could use the INKT cells, and because they have a common receptor, common in all of us, we could administer them without depleting a patient's embedded immune system, their active immune system, which is such an important feature of these cells, not only for infections, but also for the disease setting that I mentioned, GVHD. Very important.

Garo H. Armen (Chairman and CEO)

And I know that there are other logistical advantages that may accrue shortly in terms of both storage and transport of these cells. We don't want to let it out just yet, but I think you're working on some very exciting developments here. And the government could become increasingly a major stakeholder in all of this in driving some of this progress forward. Now, of course, we as Agenus are delighted that you have taken the company to these exciting territories. And not only do we have the synergistic benefit of iNKT cells in connection with potentially using as combination treatment for cancer patients, but the standalone opportunity in areas outside of cancer is also very exciting. And we're very, very delighted that we're a major stakeholder in here, both from a synergistic perspective, but also as an owner of this entity. Agenus owns about 48% of MiNK.

We don't want to use that as leverage, but on the other hand, it is a major benefit for both companies for us to be intertwined in that way. But thank you very much. We're now pushing 505, actually. We can choose to show Jennifer's, not this Jen, but one of our patients, video, if you will. This is a very touching video. It speaks to Dr. Nicholas DeVito's point about life with chemotherapy in the same patient versus life with an immunotherapy. If we can roll that video, Andy, that'd be.

My name is Jennifer. I am from Uxbridge, Massachusetts. I am a mom of two boys. And I love to climb mountains. I love to go hiking. And then the doctor came in. And he stood by the side of the bed. And he said, "We found a mass." And I think I went, "No, my goal is to stay here for as long as I can to enjoy kids." And then the plan was for after surgery, you get three more months' worth of chemo, and then we do a CAT scan. Every other week, I'd go to bed for four days, and I wouldn't eat or drink. And I couldn't really talk to anyone. My nurse, Terry, is saying, "You should consider clinical trials." And I said, "Okay. Do whatever.

I'll do whatever I have to do." Like, I saw a little bit of light, but I didn't dare hope yet at that time, and the infusion was easy, and we left being a farmer, and I wasn't sick going for an infusion now. I go in for my infusion, and then I hop in my car and crank my radio up high, and I drive home, and I get home, and I cook dinner, and I walk my dog, and I appreciate how good I feel. Now I feel greedy. Now I want to see them be adults, and I feel like I can have that glimmer of hope. This opportunity to participate in this clinical trial has been a game changer, for sure. I would hope that it would become approved. Just based on it, it just has been so easy for me. It's wonderful.

I'm grateful that my oncologist, thank you, Matt, thought enough of me to fight for me to get me into this clinical trial. It's been amazing.

So with that note, I think it's all of our moral responsibility to work collaboratively, particularly with the new leadership in Washington, in the health agencies, the FDA with Dr. Makary, to make sure that patients do their best treatment options as quickly as possible. I mean, waiting for 5 years for a randomized trial readout before patients get wide access to drugs like botensilimab and balstilimab is really not an acceptable outcome for us. And for patients, it's not just for us. It's not acceptable for patients. So in my closing remarks before we take on questions, I know that in everybody's mind, as a company, we've had challenges. Being around for 31 years is not an easy undertaking. And 31 years with unwavering commitment to the belief that immuno-oncology would be the holy grail to curing cancer. And it has come with its financial challenges. We have persisted.

It has come with its regulatory challenges. We have persisted. And here we are. Here we are at a point where I think we're seeing the light at the end of the tunnel on all fronts. And I'm delighted that, for example, in our recent undertaking with Zydus Lifesciences, that we will be given the opportunity on all fronts because there's a sharing of some of the burden in terms of our manufacturing burden to be transferred to Zydus and for them to explore other opportunities with other clients because we have a state-of-the-art manufacturing facility in Emeryville that will become a facility of Zydus with us having access to it for our own needs. That transaction is slated to close soon. And I'll tell you what soon is because this is a point of question among investors and others.

There are so many bureaucracies, like in anything else, to overcome, and when we entered into this collaboration towards the closing, the first challenge was Hart-Scott-Rodino clearance. I'm very, very delighted to announce that we have cleared HSR just in the last couple of weeks, and the next hurdle is a hurdle that I wasn't even aware that existed. That will be a hurdle with the Treasury Department that is particularly concerning companies that get into business with U.S. companies, and that hurdle is expected to clear in the next two to three weeks. After that, we should very expeditiously be able to close the transaction, so I will end my talk. I want to thank our participants because they have been the real stars of this session. If there are questions for me and our participants, all four participants, please do so.

Stephanie Nakar is going to be moderating the question and answer period. So go ahead, Stephanie.

Great. Thank you very much, Garo, and thank you all for your continued engagement throughout the webcast today. It's been fantastic, and we've had a number of questions already come in. If you didn't already miss the beginning of the call, you are able to submit questions either via text or via email. Please text 510-323-5188. Or you can send an email to [email protected]. But we do already have a couple of questions come in. So let me go ahead and get started with that. Some of the questions, Garo, actually did have to do with the status of the Zydus collaboration. And so thank you very much for addressing the state of that transaction and the next steps there. We do have some questions here related to the phase III study. The first question, I will ask Chris to go ahead and answer.

And you did provide us a great background, Chris, of the collaboration and the interest that CCTG had in conducting this study with BOT/BAL. The question here is related to, can you share some additional resources that CCTG provides the partnership? And what does the monetary commitment look like in order to execute this study?

Chris O'Callaghan (Senior Investigator)

Sure. Thank you very much, Stephanie. The CCTG has a long history of executing clinical trials. As I mentioned to Garo, we've been around for 45 years. As an academic cooperative group, we are capable of doing everything from phase I to phase III. We don't limit ourselves to colorectal cancer. We research all types of cancers. We research all modalities of therapy. We are really a clinical trial organization. We are renowned for our excellence and our ability to get those trials done. That said, a large phase III trial like we have proposed and that Agenus has agreed to support, of 834 patients, really requires an international effort. Thankfully, we have cultivated a longstanding and productive collaboration with other groups like ourselves around the world, specifically the Australasian Gastrointestinal Trials Group in Australia and New Zealand.

We have done multiple trials successfully in this same patient population. We've done other GI trials with our Unicancer colleagues who are a federation of French cancer centers over the years. And bringing all three of our organizations together in the context of demonstrated abilities to recruit patients from this population really provides an assurance that we can get this study done. And we should be able to get it done in a quite timely way. I know it's never fast enough. It is a requirement for regulatory authorities around the world that we demonstrate these positive phase III studies. So we have to do it, but we need to do it quickly. In terms of the financial support for the organization, the Canadian Cancer Trials Group is funded in our core funding from the Canadian Cancer Society.

We are a major program grantee of them and have been for 45 years. We leverage funding, core funding from the Canadian Cancer Society from a variety of other sources. Academic grants are one. Pharma support, unrestricted pharma support is another, but it works out to about 10-1. We are a solid, stable organization able to conduct and fund the trials that we do.

I see. And do you see any gating steps in actually initiating the phase III study this year? And you already shared a little bit about the number of patients that we anticipate enrolling. But maybe you could share a little bit more about the scheme of the study design itself and what the control arm will be.

Yeah. So the study is about as far away from the patients that Dr. DeVito was describing as possible. So the typical patient that we would be considering for our study is a patient who has undergone the full trajectory, the full gamut of the treatments that are available for their colorectal cancer. Progressively, their disease has become resistant to one after the other. And there's a large proportion of these patients who end up in a situation where there are no standard available treatments for them. And those patients are usually still fit and healthy and looking for treatment options, looking for options to extend their lives. And so that is the population that our trial will target. They will be patients who have microsatellite stable disease. So that's what would have normally been considered a cold tumor.

We will enroll those patients in a one-to-one randomization so that half of the patients will receive bot and bal according to the same treatment regimens that you have been using on your phase I and II studies. The other 50% of the patients on our trial will be patients who will proceed with what are known as best supportive care measures. That is actually, it sounds terrible, but it is appropriate in the context of patients who have exhausted all other lines of therapy. There really is no available therapy left for those patients. That trial will recruit, as I said, 834 patients. We're projecting that recruitment to occur over a period of approximately 20-24 months. There will be a period of follow-up as we mature, wait for the data to mature. Then there will be an analysis.

We're confident and cautiously optimistic that it will be supportive for registration of bot and bal internationally.

Very much, Chris. Wonderful. And stay tuned because I may call you for additional questions as they come in. But still on the topic of the phase III, Garo, I have a question here for you. I know that there's been a lot of work that the organization has done, certainly, even as we've announced recently with the outcomes of the regulatory and the FDA meeting just in July. But there was a question that came in that, why the July? Why has the study, since the completion of the phase II, been delayed by approximately 18 months? So maybe can you shed some light on that, please?

Garo H. Armen (Chairman and CEO)

First of all, at last year's FDA meeting, about a year ago and change, the FDA was still insisting on doing a three-arm trial. Even though we had brought in some of the experts that had experience with BOT/BAL and patients that had experience with BOT/BAL to submit that doing a three-arm trial would not be ethical based on the data that was generated. It would not be able to accrue patients expeditiously. It took the FDA about a year with some minor additional data to come to the conclusion that a three-arm trial was not necessary, that a two-arm trial would be the way to go. That delayed us by at least a year. At this year's meeting with the FDA, one concession, an important concession they made, was the fact that they agreed to a two-arm trial.

They agreed to the fact that contribution of the components were demonstrated. And so there was no real reason to probe that any further in spite of the fact that they formerly had engaged with us to tell us prior to that the contribution of the elements was not reached or was not satisfactorily demonstrated. And I might add that all of this is happening with not a lot more data that was presented to the agency. So there was a change of hearts in a favorable fashion. And we're delighted with that outcome, actually.

Yeah. Thank you for that further explanation. I know that nobody other than us would like to initiate this trial as quickly as possible with the hopes of getting this combination treatment to patients. But the longer-term follow-up, as you mentioned, was essential for making it easier for patients in this study and to show the evidence for the contribution of components. So thank you. We actually are going to pivot a little bit from the phase III late-line study. We've been receiving a lot of questions regarding our neoadjuvant strategy. So I'd like to bring Steven O'Day on to perhaps answer some of those questions. So firstly, we've done a lot of neoadjuvant studies with some of our partnerships and investigators. And one of the questions is, what else are we doing in the neoadjuvant setting? And are there additional investigator-sponsored trials that are planning or initiating yet?

Are there any other data readouts that we expect for the remainder of the year as well?

Steven O'Day (Chief Medical Officer)

Thank you, Stephanie. It's great to participate in this. Rich Goldberg has really brought this high, high level of GI understanding from a clinical and a patient and a regulatory perspective. And he's had 9 months to look at the data. I've actually had 8 years to look at the data and come from really the first revolution in melanoma. And it's really remarkable to see BOT/BAL perform in over 1,200 patients in many different settings. And I think what's clear is that there is a late-line setting across multiple solid tumors of patients having deep durable responses. That we know. And then it takes sort of brave, courageous trials to move earlier lines, just like we did in melanoma, from late-line to early-line metastatic that Nick has described. And we're looking forward to watching this really exciting data emerge in the next year.

But obviously all of our hearts, and I'm speaking for the melanoma community and the IO community in general, SITC and others, the neoadjuvant space where you have an intact tumor that has not yet metastasized and that serves as the education center for the T cells is phenomenal in terms of its ability to drive memory and tumor eradication. And we learned that in melanoma in the neoadjuvant setting. And what we also learned that what Garo brought up is the rapidity of these neoadjuvant responses is remarkable. People said it would take forever for the immune system to really reignite. When you have good drugs like in melanoma with first-generation molecules, it happens within four to eight weeks, dramatic.

What we're seeing with BOT/BAL in a setting with tumors that have historically not responded. We're seeing that an intact tumor in the early neoadjuvant setting. We're seeing the same kind of responses: quick, deep, and durable. Now we've explored in multiple ISTs, one in the U.S., the NEST trial in colorectal cancer, a second multicenter Italian study with colorectal cancer with one dose of bot and two doses of bal. We're seeing remarkable 40+% of patients within four to eight weeks are having complete or near-complete responses. Then finally, Myriam Chalabi has taken the same approach at the Netherlands Cancer Institute across multiple solid tumors. At AACR, she presented the first patients there at similarly high response rates, almost tumor agnostic. This includes breast cancer, triple-negative, ER-positive sarcomas. It's sort of mimicking the trajectory of our late-stage pan-tumor data.

So the data is consistent. It gets better as you go earlier. And when you have effective IO drugs, they work. And then finally, the rectal cancer space is hugely important for all the reasons Garo and others have talked about: the organ preservation, the infertility, the chronic toxicities that patients undergo with locally advanced rectal cancer. And most of our neoadjuvant data today has been in colon cancer. But Andrea Cercek has launched a neoadjuvant rectal study with bot and bal really to mimic the MSI high cohort that she and others have had paradigm-shifting treatments. So we look forward to watching BOT/BAL perform in a number of neoadjuvant settings in the coming 6-12 months and ongoing reporting of the data.

Yeah. Thanks, Steven. And related to that studies and other neoadjuvant studies, are we doing anything specifically to identify patients that have MSS disease? Certainly, we've also a lot of our focus is certainly on filling that unmet need in the MSS tumor types. But there's also data certainly that we have in MSI high as well. But one of the questions is, what are we doing with biomarkers otherwise to help identify those patients with MSS disease?

Yeah. So this is the holy grail, right, of MSS disease. In warm or hot tumors, we have some sort of okay biomarkers, not great: TMB, PD-L1 in some settings. These are very still suboptimal markers to really enrich for dramatic IO responses. But in the cold tumor settings, we've really struggled mightily. What's interesting about BOT/BAL is this 20+% deep durable response in an end-stage setting and maybe 40%-50% as we move further as this neoadjuvant data. It would be wonderful to enrich even further to MSI-H-type approaches. And so we are actively working both internally as well as external collaborations to really find ways to deeply enrich MSS tumors so that more and more patients can have these long-term benefits.

Yeah. Thank you, Steven, for that clarification. While I have you on the line still, what's coming next between now and the end of 2025? I know ESMO is coming up. Can you reiterate some of the data that we'll be sharing at ESMO and anything else that we can anticipate for the rest of this year?

Yeah. We're very excited about ESMO. We're going to be launching our basket trial in terms of investigators from around the world in terms of getting that ready for the end of year launch. We're also going to be presenting more data in the refractory setting, not just colorectal cancer, but many other tumor types. And I think what is so compelling to me and the reason I'm here and deeply invested is when you see IO therapy works, we know what good looks like, and Rich has talked about it. I've talked about it through my career. Nick is now in his emerging career seeing it. These deep durable responses, even if it's 20% of patients, that is a game changer for those 20% when you don't have other good options, and when immunotherapy works, you can have short durations of treatment with reversible side effects.

Then the real advantage is long-term survival without the need for additional treatment. We call it treatment-free survival. We're going to see more of that data in our refractory setting and then obviously more neoadjuvant data in the coming year.

Great. Thank you. And another question just came in, Steven, that I think would be great for you to answer. So related to the BOT/BAL phase III study, there's a question that has arisen. A lot of our studies have been in non-liver met patients. Can you describe any sort of stratification or inclusion in the phase III trial related to these patients?

Certainly, Chris can also answer this. I think the short answer to this is in the original first-generation CTLA4 PD-1 study that the Canadian group did. They saw a positive study in all comers. Obviously, non-liver mets are even more enriched for IO response. But there was survival benefit across all comers, meaning liver and non-liver. We have better drugs. Obviously, they had a 1% objective response rate in that trial with Durva and Treme, with n=100, so 1% response rate, but still had a survival benefit. We obviously have 20% or thereabouts deep durable responses in ours. You can just imagine why we would want to look at all comers as well as our subgroups. We think it will win on those.

Great. Thank you very much, Steven. Wonderful. I have a couple of questions for Garo related to some additional financing and some additional partnerships. One of the questions here is so much is going on within the government and at DC almost on a daily basis. One of the questions was just related to the India tariffs that were just announced. Did any of that impact our cost of goods with the Zydus deal or for the phase III development? And could you give any background on where you see that impacting or not impacting at all?

Garo H. Armen (Chairman and CEO)

I think the impact is a positive impact on us because while I'm not an economist, it's common sense that if there are tariffs on various countries like India, that means that anything that they ship from their country to the U.S. will be subject to a tariff or taxation. Now, by Zydus purchasing this facility, they'll be able to have a means of producing biomolecules in this particular case in a facility that is a U.S. facility that will not be subject to tariffs. So it's a big advantage, and so we're delighted with that outcome for our collaborator partner with Zydus. Now, in terms of financing, you ask Stephanie, of course, Zydus was the first step. We're currently engaged in multiple discussions with one particular discussion that is closer to maturity, if you will, that will result in a significant infusion of also cash into the company.

We haven't released the details of that. But all I can tell you is that the details are such that we will keep the right to BOT/BAL, which right now is a most valuable molecule for us for the major territories. That includes U.S., Europe, Japan, and South America. Those territories will still be with us with this potential transaction coming to a head soon. Now, if you'll let me, I know we're coming to our finale here in terms of timing. Let me first thank you, all of the participants on this call, for your time. We allotted an appropriate amount of time to cover all bases here. I want to thank our participating experts, internal and external experts, very much for your insights.

I'd also like to thank our collaborators, many of whom are on this call, and also our colleagues that are not just in science and medicine, but in all divisions of the company. They've worked very hard throughout. They have been dedicated believers in our mission. So I want to thank the entire Agenus team for making all of this possible. We are yet to reach our final end game here, but I think we're getting closer, and I'm delighted that our external environment, including our regulatory environment, may be moving in the right direction.

That will be a big, big advantage for a company that has dedicated its efforts to make sure that patients benefit and patients benefit in a meaningful fashion, not in terms of days and weeks extension in life, but in a manner that is going to be transforming their lives and the families' lives in every way possible. Thank you very much.