Agenus Inc. Aktie

Good evening, everyone, and thank you for joining us today. My name is Stefanie Nacar, and I'm Chief Communications Officer here at Agenus, and welcome to our September Stakeholder Webcast. Joining me today are Garo Armen, our Chairman and Chief Executive Officer; Dr. Steven O'Day, our Chief Medical Officer; and we'll also hear from Dr. Benjamin Schlechter of the Dana-Farber Cancer Institute.

Our discussion today will focus on the progress that we've made since our July webcast, including implementation of the ROBBIN Phase III neoadjuvant program, continued physician interest in the access to BOT+BAL and recent clinical and investigator-led activity that is helping inform the acceleration of BOT+BAL into the earlier disease settings. Following the prepared discussion, Agenus leadership, including Dr. O'Day as well as Robin Taylor, Chief Commercial Officer, will join Garo for a live Q&A. Questions may be submitted at any time during the webcast using the Q&A function of the Zoom event below.

Before we begin, just a brief reminder that today's discussion includes forward-looking statements, so please be sure to refer to our SEC filings for additional details also available on our website. With that, I'm pleased to introduce our Founder, Chairman and CEO, Garo Armen.

Thank you very much, Stefanie, and thank you, everyone, for joining us today. When we had this session back in July, we spoke about the financing that was announced then. And we also spoke about the strategic shift into the neoadjuvant setting in terms of our approval strategy. And at that time, of course, the concern was -- before that announcement, the concern was our path forward I think very few people were questioning the high activity of our product or combination, but people were more interested in how were we going to take this to the finish line. And certainly, the financing played a major role in addressing that question. And since then, our stock has reacted favorably by all standards. And we believe that some of the critically important risks associated with financing the company's future were at least removed for the time being.

Now we're not going to repeat that discussion today, but what matters now, and you're going to hear about this from Dr. O'Day and if there are any questions, of course, Dr. Taylor, how are we doing since then? What are we doing to execute towards that strategic goal of initiating and completing our neoadjuvant trial?

Now over the last few weeks, there were 2 important bodies of BOT+BAL clinical evidence that moved into peer-reviewed journals for clinical cancer research, which is the prestigious journal of the American Association of Cancer Research. And the longer-term Phase Ib study, which is in the refractory MSS metastatic colorectal setting, published shows longer-term follow-up and durability, and you'll hear about this also from Dr. O'Day, durability of responses in patients that respond. These are, of course, important studies for us.

The next one is the NEST neoadjuvant study, and that also talked about how we haven't had any recurrences since the study began. Now we're also seeing increased investigator interest in studying BOT+BAL in the earlier disease setting. Of course, shifting to the neoadjuvant setting for our approval strategy helped. But we're seeing also additional investigator sponsored proposals and studies for neoadjuvant. You're going to hear more about them, including the RECTIFY-1 study led by Dr. Ben Schlechter, and Dr. Schlechter is going to be joining us in just a bit. We interviewed him 2 days ago because of his patient schedule, and we're delighted that he had the time to discuss some very important points with us.

Now all of this is important because it gives patients the opportunity to be able to benefit from BOT+BAL. It doesn't change our course with the ROBBIN study. That is the strategic focus of the company, both for a financial allocation of resources and people allocation of resources. But it also reflects the broader clinical interest in asking what BOT+BAL may do before surgery and creates additional clinical trial access to patients. At the same time, physician interest in accessing BOT+BAL outside of clinical trials also continues.

We've had geographic reach and our access programs have expanded. We're seeing repeat interest coming from physicians. As you know, we have the French AAC program. And then outside of that, we have the Paid Named Patient Program, and those requests are coming in, and that demand is growing.

Now at Agenus, our development priority, as I said before, remains very clearly advancing ROBBIN, our neoadjuvant CRC study in the colon cancer setting forward. Steven will update you on how this program is moving forward. We've had some very exciting initial interactions. Well, they're not initial interactions anymore because I think we've covered the majority of the sites that will participate in this trial already.

We'll also discuss what we're seeing through our access programs in addition to what I mentioned before. So as I said, you'll hear from Ben Schlechter, Dr. Ben Schlechter of Dana-Farber, why the timing of immunotherapy may matter in colorectal cancer for the first time, why MSS disease has historically resisted first-generation immunotherapy, while we're seeing responses in BOT+BAL patients even in the late-stage setting where there's really no treatment options left for them.

So that's where I'd like to stop and turn this over to Stefanie to take the program forward.

Thank you so much, Garo. And with that, Steven, let's actually start on a conversation here together and kind of take -- take up where Garo left off. So when we announced the ROBBIN Phase III neoadjuvant study back in July, we had done a lot of work, you in particular, to define the study, the component that we received FDA feedback on, on those key elements of this program to move forward and really establish the resources to move forward, including the financing that Garo just alluded to.

So I know it's only been about 2 months, but there's obviously been a tremendous amount of work and activity from you and the team and the organization towards opening up this global study. Can you share a little bit about what has changed operationally since July and where the team is focused today?

Well, thank you, Garo and Stefanie. And boy, has it been a busy couple of months. Really unprecedented in my experience with excitement and enthusiasm. We obviously have a deep network of thought leaders and principal investigators around this very mature BOT+BAL program. But in July, we were focusing primarily on the design of ROBBIN, aligning with the FDA rationale for moving BOT+BAL into the neoadjuvant setting, a very important pivot that really optimizes the signal that we're getting with BOT+BAL with an intact tumor and draining primary lymph nodes.

But since then, our focus in the last 2 months has been really increasingly and almost exclusively a shift to implementation and start-up of this very important ROBBIN global study. This includes building and continuing to expand our global investigator and site network advancing the regulatory and ethics work required in the countries where we intend to conduct the study, establishing pathology and translational infrastructure and aligning our clinical, operational and drug supply functions around the study initiation.

There are a lot of individual work streams in the company right now involved with opening this global Phase III trial, and we are moving in parallel with rapidity and efficiency and excellence, and our goal continues to be enrolling the first patient in quarter 1, 2027.

Well, that seems to be a huge undertaking, but very confident, particularly even you are no novice to clinical studies being an investigator yourself before coming here to Agenus. So give us a little bit of a sense of the scale of that effort, Steven. How large of the clinical network are you building for ROBBIN? And what can you tell us about the geographic footprint, particularly? I know we haven't shared much about that as of yet.

So this is a Phase III global trial of approximately 850 patients. It will involve North America, Europe, South America and Asia. We are extremely mindful, and I am in control with my team of selecting high-volume and high-quality sites. And this is particularly important with a neoadjuvant study. It's really very different than studies in the late-stage metastatic setting. It's important these sites see the patients, which are high-risk Stage II and III cancer.

As you know, there's an epidemic worldwide. So these cancers are prevalent, particularly in the MS stable, 90% of all colon cancer. And most importantly, though, that neoadjuvant studies require multidisciplinary teams to identify these patients, become aligned around neoadjuvant treatment. Now this involves a medical oncologist clearly. But what's different here is we need alignment and leadership from our surgical colleagues but also our radiology colleagues, our pathology colleagues, our gastroenterologists and our research teams. And this is no small chore.

But our deep networks, my experience across 30 years in the clinic and networking with KOLs around the world has definitely been very helpful. But the data itself is what is most helpful and is really exciting people to participate in the trial. Most of the sites are major academic centers, but we're also selecting high-performing, high-quality community-based centers and networks as long as they're integrated in terms of the multidisciplinary neoadjuvant setting. Interacting with medical oncologists alone is simply not enough. In order to be successful, we need to align and the enthusiasm from these multiple stakeholders.

Thanks for that Steven. Question, so you just talked a little bit about the broad scope and your personal involvement in site selection as well, likely because of all of the relationships that are out there and the experience. Are these sites and some of the investigators primarily investigators that are already familiar with BOT+BAL? Or are you seeing that ROBBIN is also bringing in new investigators and institutions that don't have prior involvement or haven't really been connected much more broadly with the program previously?

So it's a combination. But I will say with over almost more than 1,200 patients treated in our Agenus-sponsored trials as well as our investigator-initiated trials across the globe, we have an extensive network of investigators and thought leaders, but what's interesting is there's also thought leaders and investigators that have been more concentrated in the neoadjuvant space, and we're leveraging this. So we are bringing in additional new thought leaders and investigators with a particular experience in neoadjuvant settings.

And as you know, in MSI colon cancer, there is now an evolving experience in this neoadjuvant setting for GI oncologists. And so we're really piggybacking and really driving that experience. And so the short answer is it's a combination of our existing, but a whole new group of investigators are seeing this data, have done neoadjuvant trials and want into this large global trial.

Yes. I think that we'll get to this a little bit later, but even more so recently, a lot more new adjuvant investigator-sponsored studies are launching as well. In our July webcast, right, we had Dr. Pashtoon Kasi with the NES 3 study and Dr. Benjamin Schlechter today, who started the RECTIFY-1 study at Dana-Farber. And then there's other neoadjuvant studies as well going on at MSK and then also in the Netherlands. So a lot of interest in the neoadjuvant setting, which I'm sure is a part of a lot of the excitement too, around ROBBIN.

Earlier, just getting back to something that you had mentioned though, Steven, about the multidisciplinary nature of these sites. You started to allude to this a little bit, but what is operationally a bit different about a neoadjuvant study like ROBBIN compared to a traditional later line study? And why is that experience so important as we think about appropriately and efficiently getting ROBBIN off and opening and enrolling and that consistency that you alluded to earlier across all these different global sites. Can you talk a little bit about that?

Yes. So let me build on -- I've obviously talked about the multidisciplinary alignment that's really critical. What people are very excited about is that this could be a paradigm shifting study that will not only reduce recurrences and improve survival, but deescalate chemotherapy in this very early-stage setting. So that's really important. But there are other issues here. In addition to aligning the medical team, there's health -- you're dealing with patients that are newly diagnosed. They're in health care systems expecting potential standard of care surgery and adjuvant chemo. Patients want more than that. Doctors want more than that. And ROBBIN trial inserts a defined treatment period before the surgery so that part of the process must fit within this established clinical pathway. I think patients are more than willing to delay their surgery a short period of time, given the data that we've shown that none of these patients have progressed during this period of time and the opportunity to improve survival and reduce chemo is a win-win for doctors, surgeons, medical oncologists and everyone involved.

So -- but you do have to identify the patient, you have to stage them. You have to identify their MS status, which is now routinely done in all colon cancer. And then you move forward in a relatively short interval and you need the teams to be ready and teed up. And that's what we're spending a lot of time talking to the teams and really being sure that they're set up for success. Success will require that patients be present, but also that the teams really function at a high level to get the treatment in and the surgery and the adjuvant therapy.

Yes. So that's a lot of coordination and across the different parties at the different sites. And you also mentioned pathology and the importance of that particular expertise within the multidisciplinary function because it's also a very important feature of how we're going to begin learning about the impact of BOT+BAL within the ROBBIN study. Can you share with us a little bit about what needs to be in place to ensure that the pathologic response, the assessments, right, we know that this is a huge milestone for us are consistent and rigorous across how it's going to be assessed across this large global study?

Yes. So I think what's important is we're not starting from scratch here. The neoadjuvant setting with immune therapy has been established in melanoma. It's also prevalent in breast cancer now and lung cancer in terms of neoadjuvant perioperative. So things are in place in terms of leveraging that history. But what's really exciting for everyone is that even though time to distant recurrence or metastasis in the cancer is the primary endpoint of the study. We will get an early readout after the first 8 weeks or so of treatment on the depth of this pathologic response.

And more important than ever in immune-mediated therapy, more so than chemotherapy or targeted therapy, the depth of these responses are so highly predictive of eventual metastasis. So we will be looking at complete and near complete responses, and that will give us a lot of confidence as we go through, and this will be centrally reviewed by the trial that we are consistent with our Phase II data and highly set up to succeed in terms of the primary endpoint of the study.

Now this does require that we coordinate this, and we have leading centers around the world that have a lot of experience with pathologic response, and we're leveraging and identifying these centers to help us coordinate and make sure that this is a rigorous process of pathologic assessment. We're also collecting ctDNA and other biomarkers that will also be very helpful, not in real time in this study, but it's important supplementary information as the -- as we wait for additional primary endpoint time to event.

Great. Thank you, Steven. And certainly, once the sites begin opening and enrolling, that's really where I think the attention natural will be like how quickly are we actually enrolling patients. What do you see from your perspective and your role? What will determine how efficiently ROBBIN moves from all of this builds up to the site activation into actual patient enrollment?

Yes. As Garo and I often discuss, it's not -- I mean, the first patient is very important, and we're on target. But we want to get really accrue quickly, and I think we're setting this up. So it's not the number of sites ultimately, although we're well set up with a global trial, but it's the quality of these sites and their enthusiasm and alignment around identifying and treating the patient. Colon cancer is common, but ROBBIN is enrolling a defined population of stage high-risk 2 and 3 patients that have -- so ideally, we look forward to, in parallel, opening a number of early sites and then obviously, as quickly as possible due to regulatory time lines, continue to open sites in early 2027.

Great. Okay. So I have one last question for you, Steven, before the live Q&A at the end. But for all of our listeners and the stakeholders that are following ROBBIN, what are the most meaningful indicators of progress between now and that first patient in that you just alluded to? And then as the study begins enrolling more so, what are you looking for?

So the first thing is the work we've done in the last 2 months, and we'll do in the next 2 months is really rigorously identifying sites that will succeed and produce rapid accrual and high-quality data. So that's number one. And then driving enrollment, and we have a plan for very active connection and really staying very close to these centers as they ramp up. So I think -- but I think in terms of ROBBIN, I think it's best to think of this in 3 stages. You build and activate the network. We're doing that with wholehearted enthusiasm, both from our team and our investigators around the world.

You then drive enrollment. And as these responses become apparent, it will only increase the enthusiasm of the sites. And then obviously, getting a readout of the surgical pathology results will be also very, very important. But we are on track to first patient enroll it in the first quarter of next year and getting some pathologic data in the second half of next year as we've outlined previously. But ultimately, it's all about can we -- through BOT and BAL and surgery, can we reduce recurrences and improve survival and at the same time, reduce the need for chemotherapy in a curative intense setting. And this will be the paradigm-shifting feature of the study.

Great. Thank you so much, Steven. Thank you for your time and walking us through that today. So Garo, I'm going to come back to something you mentioned earlier at the beginning of the call because this is another area where the team is really focused and also seen some meaningful activity since our last discussion in July. ROBBIN, as you mentioned, is clearly the company's development priority and our focus. But at the same time, as you've mentioned before, our kind of moral obligation that there are patients who need treatment today and physicians who continue to approach yourself and Agenus seeking access to BOT+BAL. Can you give us an update on what has changed across the access program since we last spoke in July?

So just to be clear, we have, as you know, 2 access programs in addition to any trials that are ongoing that allow a patient to have BOT+BAL treatment. One clearly stated is the program that was approved in France. And we have not disclosed the number of patients treated. However, we have disclosed the reimbursement revenue that we get from the French government every quarter, and we will be talking more about the progress that we're making there. So that's a very important program, and French patients have been privileged enough to have access to this and have the government reimbursement.

Now in addition to that, we also have the Paid Named Patient Program. And that's a program that allows a patient whose physician is seeing it appropriate to refer that patient to a country and a center where the treatment can take place. And these include, of course, as we've talked about before, the U.K., Switzerland, France can treat patients with Paid Named Patient Programs that are willing to pay out of pocket in addition to reimbursing their own patients. Belgium, Spain, Brazil, Argentina and the number of countries are growing.

Now under this program, a patient can request or the doctor can request to be treated for any indication that they seem to be fit for the patient. It doesn't have to be restricted by the ASC program indications or anything else. As long as there is data, and as you know, we have data on over 9 different kinds of cancers where we have shown consistent activity. In fact, at last year's ESMO in Berlin, there was an oral presentation where we showed the consistency of response rates in late-stage patients that have exhausted all other treatment options. So this is quite exciting actually. It's exciting because we're seeing the momentum develop.

And in terms of the named patient programs, for example, we have U.S. physicians referring patients to any country or any center where they can be treated with Paid Named Patient Programs. And as long as the physician sees it appropriate to -- for the patient to undergo such a treatment, they can get it. Now the unfortunate reality is that can you imagine a patient struck with cancer, they may not be in the best of health. They may not be in the best of shape to travel. But unfortunately, U.S. patient has to travel to some other country willing to pay out of pocket and be treated. And we hope that, that reality will change sometime soon. But that's the reality right now.

But one of the things that I wanted to also mention is that, as you know, Europe shuts down in the month of August. And in fact, increasingly, U.S. is also shutting down in the month of August. And we expected a slowdown in demand by doctors for August. In fact, we've seen a growth, not a slowdown, but a growth. And so those are very indicative of the fact that there is substantial enthusiasm by physicians and by patients to be treated with BOT+BAL because it can offer them a hope and a reality of survival for an extended period of time.

Dr. O'Day always says the durability of responses with immuno-oncology combinations is really very notable. And so that's what we're seeing, and we're very excited that the roster of physicians who are familiar with the data and are willing to treat patients is growing.

Great. Thank you. And I know that the team anticipates to share more specifics during our Q3 earnings update. But again, very positive that the interest still continues to grow even over these periods where we were expecting and anticipating maybe some leveling. But you've mentioned in the past, Garo, too, that not just the expansion of additional countries and making the access to BOT+BAL available for their patients, but you're starting to see physicians, repeat physicians treating multiple patients at their centers. What do you think is driving the physicians to come back and seek access for additional patients after they've initiated treatment?

I mean, Stefanie, this is a very important point. Of course, one very important aspect of this, and we've heard this from physicians that most recently have shown very high enthusiasm in participating in our trials, particularly the ROBBIN trial. One very notable reason is that, as I talked about a little while ago, for example, in the last few weeks, we had 2 publications discussing long-term outcomes for patients, one in the late-stage disease and one in the neoadjuvant setting. We expect more to come between now and the end of the year, of course. These are very important drivers, the credibility of the data and their own personal experience.

So if you treat one patient and you see something happening, you want to treat another patient. That doesn't mean that every single patient is going to respond, particularly in the late-line setting, that's not going to happen. But it's encouraging because it's last hope for patients. And hope is a very important element here, very important element because how could you tell a patient that we've exhausted all treatments, and there's nothing else we can do for you.

So we offer that last hope for the patients who have exhausted all treatments. And that's clear based on the data that's been published and presented. And we also hope for patients in the neoadjuvant setting to be treated less, I should say, less in a punishing way, more in a sustainable benefit. Dr. O'Day explained this beautifully. It's a very important point for patients. And in some cases, what we hope is that patients will be able to benefit from lesser surgery, lesser surgery, meaning some of these surgeries are quite radical, debilitating for the patient.

For example, if you have rectal cancer or colon cancer that's near the rectum, you have a life-changing surgery. I mean we have some patients, including relatives of our colleagues where they have been treated with radical surgery and life is never the same for them. And what we hope to do with the ROBBIN trial is to change that reality for patients. I think this is going to be a very, very, as Dr. O'Day said, potentially life-changing outcome for patients.

Yes. Thank you, Garo. And I know that you had just mentioned, certainly because of the different pathways of these different access programs, both being the French AAC as well as the Paid Name Patient Program, which is available across various countries around the world, that offers a lot of accessibility to patients, but that also comes with the responsibility that you've mentioned before.

So as physician interest grows, right, and these programs continue to expand, how are you thinking about Agenus' ability to support them in our infrastructure and our personnel? Can you maybe share a little bit about with our audience here what we're doing to ensure safety and our efficiency and then also our response time to support these patients and physicians around the world?

Of course. Let me step back for a moment and recount the fact that the last 2.5 years for the company have been one of the most trying periods in the company's existence. And what's confused us and our colleagues, our scientific, clinical and other colleagues is that we've seen some absolutely remarkable clinical outcomes, both in the late-stage setting and in the neoadjuvant setting across multiple tumors.

And I may want to remind you that we had another webcast a little while ago on December 3, where Dr. Christopher Lieu of Colorado, he said, there was a patient, he treated. It's in the webcast. And this patient has exhausted all treatment options. And he said our choice was either sending her to hospice or treating her with BOT+BAL. And this patient was treated with BOT+BAL and the patient is now alive after 2 years, essentially free of disease and conducting a regular life. Of course, this doesn't happen to every patient. But for the patient that this happens, it's a miracle. Nobody can deny that.

Now we have been of the mindset, Stefanie, that our responsibility as a company was to take the product to patients on a mass scale as expeditiously as possible. And one of the very important cornerstones of the strategy was to make sure that we have commercial product ready for patients when the product is approved. Now unfortunately, for reasons that everybody pretty much knows, unfortunate for the patients, unfortunate for our company and unfortunate for our investors that, that didn't happen as we expected.

However, we have lined up a significant amount of commercial product, commercial grade product ready. And that product, by the way, has a very long shelf life. So if we play right, which we are, of course, this product is good for essentially the next 10 years. And so from a product perspective, we have plenty of product, both BOT and somewhat lesser BAL, but we have the pathway to make more BAL, commercial BAL very, very quickly. And so we're -- we have no product shortage. That's one part of the answer to your question.

The second piece is, well, we have product and it may be sitting in a distribution center or 2 [indiscernible] to patients and hospitals or hospitals and patients. And that's where we, a little while ago, announced a collaboration with a company called BAP. And I'm skeptical any outsider but BAP has been an absolute delight to deal with because they have the same focus on benefit for patients as we do. So if a patient under any of our programs, Paid Named Patient Programs in countries where this is allowed to be administered or the French AAC program or any of the ongoing clinical trial programs.

We can get product to patients at a lightning speed at a cost that is very modest, very modest and with an infrastructure of professionals, which we're starting to expand, both in Europe and South America, where education is properly provided for physicians such that we can monitor patients' progress with treatment. We can monitor any safety issues carefully and record them. And so these are very important elements of our sense of responsibility in making sure that patients are well served.

Thank you so much for that, Garo. Thank you for that very thorough review and description of the preparations of the organization. So let's switch gears a little bit. So we talked a lot about ROBBIN and how we're moving forward to implementation with Steven. Thank you, Steven, and what we're seeing through the access programs. But to really put the clinical rationale for moving earlier in the disease into context, you yourself, Garo, recently sat down with Dr. Benjamin Schlechter who's treated patients with both BOT+BAL in the advanced colorectal setting. But he as well is also now leading the RECTIFY-1 study, which is a neoadjuvant study in rectal cancer and MSS rectal cancer. So it really gives him a direct investigator perspective on using immunotherapy before surgery.

So your discussion range from what neoadjuvant treatment means and why the timing matters to why MSS colorectal cancer has historically not responded to first-generation immunotherapies and really what the long-term BOT+BAL experience has shown. And as you mentioned earlier, why the NEST neoadjuvant findings have really prompted investigators to explore the combination earlier in this disease. So why don't we go ahead and take a look at that discussion from earlier this week?

Hello, Ben. We're joined today with Dr. Ben Schlechter, who is a senior physician at Dana-Farber Cancer Institute. And we've had the privilege of working with Dr. Schlechter for a number of years now, particularly in the context of our lead programs with BOT+BAL. So maybe you can start with defining what the neoadjuvant setting is and what is typically different about those patients in the neoadjuvant setting versus the typical patients in the late-stage setting who are in a much more desperate predicament?

Yes. So in colon cancer and in a lot of solid tumors, we're talking about solid tumors here, not, for example, blood cancers. But in solid tumors, everything rotates around the access of surgery. Surgery is sort of this very important point. And traditionally, we did surgery and then chemotherapy was given after surgery as a helper to prevent recurrence. That's the term adjuvant, adjuvant is a helper. So that was the role of chemotherapy, and we used risk factors at surgery. So the surgery is done.

We look at the pathology and the biology, all the specimens in the microscope. We make a guess about how high likelihood it is of recurrence. And then if the likelihood is high enough of recurrence, we give chemotherapy to prevent that recurrence. Neoadjuvant just means the exact same chemotherapy or immunotherapy or other targeted therapies before surgery, and that can be used in a number of ways.

Number one is if a tumor is big and scary and just can't come out and you can use neoadjuvant therapy to shrink it. It's actually relatively uncommon. For the most part, that's not the case, at least in colon cancer. But another way to think of it is that surgery is hard on patients in a number of ways. And sometimes, if chemotherapy is challenging and surgery is challenging, chemotherapy is critical, but it could become too challenging after surgery.

And so increasingly, in certain diseases it's moved to before surgery as a way of getting it in, letting someone heal and then go to surgery. It's a little bit different when we talk about immune therapy because immune therapy is fundamentally different from chemotherapy. And that's what's really important for the discussion today really is not just what is neoadjuvant therapy, but why is immune therapy so different from chemotherapy and why it's probably better in the neoadjuvant setting, the preoperative setting than the postoperative setting.

So based on what you're saying, patients when they're first diagnosed with cancer, I'm assuming then that their initial reaction is, let's get the cancer out of our body. And so when you are trying to explain why certain treatments prior to surgery, including chemotherapy for that matter, but particularly with immunotherapy makes sense, how do you convince them? What is their reaction typically? And also, what is the interaction between, for example, your discipline as an oncologist and the surgeon who is typically accustomed to getting the tumor out, provided that, as you said, the tumor is operable?

But they want to do surgery at the moment that is best for the patient. And so if a patient is sick in some way, they want us to get them healthier, but they also want to set the patient up for success. The goal of surgery is to cure patients of cancer. And so if you say to a surgeon, this is a patient with cancer, your job is cure, my job is cure. And I think there may be an advantage to doing a treatment before surgery rather than after surgery, they're going to sign up for that. We're not taking away surgery. We're simply changing the time of surgery so that we can sort of boost the benefit to patients.

And so in terms of the surgeons, surgeons can work with this, surgeons know how to work with this. We have many paradigms within colorectal cancer to do this. So within the time that I've been a doctor, we went from -- before I was a doctor of surgery first in rectal cancer and then all these treatments afterwards. And then there was an era of radiation first in rectal cancer and then surgery and then chemotherapy. And now we've moved to all the chemo, all the radiation, everything before surgery, and we finished the surgery.

So these are not novel concepts for surgeons and they're not novel concepts for oncologists. The benefit of treatment before surgery with immune therapy in particular, is that surgery does something. Surgery does something good, it removes a big tumor, but surgery also removes things that are there for a reason. Your lymph nodes play a role in your immune system. Your lymph nodes are the surrounding immune tissue in your colon and every organ really. And there is immune cells in there that are learning how to fight infection and cancer and viruses and all these things.

And you have to remove those with surgery because by removing those, you remove lymph nodes that may be contaminated with cancer. But by removing them, you also sort of remove the university system of the immune system. The immune system needs to learn how to fight cancer. And so we have to get those lymph nodes out. But by doing that, we actually handicap the immune system a little. So immune therapy, in particular, after surgery is uneducated immune therapy.

And so giving immune therapy before surgery is where you have the most infrastructure to teach the immune system how to fight cancer. So by giving these treatments earlier, and the same surgery you're going to do anyway, you actually end up with a more vigorous immune response because you haven't yet removed those lymph nodes, which play such an important role in fighting cancer even though they have to come out because they could be contaminated by cancer.

So it's interesting because even though chemotherapy also works systemically, what you're saying, Dr. Schlechter, is that immunotherapy seems to have a longer-term potential memory sort of response. So you're training the body to remember so that if there is a residual emergence of disease that the immune system will remember and shut it down or chemotherapy may not do that exactly the same way.

Yes. Chemotherapy is sort of agnostic to when you do it. If you do it, it's the same. Immune therapy is quite different. It's like a vaccine, right? You don't get the flu and then get your flu shot. You get your flu shot, so you don't get the flu. And so it's not a vaccine that's a different biology, but there's a lot of things in common. And so activating immune response when the immune system is at its best is really what you want to do with cancer immune therapy. And so giving patients the opportunity to derive the most possible benefit from their own native immunity is really important when you think about the best application of immune therapy.

So let me switch gears for a bit. Now of course, when immune therapy came to existence with some of the leading targets like CTLA-4 and PD-1, the first emphasis was melanoma, which is typically known as a cancer that is visible to the immune system. And then that was followed by, to some extent, with lung cancers as well, not quite the same level of success perhaps, but still very successful.

Now when we look at colorectal cancer, we have heard, of course, some very striking developments in colorectal cancer with a minority of patients that comprise the colorectal cancer population known as MSI-high patients. Now -- but the majority don't benefit from immunotherapy. Can you explain a little bit more about what is the difference between the 2 different types of colon cancers? And what has changed based on your experience over the last few years?

So when you say colon cancer, you really just mean the typical colon cancer, not MSI high because that's actually quite uncommon. In advanced disease, it is rare. It's like 3%. It's probably a little bit more in earlier-stage disease. MSI-high cancer is -- the term is genomically unstable. Its DNA is wet and wild. Its DNA is profoundly different from the normal colon. And so there's a lot of stuff for the immune system to recognize. Immune system's job is to find differences. And when you have something which is likely different than normal, it's easier for it to do its job.

And so there's a lot of stuff for the immune system to latch on to and generate inflammation against and attack. And so it doesn't take too much to push the immune system from the off state to the on state. Now the cancer is fighting back. That's what all those drugs are doing. They're fighting back against the immune system. We interfere with that, giving these drugs. But MLRD cancers or MSI-high cancers, those are wet and wild. They're weird looking. They're really strange genetically.

And so the immune system has something to work with. More typical colon cancer is actually quite different. More typical colon cancer is profoundly similar to the normal colon. And so there's not a lot of things to latch on to. And so you need to kind of coke the immune system more. The other thing is more typical colon cancer has a profound kind of immunosuppressant desert around it, it produces things that suppress the immune system. And so the immune therapies that work in other cancers need to be kind of jiggered a little differently, not just to take T cells that are sort of sleep but know there's a cancer there, but instead get rid of the guardrails.

And so different drugs do different things. And some of those drugs had early successes in melanoma, but honestly, they were overkill in melanoma. They weren't necessary. But in colon cancer, they're not overkill. And so you need to think differently about immune therapy. And so the experience of the last 10 years has been beginning to understand that averaging all cancers was a mistake and thinking much more nuanced about cancers and averaging all immune therapies was a mistake and thinking much more nuancedly about the different drugs and using the right drug with the right disease. So I'm the first to say that I had become a pessimist for these classes of drugs.

We had 10 years of failure, something like that. We also know more about the immune system. We can think less simplistically and more complexly about where these different things are operating, in particular, CTLA-4. And so botensilimab is that sort of like rationally designed CTLA-4. The first-generation CTLA-4s are good drugs in the right disease, but they didn't work in colon cancer. And with sort of careful work, really it's your work, I'm not going to take credit for it. Careful work, things were identified that could be done to alter CTLA-4 drugs to push them a little bit harder, make them behave a little bit better in ways that are relevant in colon cancer.

So colon cancer has a ton of these T cells that are bad actors. We want to get rid of those. We want to get rid of bad T cells, okay, we want good T cells. And so botensilimab is good at kind of doing that nuanced approach. Balstilimab, the thing that works with it is also important because there's different components to the immune response. There's regulatory T cells. We can get rid of those with botensilimab. Those are bad T cells. There's good T cells, but cancer fights back.

Cancer delivers a knockout punch to those T cells, just really like wounds them. And balstilimab and similar drugs of nivolumab, for example, and pembrolizumab, those work on that more chronic wounding of the immune system. So you need different components. You have to turn on the immune response with botensilimab by removing regulation by taking off the brakes. You need to prevent the immune system sort of tumbling down into sleep by using balstilimab or those other PD-1 drugs to keep that active.

Yes. So I'll brag a little about our clinical cancer research paper that just came out. How about that? Some of yours as well. So that was from the C-800-01 study. That was the original trial of BOT and BAL in colorectal cancer, among other cancers. And there was an initial presentation a couple of years ago in Nature Medicine. This is a follow-up paper in clinical cancer research, looking at Nature Medicine was 77 patients with colon cancer.

This is 123 patients. Nature Medicine was short-term follow-up. This is long-term follow-up, 3 years of follow-up. And there's a couple of really important findings. So the first thing is that who it worked and is relevant, it works really best outside of the liver, and there's some interesting biology about that, and we can talk about that for hours. It's not the most relevant point today. But the further from the liver you get, the better things get, okay? And so that's very clearly demonstrated in the paper that we just put out.

The other thing that we noticed is that a subset of individuals drive deep benefits, like major responses. Some of them, as far as we could tell, like all visible cancer disappeared, which is called a clinical complete response, and that's a great thing. We don't know what that means in the long run because it's just too new, but it's certainly -- no patient is sad if all their cancer has gone from a scan.

The other important point from C-800-01 was that a significant number of patients, and this was a really, really sick population. These were not early stage. These were not first and second line. These were late-line patients. A significant number of patients just kept living. They failed to get sicker from their cancer. And that's an important point. So something like 1/3 of patients in this very, very advanced disease population are alive 3 years out, which is quite remarkable when you think about how bad colon cancer is. And 17% of patients, so around half of those lives have never gone on to need other therapy for their cancer.

And so there's something called the tail of the curve in immune therapy, and that is different than chemotherapy. Chemotherapy works and doesn't work. And so you get a deep response for a period of time and then it fails and eventually it stops working in everyone. Chemotherapy does not cure colon cancer in the advanced disease setting. And in immune therapy, there's going to be a subset of individuals who just keep doing well and they keep living in spite of their cancer. They may be disease-free. They may be disease managed. It might be the immune system, just kind of like knows what it's doing here.

And those tails of the curve are really important because they're not accounted for in averages. You have to look different. You have to look at these landmark points, like how many people are alive at 1 year, how many at 2 years, and now we can say how many at 3 years. And 3 years is a big number in advanced colon cancer. So I'm very proud of this work. A lot of people put a lot of effort into getting these patients on at a really tough time in the world, and we got them through treatment and they did well. And there's patients still alive today who I see in my practice because they received those drugs.

So first of all, pretty much every trial of immune therapy before surgery or radiation, immune therapy is better than if you do it after. And so immune therapy gets better, the better the patient, the better the patient fitness, the better the patient anatomy. So that's point number one. Point number two, investigators in Italy and the GONO group, the unicorn study and investigator in the United States did a clinical trial called NEST-1 and then NEST-2. And they took patients with colon cancer, not rectal cancer, and they gave them BOT and a few doses of BAL and then they did surgery, and they did it as a test.

They gave BOT. They gave BAL. There is immediate surgery and like, wow, the cancer is already reducing even in a few weeks compared to what we would have expected to see at surgery, okay? So that was pretty cool. And then it was BOT and a little bit more BAL, wait a little bit longer. And the longer you waited, the better it got. NEST study showed that we could majorly reduce the amount of cancer in a subset of patients, and it's very important because maybe we could reduce it so much, we can avoid chemo. And that's a big deal. We've done a lot of work to try and reduce chemotherapy in colon cancer. So that's what NEST like.

So this is -- this could be a game changer, of course, for patients who would benefit from it because I'm assuming then that there are competing priorities here, meaning a surgeon may indulge in taking as much of the organ out as possible so that they can be sure of not leaving cancer behind.

I mean colorectal surgeons, I think, are a particular breed. They've actually -- they have led the research on not doing surgery, and that tells you a lot about how these surgeries go. So I think colorectal surgeons really have weighed in on understanding that a good cancer surgery can have a bad functional outcome. And so I want to give a lot of credit to the colorectal surgeons who've led this field. And so they deserve a lot of credit for that. But yes, I mean, the problem is the right surgery is rough on patients. We don't want to jeopardize the chance of cure because of the functional issue, but we don't want to jeopardize function if we can cure people anyway.

Thank you very much for all of this, by the way. I know that you're a physician who cares about patients because we have referred some patients to you that were in desperate need. Unfortunately, some of these patients are very young.

Yes, I mean it's pretty scary, right? The leading cause of cancer-related death under the age of 50 is now colon cancer. And in women going to suppress breast cancer pretty soon within the next couple of years. That is new. That did not exist 30 years ago. Something is happening that colon cancer is the disease that is getting worse over time. And honestly, we don't know what it is. There's really not a major genetic hallmark.

These are just average colon cancer that generally don't respond to conventional therapies. And the younger the patients are, the worse they do. And so this is -- as far as I'm concerned, this is a medical crisis. There should be alarms going off that I've treated a 16-year-old and like 20s and 30-year-olds are dying of colon cancer. That's not acceptable, and we need to sort that, and we're working on it. But boy are painfully slow. And yes, boy, do we need new drugs.

So Garo, I wanted to thank you and Dr. Schlechter for taking the time to have that discussion. I think it brought up a lot of really important elements and components. Given the time, I know that we have a lot of really important questions that have been submitted. So we're actually going to jump through to answer some of these questions.

I'm going to start off, Steven, there's a couple of questions here about the ROBBIN design that I think would be helpful to clarify. One question here is, this is a randomized study. It's a Phase III program. But given the control arm in ROBBIN doesn't include neoadjuvant treatment, how do we ensure that patients randomized to that control arm are going to complete their treatment and not drop out of the trial? I know that's always kind of a consideration, and that was something that we had thought about for the late-line setting. Can you comment on that, Steven?

Yes. Well, I mean, the standard of care, this is surgery and adjuvant chemotherapy. There is not an opportunity to get BOT and BAL in this study except by participating in the study. And we've done this multiple times in Phase III trials. So it's pretty simple. Patients will get standard of care, randomized to standard of care or they will have BOT+BAL, but we don't anticipate that there will be a large number of dropouts because this is the standard treatment in a curative setting. And so obviously, patients are not going to jeopardize curative potential.

Thank you. So I do have one other question for you related to the pathologic response data that we are anticipating in the second half of '27. So the question here is, you touched upon this slightly, but is there a minimum pathologic complete response rate that we believe we would need to ensure confidence in the EFS primary endpoint. I know when we're looking at it, it's on a very small component of patients considering how many we are going to be treated in the full study. But is there kind of a guidance there, even though it's not the...

No, I'm not going to speculate on that in this setting. I will say that in the neoadjuvant FOxTROT chemo trial, a 3% or 4% complete response rate produced a mildly positive study that has not been adopted worldwide because of the toxicity. But let's just look at our data in Phase II. Obviously, where we're approaching 35% to 40% in 2 independent trials with pathologic complete. So you can imagine and do the math regarding that.

Yes. Thank you. Thanks for that commentary, Steven. So Robin, there are some questions here related to the commercial opportunity. So we had communicated that the patient population is approximately 30,000 addressable patients within in the U.S. that are diagnosed. The question here is how many of those patients get treated in some of these academic centers that have the multidisciplinary teams in place to essentially ensure that we -- if approved and the trial is successful, that we won't lose patients to surgery before they actually have the opportunity to get treated in a neoadjuvant setting. Can you maybe talk a little bit about that and what you're already thinking down the road for when and if the combination is approved in this setting?

Yes. Well, we actually have a nice example in colon cancer already because patients who are MSI-high or DMMR and that is now a standard test that is performed for all of these early-stage colon cancer patients for whom neoadjuvant immunotherapy may be an option. Those patients are already tested, whether it's community or an academic center, and a majority of them are going to be referred to get immunotherapy prior to surgery.

If you look at the NCCN guidelines, that's the recommendation. And so practice changes when there is data that supports that change of practice. And that's what we are intending to do with the ROBBIN study. Our goal here is to be able to generate data that will support a change in practice. And if that data is as robust as we anticipate based on what we're targeting for our hazard ratio or if we see something better, then I fully expect that we're going to see a change in practice.

Great. Thank you, Robin. The next question here is -- could be a little bit of a combination, maybe Dhan Chand for those that don't know, Dhan, who's Head of Research here at Agenus, but this was kind of a combination question. So there was a question about the recent adjuvant vaccine discontinuation in resectable colon cancer. How do we think about the difference between treating molecular relapse after surgery and priming immunity before it? And does that -- the other product failure change any assumptions about how we view the competitive window?

Thank you, Stefanie. That's an excellent question. In fact, it raised a point that Dr. Schlechter made earlier as well. The best time to prime is when there is a tumor present so that the immune system can recognize the tumor-associated tumor antigens. When you remove the tumor, you have very little to recognize, very little to prime again. So that is why in the neoadjuvant setting, BOT+BAL works so efficiently versus giving it, say, after surgery. And what was the second part of that question again, Stefanie?

So this might be a little bit more for Robin, but comparing -- essentially, given what you just said and then thinking about what's happened in the competitive setting, does this recent failure of another investigational product change our assumptions or our view of what that competitive window and the differentiation of BOT+BAL.

Yes, I think you're talking about...

I think Robin can certainly add to what I have to say. But I want to be very clear, that was a vaccine monotherapy in a cold tumor in an MRD setting. And in melanoma, we have -- and so there's no PD-1. They do have a PD-1 combo that's still under study. But I think what it says, we've known this for a long time, vaccines in the -- when the tumor is removed, in cold tumors are not -- have never been effective. Now in melanoma, we actually in SWOG 1801 did the proper experiment. We gave a limited number of cycles of -- this is hot tumor where PD-1 works after surgery.

And we gave one -- several doses before with an intact tumor followed by after versus only after. There was a 20% survival benefit in just giving a couple of doses of a PD-1 in a hot tumor. In cold tumors, you need better priming CTLA-4s before you can add the PD-1. And so it doesn't surprise me at all that a vaccine in a cold tumor alone wouldn't work. So BOT is really set up in a neoadjuvant, but potentially in an MRD setting, and we're testing that in combination in cold tumors.

Thank you, Steven. Robin, was there anything that you wanted to add to that before we moved on to the next question?

No, I think that it was an interesting contrast, right, because recently, Moderna had announced positive data in melanoma with basically a neoantigen vaccine, a similar vaccine in colon cancer with negative. Is that a commentary on the vaccines? Is it a commentary on the disease setting? Hard to say. But clearly, those are very different disease settings in terms of the immunological environment, as Dhan can tell you as well.

Great. Thank you. So this is going to be, I think, a joint question too, probably for Robin and Steven. And Garo, I'm sure you might have some comments. But -- so as you guys know that there's been some additional news this week within -- in the space of MSS colorectal cancer and looking at other neoadjuvant studies. Certainly, the question here or maybe more of a comment is what can we do to speed up ROBBIN. And I know that everyone is working diligently, very large study, robust. The work upfront is going to make a difference.

But some of this question here is kind of just related to comment on competitors. I don't know if I would say similar to BOT+BAL, but maybe similar mechanism in a certain way, but partnering with other PD-1s in the same setting. So can you guys maybe provide some commentary of that or more importantly, comment on BOT+BAL, the program and the differentiation and where we are within the program, particularly in MSS disease? So Robin, I don't know if you start.

So I think part of that question was what about partnering with a different PD-1. And I'd say, why would we do that when we have a perfectly good PD-1, thanks to what Dhan Chand designed in terms of a PD-1 that is comparable to existing PD-1s already in the market. So there's no reason for us to do that. Secondly, I think the question was approaching where are we from a competitive perspective? Well, clearly, we're ahead. We're starting a Phase III study. We have data. The only other CTLA-4 with data in the neoadjuvant MSS colon setting was ipilimumab. That was actually helpful data for us. But none of the next-gen CTLA-4 have presented any data in this setting, and we're often running into starting up our Phase III study.

Perfect.

Yes. I might just add that I agree we're well on our way with 1,200 patients treated across multiple tumor types at a Phase III trial. What encourages me about this whole field now is it's coming back to CTLA-4, right? We failed with TIGIT. We failed with multiple other targets in cold tumors, thinking that adding PD-1 to a new target or chemo is going to be the solution. The solution is a better CTLA-4 that not only primes and activates memory, it depletes Tregs and it repolarizes myeloid and dendritic cells.

And our neoadjuvant data that you'll see in the publication already and a soon-to-be publication really reinforces that we have a differentiated CTLA-4 that makes cold tumors hot. And honestly, it reminds me of it looks like melanoma. So that's the difference. CTLA-4 is the target that matters the most in broad tumor types. We just need a better CTLA-4, and we have that in BOT.

All right. Well, thank you. And we're a little over time, but I think it was really important to be able to answer some of these questions that were submitted. So thank you for everyone whose stayed a little bit over. And with that, Garo, do you want to make any just closing comments before we close out the call for today?

Well, thank you, everybody. My colleagues have done such a fantastic job in describing our strategy, the data, the next steps. So I think that we're focused on what we need to deliver over the next months, not next year or two. And I feel confident that with the team we have right now, we're going to be able to achieve these targets. So thanks again, and we'll see you next time.

Reporting communications Officer at Agenus. Thank you for joining today's webcast [indiscernible] earlier this morning. Joining today from Agenus, Garo Armen, Founder, Chairman and Chief Executive Officer; Dr. Steven O'Day, our Chief Medical Officer; Robin Taylor, our Chief Commercial Officer; and Dec Arnon, VP, Corporate Development and Investor Relations.

We also have the pleasure of having 2 globally renowned thought leaders in the space of neoadjuvant colon cancer treatment and research, also joining today is Professor Miriam Clay at the Netherlands Cancer Institute, a globally recognized leader in gastrointestinal oncology, Scientific Co-Chair of the ESMO Congress the pioneering investigator behind the landmark niche studies in neoadjuvant immunotherapy for colon cancer in the 2026 Innovation & Science Award for Cipient and a Robin investigator.

Also with us is Dr. Pastan Kashi, the RAG Family Chair in Gastrointestinal Oncology and Medical Director of DI Medical Oncology at City of Hope Orange County, whose leadership at the landmark NES trial has helped establish neoadjuvant Botensilimab and balstilimab as one of the most promising new immunotherapy approaches for patients with MSS colorectal cancer. Both are investigators in the upcoming Robin trial.

The following webcast contains forward-looking statements regarding agenesis businesses that are made pursuant to the safe harbor provisions of the federal security laws. Please reference this full forward-looking statements in our statements shown now, which can be also found on our website in this webcast presentation, along with our company overview presentation.

So with that, I will turn the call over to Garo.

Thank you very much, Stefanie, and thank you, our guests, Professor Shalabi, and Dr. Kase, as well as all of you for joining us this morning. Today's announcement marks an important development for Jens. At its core, it represents a genius focusing on a program which can be life-changing for patients and create unprecedented value for Agenus stakeholders.

It also signifies a deliberate decision by the company to concentrate our resources behind what we believe is our highest impact and highest value opportunity that is neoadjuvant but ball in MSS colon cancer. And for those of you that may not recognize that term, MSS colon cancer accounts for approximately 85% of all colon cancers, well as it is the most difficult to treat colon cancer and unresponsive to immunotherapy until backbone.

And with this additional infusion of cash, it will provide us with the opportunity to execute that strategy from a position of financial strength. We made this decision to pursue the Robin trial our Phase III registration-enabling study of neoadjuvant pupil in high-risk Stage I and Stage II MSS colon cancer. We designed this study based on data generated in multiple ongoing ISTs, and you'll hear more about them from our guests, highlighted by Neste unicorn.

And with the input of some of the most prominent clinicians 2 of whom have joined us today. The data from Nest and Unicorn, along with Dr. Trilabs NeOASIS trial, are consistent across more than a dozen clinical centers in the U.S. and Europe. Importantly, we have discussed the Robin trial with the FDA and and received feedback supporting it as a registrational pathway for but plus bar in this prevalent treatment setting with non newly approved therapies in the last 2 decades.

This is the setting where we believe the biology of BOT+BAL, the clinical need and the patient impact and the value creation opportunity come together, converge basically most powerfully. While we have generated exciting and for some patients, life-saving clinical data, in late-line metastatic disease.

Patients with advanced disease are generally very sick, heavily pretreated and often have limited time in the neoadjuvant setting on the other hand. We are treating patients earlier where the treatment setting is most appropriate. While the primary tumor is still present, while the immune system is more competent, and while the intent is to cure patients, this has always been central to Agenus mission to move next-generation immunotherapy agents to the settings where it can have the greatest impact.

The financial -- or the financing announced today, lets us pursue that path. The $85 million upfront is expected to renew near-term financing pressure -- and with full warrant exercise, the structure objective for this is to fund the Robin trial and Agenus operations through the year-end 2031, carrying us through several key value inflection points of this registrational program. You will hear more from Zach on the transaction, Robin on the strategic rationale Befesa Colaba and Dr. Kate on the Clinical Foundation and Stephen under Robin design.

And I'd lastly like to thank our new distinguished investors for having done the significant amount of work to make this decision.

With that, I will turn it to Zach.

Thank you, Garo. Earlier this morning, we announced a private placement of up to $340 million, led by Commador Capital with participation from RA Capital Management, TCGX, Invis and Ligand Pharmaceuticals. This transaction includes $85 million of upfront gross proceeds and 2 or in tranches totaling potential additional gross proceeds of $255 million. Each of the 3 funding tranches, including the $85 million upfront, were priced at a premium to the market closing price as of last Friday, July 10. This structure aligns capital with key value inflection points within the Robin trial time line and our path toward full approval.

Our conviction is that the Robin trial will unlock Bots Ball's promise to deliver significant patient benefit and shareholder value. And this financing provides us with the resources needed to execute on that promise. We are excited for the path forward and thank all of you for joining us on today's webcast. We are fielding Q&A questions now if you would like to submit through the Zoom webcast application.

I will now turn the call over to Robin Taylor, our Chief Commercial Officer, to frame the unmet need and strategic rationale.

Thank you, Zach. Let me start with the unmet need. Colorectal cancer is now the leading cause of cancer-related death among Americans under 50. Across all ages, the overall disease incidence is 155,000 cases every year in the U.S. About 70% of these tumors are colon cancer and about 15% of early-stage tumors are microsatellite high, which are candidates for immunotherapy, but about 85% of resectable colon cancers are microsatellite stable, which are immunologically cold and refractory to conventional immunotherapy. That is where BAT and BALL comes in.

Botensilumab is a next-generation Fc-enhanced anti-CTLA-4 antibody designed to work with balstilimab, our anti-PD-1, to turn cold tumors hot driving broad immune activation and T cell memory.

Go to the next slide, please. There we go. These images are from a patient with MSS colon cancer treated in the neoadjuvant setting from the NEST study. On the left, an 8-centimeter mass in a 40-year-old woman, on the right, the same colon 7 weeks later after just one dose of BAT and 2 of Ball immediately prior to surgery, and this was subsequently confirmed as a pathologic complete response. One of many across the bat and ball neoadjuvant studies. This example clearly demonstrates what BAT and FC enhanced CTLA-4 can do when the primary tumor with its full repertoire of neoantigens is still in place.

We have shown broad activity of BOT and BAL ell in late-line metastatic tumors, including MSS colorectal cancer -- but the benefit we can deliver in the neoadjuvant curative-intent setting, the high-risk Stage I and Stage II MSS colon cancer dwarfs the impact in metastatic disease, for a population with no major therapeutic advance in over 20 years since Oxaliplan was approved.

Our strategic pivot rests on 4 points. First, the population is larger. -- roughly 38,000 high-risk Stage I and II MSS patients treated annually in the U.S. Second, the impact for patients and for payers is greater in a curative intent setting. Third, 2 Phase II studies demonstrated deep, rapid pathologic responses and support a high probability of success in Phase III. And fourth, Robin's design is aligned with FDA feedback and backed by financing through the program's major value inflection points.

In short, we are focusing BOT and BAL, where the rationale, the need, the data and the value were most aligned. In Nest and Unicorn, neoadjuvant bought ball produced consistent results with respect to pathologic response. The key measure used for pathologic response is the pathologic complete response rate or PCR, for short, which is defined by the finding of no viable invasive cancer cells in the resected specimen after neoadjuvant therapy as determined by a pathologist after surgery.

For event-free survival, the benefit is measured as a hazard ratio, which is a statistical measure of the relative treatment effect on a time-to-event outcome. The ROBBIN Phase III study is targeted to a hazard ratio of 0.65 or a 35% reduction in the risk of recurrence or death. To understand the effect of the PCR rate on the potential hazard ratio of the ROBIN study, we analyzed 21 neoadjuvant and perioperative trials, examining the relationship between the PCR rate delta between the experimental and control arms, and the event-free survival hazard ratio.

As you can see, there is a strong correlation between the 2 measures in the plot on the left. The table on the right shows the projected hazard ratios at different PCR deltas. We expect a PCR rate of 0% in the control arm, as was seen in prior studies such as FOX Tri, NeoCol and optical for patients who went straight to surgery without neoadjuvant treatment. A PCR rate delta of 17% in the ROBBIN study would be projected to achieve a hazard ratio of 0.65. The target hazard ratio for the ROBIN study -- the PCR rate observed in the NEST and Unicorn in Phase II trials meaningfully exceeds that target, replicating the 30% PCR rate would correspond with an estimated hazard ratio of about 0.5.

Now let's consider the market opportunity. Approximately 85,000 people are diagnosed with Stage 1, 2 or 3 colon cancer in the U.S. each year. About 15% of these patients have MSI-high tumors and are RRD candidates for currently approved immunotherapies -- the remaining 85% of patients with MSS tumors equals about 68,000 stage 1 to stage 3 patients. Of this group, ROBBIN focuses on the high-risk Stage I and Stage II MSS population which is about 38,000 eligible patients annually.

At an illustrative $200,000 course of neoadjuvant treatment, the addressable market opportunity translates to greater than $7 billion market opportunity. This is why the ROBBIN study is commercially and clinically different from a late-line metastatic program. The patient population is larger -- the clinical goal is tied to preventing recurrence and preserving long-term survival and has a greater impact on life year saved and the endpoints are aligned with the goal of changing clinical practice. To put this into clinical context, I will now turn to Professor Miriam Telavi whose work has helped shape the field of neoadjuvant immunotherapy in colorental cancer.

Good morning, everyone. It's great to be here to discuss the exciting avenue of neoadjuvant immunotherapy in colorectal cancer, something that I think over 10 years ago, we didn't think was possible, especially not for MSS colon cancer. So I'll be discussing some of the data on where we stand in terms of treatment of colorectal cancer in general as well as what we have on neoadjuvant immunotherapy in colorectal cancers, both MSI and MSS colorectal cancers.

So first of all, it's good to set the stage on how do we treat patients with colorectal colon cancers I would say, at this time. And this hasn't changed over the past 20 years. we treat patients with direct surgery usually unless there's a real need for neoadjuvant therapy, which is not the standard of care. We treat them with surgery, and then we decide based on the pathologic assessment, whether there's adjuvant chemotherapy needed yes or no.

All patients are treated mostly with the same type of chemotherapy regardless of whether they have an MSI or MSS tumor. We don't look at molecular subtypes or anything like that at this time yet. So everybody gets the same treatment usually have a high-risk stage 2 tumor when it comes to MSS colon cancers or when they have a stage III tumor, meaning that they have lymphnode positive disease.

There is -- despite this treatment with surgery, followed by chemotherapy, there's still a very high recurrence rate for these patients who receive up to 6 months of adjuvant chemotherapy sometimes and the surgery 20% to 40% of these patients can still recur. So we still need a better treatment option for these patients. And ultimately improve their long-term outcomes and decrease toxicities, of course, because chemotherapy is not without side effects -- many patients suffer from polyneuropathy also in the long term.

And there's definitely room for improvement in both outcomes but also in side effects that we incur based on our treatments.

Next slide, please. So the FOX Rove study, what I mentioned before is that neoadjuvant therapy is not a standard of care. It's becoming standard of care more and more. And this is also thanks to the [ FOX THAT ] study. FOX START study was actually the very first study in which patients with colon cancer were treated with neoadjuvant chemotherapy. And these were patients that were treated randomized to either very operative chemotherapy, so either neoadjuvant plus adjuvant chemotherapy or adjuvant chemotherapy alone, and this was based on clinical staging. So patients were selected based on on their T stages in their tumor, such as will be the case for the ROBBIN trial.

In this study, there was no specific requirement of having an MSS or an MSI tumor. And that was because back then, we did not know what these data were going to show us in terms of the differences in responses between MSI and MSS tumors. What this study showed is that neoadjuvant chemotherapy was feasible because we didn't have a large trial showing us that that it was safe, that the rate of complications was not higher compared to adjuvant chemotherapy.

Also, there seems to be ultimately an improvement in outcome for patients who received neoadjuvant chemotherapy. So there's definitely a subset of patients that might benefit from neoadjuvant treatment. This actually sets the stage for the possibility of neoadjuvant treatment, be it chemotherapy or immunotherapy in that sense to be given prior to surgery in patients with colon cancer.

What this study also showed is that if you look at the pathologic responses, pathologic responses in MSS colon cancers where this chemotherapy is the standard of care, of course, also in the metastatic disease setting still.

The response rate to neoadjuvant chemotherapy is about 20% to 25% if you consider other trials as well. So that is kind of what we're looking at in terms of the standard of care and how that performs in the neoadjuvant chemotherapy setting. And that is something to keep in mind when discussing what we're looking for in terms of responses and ultimately also improvement in outcome when considering neoadjuvant immunotherapy because MSI tumors respond exceptionally well to neoadjuvant immunotherapy, and that's almost 100% of patients that may respond, but that's a completely different biology. And that's a small subset of patients with colon cancer.

While the 85% of patients still have their chemotherapy as the standard of care, and that's all we have. Actually, other chemotherapies have been tried and that hasn't worked. So there's definitely a need for improvement for that patient population.

Next slide, please. So what we did in the NET study, and this is a large platform study where we have treated patients with MSI colon cancers. And as I mentioned before, immunotherapy works exceptionally well for that group, but that's not the group that we're talking about here. We're talking about the patients with MSS colon cancer that encompass most of the patients with early stage nonmetastatic disease.

What we set out to do in the NICE trial, and this was the very first trial to look at the neoagifan immunotherapy in a group of patients with MSS colon cancers. We had the hypothesis that if you treat patients with early-stage disease that there was a higher chance of them responding to immunotherapy compared to the data that we had back then, that was before BAT and BAL and before the next-generation CTLA-4 that was with ipinivo in this case, patients with metastatic disease were not responding to immunotherapy.

But we have the hypothesis that treating earlier such as is the case also for other tumor types, leads to better responses. -- also for colon cancer, where we know that a subset of MSS colon cancers can be immune and can respond. So we treated 31 patients in this trial with neoadjuvant, ipilimumab and nivolumab, just 2 cycles of nivolumab, 1 cycle of ipilimumab. And that was the whole treatment of patients went to surgery within 6 weeks thereafter. And very much according to our hypothesis, we found that a subgroup of patients did respond, and this was just not just a little bit of response.

These were patients that had deep pathologic responses, including PCR, within 4.5 weeks from first dose of immunotherapy to surgery. So there's 26% response rate that we saw in this study with just 2 cycles of neoadjuvant immunotherapy, meaning that if you have an even better treatment including a better anti-CTLA-4, hopefully, that will lead to more responses in this patient group when you look at a very large data set in a randomized trial.

And ultimately, you will want to compare this to the standard of care, which is adjuvant chemotherapy in this case and compare that, of course, also to what we're seeing with neoadjuvant chemotherapy from the FOxTROT trial. We also saw that when patients respond to immunotherapy that they don't have any recurrences and this is something that has been shown in melanoma trials. This has been shown in McClean cancers as well. and this being a small group of patients, of course, and that has to be kept in mind.

But we also see here that patients who do have a pathologic response to that very short duration of treatment have an excellent long-term outcome without recurrences, while patients who don't respond are at significantly higher risk of recurring.

Next slide, please. And that was my last slide. So I think now I will pass it on to Dr. Pashu Kaz. You will be talking about his experience with Neste Unicorn with the neo adjuvant BAT and BAL.

Thanks so much Chelavi. I'm glad to be here as a conation, an investigator of the new adjuvant studies, the so-called NES Grupo studies. And also we're talking about the unicorn study as well in Nestinutocon, both matter because they're exactly evaluating the combination of bar and bowel in the setting where Robin trial is going to happen, which is before surgery, where the tumor is still present and a time line that fits into a surgical schedule.

Now as mentioned earlier, a few times already, the new adjuvant setting is attractive because the priming tumor is still in place, the draining lymph nodes are in place, the tumor can serve as a source of antigen. And as Dr. Slabialso mentioned, there are reasons why the same setting can be more conducive to immunotherapy in this case, checkpoint blockade.

The other thing that's also very powerful in the agent setting is the ability to get tissue. So we're not talking about responses on scans. We're talking about pathologic responses, resected tissue and also the opportunity to assess the biology in real time. As shown here in the schema, the next group of studies, the Nest 1 as I looked at schedules, essentially, we looked at if the longer time to let the immunotherapy grew. Initially, when we proposed an X1 study, the standard of care is you get to surgery as soon as possible, whether that's next week or in the next couple of weeks.

So we had a very short window of opportunity to -- not to delay curative treatment. So patients on average went for surgery within 3 to 4 weeks as early as days from the first dose of bought, we had patients going for surgery. Once we had more data on the first set of patients showing deep pathologic responses and no safety issues, the Nest 2 was looking at the same single dose of bought, but a couple of extra doses about, but more importantly, a higher time to let the surgery happen at about approximately 8 weeks. Unicorn study is shown on the right side of the schema. It's a very similar design that done independently, and the average time of surgery was a median of about 5 weeks.

Now if we can go to the next slide. The summarized here is the next group of data. Again, we had a few MSI high patients treated as part of the initial design to provide proof of principle, but most of the data is focusing on MSS tumors. In the MSS tumor approximately, if we look at by the definition of at least 50% tumor regression, this was nearly about 59%. Now if you look at at least 90% of the tumor being dead, it was about 41% and completely pathologic response or no tumor viable at the time of surge was about.

Now again, I want to reemphasize this was pathologic responses on tissue, not imaging changes. And that is the big distinction when we talk about new adjuvant setting. I'll show more data, but again, one important thing to highlight is there have been no recurrences reported across these 3 different studies to date.

If we can go to the next slide. Now our Italian group of investigators, the unicorn trial, why is it important, it provides independent corroboration. So while you can argue 1 center 1 investigator here. It's a similar design. Again, BAT and BAL. One key distinction was this group also looked at monotherapy with BAT so the question of contribution of components and what does BAT monotherapy adds? It at least helps us understand the contribution in both MSS and MSA high tissue.

And you can see you do need the combination as highlighted in the schema showing deeper pathologic responses, both in MSS and MSI high setting for a similar patient population.

So if we go to the next slide, now multiple patients, approximately 38 treated with MSS with the BAT and BAL combination. There have been no recurrences reported to date. Now in this follow-up is a little early. We -- I've treated my first patient on March 17, 2023. We'll have updated data coming out soon. But what is very heartening across these studies is no recurrences to data and that's of paramount importance, which highlights that an immunotherapy responder, even if it's not necessarily the arbitrary cutoff of 90% or 100% or 50% is a very different kind of biology and what it might entail, which is in the new adjuant setting is potentially more cures.

Next slide. If we look at another variable and the area of interest for me in particular, is the value of circulating tumor DNA, these liquid biopsies and we knew in some respect, if we look at the 100% disease free survival that, that was going to be a very likely possibility is because if you look at some of the CTDNA data, a person who is ctDNA-negative, is likely to have over 90% to 94% chance of being cancer-free disease survival at 2 to 3 years of follow-up. And as you have more CTDNA negativity, the sensitivity increases further.

So this is a very important early surrogate and it's an important part of the foundation provided here because we saw, number one, not only that the CTDNA cleared and remain cleared, which equates to the 100% DC survival down the line. but also the rapidity with which this happened when we were checking it on cycle -- the second dose of the bowel, which was within 2 weeks, we saw rapid CTT clearance, which is exactly what we want to do for patients undergoing surgery with the intent to cure where the goal here is to eliminate the micrometastatic disease.

Finally, a quick word on safety, which is of Panama and potent. And again, in a curative intent setting, the last thing you want to do is to cause any issue from a safety standpoint, regardless of the fact that at least 1/3 of these patients, if not more, are not unfortunately cured with surgery and chemotherapy. It's still the standard. -- and you cannot do anything that would compromise the standard. So that part is in terms of safety, toxicity, surgical feasibility.

And that actually was the primary goal of the next group of studies was showing that it was feasible and that was a nonnegotiable factor in this setting. What is heartening to note is no surgery was delayed.

There was only one patient in the Unicorn group of investigator that had a period of hyperthyroidism that patient still got surgery, but it was delayed by 10 days. But -- so across over 52 patients, we have manageable expected immune-related adverse events that we know how to manage from experience from checkpoint blockade and toxicity over decades and now with hundreds of patients in the bad valeting -- and this is also to echo Dr. Slavis note.

One is, of course, the goal is to reduce the current. That's the most important thing. In colon cancer surgery can still happen. But again, it's also potentially causing sparing chemotherapy-related toxicity, the polyneuropathy I mentioned earlier as well as protect recovery and quality of life. Many patients in both these studies, chemotherapy with standard of care and the elected to refuse that, that was not part of the study, but despite many patients if using chemotherapy, which was not the intent, they still achieved the 100% disease survival.

So why is this approach in a Phase III Acision trial? I think these signals are multiple across multiple studies and are hard to ignore. The ROBBIN trial is the right next step to not only assess this in a formal randomized setting, but looking at pathologic response, CTDNA clearance recurrence-free survival so that we can benefit a larger group of population with the intent to cure.

I'll now call Dr. Steven O'Day to walk us through the ROBBIN trial design and then the broader precedent, laying the foundations for investigators like us for moving immunotherapy earlier in the disease course.

Thank you, Pashtoon and Mariam for the excellent contextualization of the data, Mariam for setting up sort of the standard landscape of these high-risk a colon cancer patients who undergo surgery and then 3 to 6 months of chemotherapy and still have a 20% to 40% risk of distant recurrence and death and with toxicities that can be chronic from the chemotherapy and then setting up the neoadjuvant field first with chemotherapy and then with first-generation immunotherapy through her niche trials.

And then, of course, Pashtoon really showing us this compelling and exciting bought out data that appears to be differentiated. -- from first generation. So I want to put this all in context by going back to melanoma, which lays the foundation and really further supports our plans with Robin.

Along with my melanoma colleagues, I have been at the forefront of cancer immunotherapy throughout my entire 30-year career. Over the past 8 years, I've focused intentionally on BAT and BAL from first-in-human studies to late-line trials and now to these exciting neoadjuvant trial results. We have treated more than 1,300 patients with bought monotherapy or bot bow combination therapy across multiple poorly immunogenic tumors and I/O-resistant solid tumors.

This is predominantly in the metastatic setting. This allows us to clearly see the differentiation of BOT from first-generation CTLA-4 antibodies. Importantly, the body of this extensive work and data establishes a selected dose of bot bol and also establish the contribution of BAT and BAL components, both in the metastatic setting and as you saw from the unicorn trial, in the neoadjuancy setting. And this forms the basis of registration-enabling studies.

But now let's go to the arc of the melanoma story that is particularly close to my heart. And the lessons learned from the late stage to early stage, which is particularly informative today as we focus on the registration path of Bob. If you remember, in melanoma, CTLA-4 monotherapy and then the combination of CTLA-4 with PD-1. -- first demonstrated this long-term survival in late line, not early line disease.

This long-term survival was characterized by extraordinary survival plateaus that had never been seen before in solid tumors that began after 2 years and importantly, we're accompanied by treatment-free survival, meaning patients were living with no additional therapy. This was transformative and continued beyond 10 years and now beyond 15 years in these initial studies.

Combination PD-1 and CTLA-4 therapy now cure more than 50% of patients with widespread melanoma. This is extraordinary. And after this extraordinary success in late-line disease, we moved PD-1 agents into the adjuvant postsurgical setting. Now this is not a neoadjuvant. This is after surgery where the tumor has been removed, but has not recurred yet.

And we showed remarkable clinical benefit. Substantially reducing distant recurrence of metastatic melanoma. But it was really the last several years that seminal trials have Trent formed the melanoma field even further. And these were 2 practice-changing trials1801 swag and then, of course, the Adena study with Christian Blank, Miriam's colleague at the Nashville Cancer Institute of the Netherlands, which was presented as a plenary presentation at ASCO 2 years ago.

These 2 trials in Stage 3 melanoma clearly demonstrate a substantial decrease in the development of metastatic disease with immunotherapy in a presurgical setting, where others have reminded you, you have an intact primary tumor with is straining regional lymph nodes. This intact tumor in these lymph nodes leverage the power, adaptability, priming and memory of the immune system.

Now these principles are highly relevant here and now with BAT and BAL. The neoadjuvant data you've seen from Nest, unicorn and Marion's experience with neoasis, a pan-tumor setting are compelling, but not surprising based on the neoadjuvant melanoma experience and further bolster by neoadjuvant's success in breast cancer and lung cancer, leading to a recent regulatory approvals in these diseases.

Okay. Now let's focus on the all-important ROBBIN study. The ROBIN study is designed as a registration-enabling trial. It's global. It's a Phase III, it's randomized. Approximately 850 patients. It's in the group, we've talked about all morning, the high-risk Stage I and Stage II MS-sable colon cancer.

The treatment arms will compare 6 to 8 weeks of neoadjuvant, botansilumab plus balstilimab, followed by surgery, which is standard of care compared to immediate surgery within the first 4 weeks. Both arms to the trial will receive standard adjuvant chemotherapy, but it will be based on the surgical pathologic staging.

The primary endpoint of the study is event-free survival. And for those of you who may not be as familiar with this, this is the time after surgery and adjuvant therapy to the time to a recurrence, predominantly distant recurrent Stage 4 disease. The study is powered around, as ROBBIN said earlier, a target ratio of EFS hazard ratio of 0.65 and we will have an interim EFS analysis at 75% of events and a final analysis when 100% events have been accumulated.

Now importantly, the FDA has aligned around key elements of the ROBBIN Phase III study design, including the proposed patient population, both the experimental and the control arms and, of course, the primary registrational endpoint, the EFS. We are targeting first patient enrollment on the ROBIN trial by the first quarter of 2027. And an interim top line pathologic response readout by the end of 2027, the interim EFS analysis in the second half of 2029, and the final study analysis in the second half of 2030.

I will now turn it back to Garo for a short conclusion before Q&A.

Thank you very much, Dr. Day. And thank you for the rest of our Agenus team and particular thanks to Dr. Telavi and Dr. Pashtoon, not only for participating on today's call, but for their pioneering work with BAT and BAL in the new adjuvant setting. What you've heard from our speakers today speak to the why and what of the significance of this moment for patients as well as Agenus stakeholders.

The ROBBIN trial is a focused FDA aligned registrational path in a large underserved curative intent microsatellite stable colon cancer population. And you've heard the rationale for it as well as the data that supports initiating it.

The next and the Unicorn data, of course, provide the clinical foundation for Lotus. The financing provides the capital path and the opportunity for us is to bring next-generation immunotherapy earlier in the disease setting, where it's more appropriate for affecting a significant number of patients.

And the trial is designed to for this purpose. BAT and BAL shows impressive activity quickly, as you've heard, after a brief course of treatment. Today's announcement and the transaction represent an important financing as well as a focused execution strategy. It is the realization of our Agenus mission in a setting where the biology, the patient need and the opportunity to create significant value are all aligned. We will now open it for questions, and back to Stefanie.

Thank you so much for all of your questions. [Operator Instructions]. But to start off with Prof. Telavi, there was a question here just to put things into context about you shared a lot about neoadjuvant utilization within your overview. And certainly, within the area of MSI high, there was a question specifically related to how many patients today, would you say, on average, you're actually getting treated with neoadjuvant setting that specifically have MSS disease.

Is this something that is a part of the treatment algorithm today? Or is this something that be really practice changing if the RAPID trial were to succeed and show efficacy.

That's a great question. I think this has been moving a little bit ever since the FoxTrot study that we're treating patients more readily in the neoadjuvant setting, but that's with chemotherapy, of course, even for MSS. And usually, that's the case for patients who need induction treatment, where we feel that the tumor needs to become a bit smaller, to make it easier on the surgeon to remove the tumor completely or when we are already based on the tumor characteristics at baseline think that this patient will probably meet adjuvant chemotherapy, then you might as well give it in the neoadjuvant setting to also decrease the tumor size.

But still, that is a very small proportion of patients that are getting neoadjuvant treatment. So in that sense, when you have a treatment that is superior to what we're doing in the adjuvant setting, that will shift to the new. We've seen that with MSI-high tumors, right? MSI High tumors, we showed exceptional responses in the neoadjuvant setting and that has been shifting.

Even though it's not even standard of care everywhere, it has been shifting to treating patients more and more with neoadjuvant immunotherapy because it's better than the alternative that we have had. So I think when you show -- if you show that this is better with neoadjuvant immunotherapy than the standard of care adjuvant chemo, then it's going to become much easier to treat a much larger population with neo-adjuvant immunotherapy.

Great. Professor Telavi. There's also a question too. There's -- we have a lot of our investors as well as the public that follows along quite closely with all of our clinical studies. And Dr. Kasi, there was a specific question here. about the Nest 3 study and how that's evolving with your program and how that fits in with the strategy now moving forward with the Robin study? And maybe you could share a little bit about how they actually complement 1 another.

Exactly. So that was exactly my comment. As of 2 weeks ago, we actually dosed our first patient. So registrational studies like this. It's not a competition with investigator share trials, things that Dr. Telvi will continue to do on the new basis or invest initiated trials like Nest 1, 2 and now 3 and ongoing work by the talent colleagues. These are investigator initiated efforts that will continue in parallel. They have separate goals.

While the registrational study will hopefully bring this to the larger patient population in standard of care. There is a deeper understanding that you can learn from transportational studies. -- other aspects that go in tandem with some of these investigators share trials that are not always possible in a Phase III setting. So that is actually officially open and enrolling. And I would imagine that the other investigatorial trials will continue as well. And will continue to complement and support each other.

Great. Dr. Kasi. Garo, this next question, I think, would be best for you to answer. There are some questions in the chat. Certainly, this is an exciting opportunity where Agenus things that we can provide the most value to patients in the neoadjuvant setting base of everything that we heard today. There were some questions, however, related to what's going to happen to the patients that are on the current Batman study? And what do we anticipate to do with the the French AAC as well as the name patient programs that are helping to provide access in the later line setting. Can you comment on that, please?

Certainly. First of all, with regard to patients on the current BAT and BAL study, CCTT is a great organization. their intent to address the needs of late-stage patients is a very noble one. And when we were proposed this study, we embraced it because of the great patient need and because of the fact that CCTG was subsidizing through their own network, a good chunk of the financial needs of the study.

All along, as we did this, dating back to the earlier part of this year, we knew that the neoadjuvant setting and thanks to the work done by Professor Chalabi and Dr. Kasi, Dr. DeFilippo, in Italy and others that this would address a significantly greater need for patients. And so when the financing became a reality, we decided to focus on this.

Now back to the patients on the existing BAT study, we certainly will meet all of our obligations to those patients in terms of providing study drug. And with regard to other late-stage programs that we're undertaking right now in France, the French authorities had review done for the dire need for these patients in the late-stage setting.

And the French government, as you know, is paying for these patients, and that will continue. There is a very important need. Unfortunately, it's only for French nationals, but we have instituted a paid name patient program whereby patients from anywhere can travel to locations such as the U.K., Switzerland, France, Belgium, Spain, Argentina and Brazil. and get treatment with pay auto packet.

Unfortunately, this is for patients that can afford to this, but we hope that, that number is going to be growing, number one, because there is a great need for these patients' treatment. And we've also had some proposals from some novel patients to potentially fund through philanthropic effort, for patients that cannot afford to do this out of bucket.

So -- but the bottom line for us is to really exercise our judgment based on our resources to bring BAT and BAL the finish line as soon as possible. And that is the intent of the company.

Thank you, Garo. There's another follow-up question. There's been some questions in here. And I think it would be helpful just to clarify. -- why the actual shift from the Batman study over to the ROBBIN. And we went through that, and Robin Taylor shared a little bit about the commercial opportunity as well as the clinical potential for patients, but there are some questions here related to, was there any outside circumstances related to data or FDA feedback that really perpetuated our development decision.

But I know this has been a developmental internal strategic discussion for quite some time, but maybe you could reinforce and clarify that a bit more.

So the answer is no. There were no exogenous reasons for our shift to the ROBIN study. As you know, we started enrolling this at the end of March or early April. And so it's impossible to gather data in such a short period of time. to suggest that the study is going one way or another. So the answer is absolutely not that the FDA and the absence of data where the triggers for is the Dr. Taylor, I think, articulate this very well.

It is an important consideration for us to help greater numbers of patients in a setting where the impact is significant. The impact, as you heard from Kasi is significant in the sense that and Chalabi also mentioned this, that you're seeing an effect in a very short period of time with a limited number of drug administrations and that is a very big impact for patients.

So the answer is very simple for us. Strategic patient impact greater number of patients affected. And in the future, of course, we will do what is in the best interest of the overall patient population.

Thank you, Garo. And another question here. Perhaps, Gary, you could start off. And then with any of the other members of the executive team want to join in. There are some questions related to accelerated approval and whether or not we might be able to still consider that for the late-line disease, and as our current strategy neoadjuvant enable a potential for accelerated approval as well.

Okay. So the question of accelerated approval. Of course, it's an open question. It is going to be a function of several things for us, number one. Our resources, and I don't then just financial resources, but also overall people resources.

We're a small company. We cannot focus on very many programs simultaneously, large companies can. So with regard to accelerated approval, I think we have a substantial amount of data generated. We don't plan on having additional data generated. Other than the programs that I spoke about, the franc program and the named patient program. And the decision on whether or not we pursue accelerated approval is going to be driven by 3 things: The FDA's input because we're unwilling to go on a wild goose chase, so to speak, and hope and pray that the FDA will proceed with our accelerated approval strategy. So that's number one.

French authorities certainly have put money into supporting this setting. And so that's one.

Number 2 is the strategic considerations for the company. And Dr. Taylor is a major driver of this consideration. There are many factors that we haven't discussed and for confidentiality reasons, we will not discuss publicly.

And the third thing, as I said, is the financial resources and people and resources that will drive this decision. So stay tuned, and we will be very transparent as we have always been on our path forward. based on all of these considerations as the time unfolds.

Thank you, Garo. I just have 2 other quick questions before we close the call. This one is for you, Robin Taylor, there was a question, given all the time lines and the study. Can you share and reiterate the loss of exclusivity and the patent life for BAT and BAL that's something that you're able to share?

Yes. No, I saw the question asking. I think basically, the question is asking, are we going to be able to complete the study, get to market still with a good window in terms of the loss of base electivity, the answer is yes. We have public information on sort of the patent term. But then there's always patent term extension. So coming up with an exact number is not something that I would venture, but certainly, there is a good runway for the product.

Great. And Dr. O'Day, there was a question here. We briefly mentioned that Nest on Unicorn. So those studies had data presented at as ASCO GI back in 2025. But with the information that you have and can share, when would we anticipate having updated data on that? And Dr. Kasi could probably rev to that as well.

Thank you for the question. So as you know, we showed you data that was publicly presented about a year ago for both of these trials. Obviously, the trials have continued to mature and are both under active manuscript review, and we expect some data very soon on, hopefully, publications that will be very, very meaningful, not only for the clinical results, but the translational results that will really help clarify the mechanism of action of BAT and BAL how cold tumors turn hot. So stay tuned. This is going to be very exciting data.

Great. And I think 1 just last question, and then we'll close before the top of the 9/30 mark here is related to the French AAC program. Dr. O'Day can you maybe just clarify whether or not we're still collecting data from that program and how that will be -- continue to be utilized.

So it's a good question. This is a very rigorous program to the French government that, number one, they looked at the data very carefully before making decisions to reimburse. But there are data collection and outcome data, not as rigorous as a clinical trial, but real-world outcome data that we are collecting under their guidance as part of this program. And so there will be data on these patients also.

Well, thank you very much for our special guest, Professor Chelabi and Dr. Kasi and for the rest of the executive team for this call this morning. for those attending globally this afternoon. We will have a replay of the the actual event, the webcast up on our website shortly, along with the presentation from today. and there will be a follow-up engagements in certainly the coming number of weeks as we look to our next earnings as well for additional questions and answers. Thank you all for your participation and engagement, and have a great day.

Good afternoon, everyone, and thank you for joining us. I'm Stefanie Nacar, Chief Communications Officer at Agenus and welcome to our March stakeholder webcast.

Today's discussion comes at an important moment for oncology and for patients whose cancers have historically remained outside the reach of an immunotherapy. And on this last day of Colorectal Cancer Awareness Month, we continue to acknowledge that CRC is one of the clearest examples of this.

Recent published data from the American Cancer Society showed that colorectal cancer is now the leading cause of cancer-related death in people under 50 in the United States with mortality in younger adults continuing to worsen. And for the vast majority of metastatic colorectal cancer patients, those with microsatellite stable or MSS disease, conventional immunotherapy has historically offered limited benefit.

And that gap, Agenus is focused on closing. Our goal is to extend the reach of immunotherapy to patients who have historically been left behind, particularly these MSS tumors, which account for approximately 95% of metastatic colorectal cancer and a substantial portion of solid tumors more broadly. These tumors are often described as cold. More simply, they our tumors the immune system has not effectively recognized or engaged. Our strategy is to change that.

Today's webcast will show how that strategy is advancing across 3 fronts: clinical development, responsible patient access, and the operational readiness required to bring these therapies forward. You'll hear how those fronts are beginning to converge, expanding our global access through a program such as France's AAC program advancing the Phase III BATTMAN trial and continuing to build a clinical dataset across multiple tumor types. Because in oncology, real progress is not defined by a single headline. It is defined by more reproducible clinical activity, durable benefit and the ability to extend that benefit to more patients over time, while considering their quality of living.

Before we begin, a brief reminder that today's discussion includes forward-looking statements, please refer to our SEC filings for additional details on our website. So as I mentioned, today's program will walk through the progress we're seeing from access and real-world experience to clinical execution to commercial and operational readiness.

Following these discussions, Agenus leadership, including Dr. Steven O'Day, our Chief Medical Officer; and Dr. Robin Taylor, our Chief Commercial Officer, who will join Garo for a live Q&A. Questions may be submitted at any time during the webcast by using the QR code on the screen or by visiting slido.com and entering the event code showed below.

With that, I'm pleased to introduce our Founder, Chairman and CEO, Dr. Garo Armen. Garo?

Thank you very much, Stefanie, and thank you, everyone, for joining again today. We're going to repeat some of these points that Stefanie made because they're very important.

Let me begin with a simple point. The need here is not hypothetical. And butt valve's ability to help patients is not an abstract idea anymore. Practicing oncologists are seeing these patients are asking for it, and requests are now coming from all over the world, literally all over the world. As we all know from recent published data, colorectal cancer, as Stefanie said, is now the leading cause of cancer-related deaths in adults under 50.

Now what's worse is that those under the age of 50 are often diagnosed with late-stage disease, advanced disease. It used to be that colorectal cancer got caught early because of colonoscopy and other diagnostic techniques, but now that has changed. People talk about the magic of recent advances made for certain types of colorectal cancer. But what's often getting left out is the fact that this magic benefit is only in a small fragment of the patients.

Of course, it's very important what we've accomplished with immunotherapy even in the 3% to 5% patients that are called MSI-high disease. But the overwhelming majority of metastatic colorectal cancer, which is known as MSS disease, microsatellite stable disease, where conventional immunotherapy has not shown any benefit.

So far, most CRC patients treatment is still in that 95% plus group is dominated by cytotoxic therapy. With all of its handicaps toxicity, and without a possibility of a cure.

Now at Agenus, we are changing that reality. For decades, our conviction has been that the immune system when properly engaged, can do what conventional approaches often cannot. That is why our focus is not on one tumor at a time, but rather our focus is on the immune system itself, how to activate it, how to sustain that activation and how to disarm the cancer's defenses. This is also very important. That's where the combination of botensilimab, BOT; and balstilimab, BAL, comes into question.

So for many years, we've been considering that cancers other than melanoma and in some cases, renal cell carcinoma have been beyond the reach of immunotherapy. Now Dr. O'Day is an expert in this because when we started the company 30 years ago, we were told repeatedly that immunotherapy only works in melanoma, and that's a very small market. And now we know that with the advent of PD-1s and other immunotherapy techniques, that's no longer the case.

So immunotherapy's reach has widened, but not wide enough. So when you begin to see durable activity in tumors, long described as immunologically cold, as Stefanie said, you're not looking at a small incremental step. You're looking at the possibility of expanding immunotherapy to patients who have historically been excluded from this benefit, with the possibility of a cure for some.

And we also know that the earlier we treat the cancer, the greater the possible outcomes. For example, when you look at our neoadjuvant data, what you see is something remarkable. Within 6 to 8 weeks, with just BOT/BAL in so-called immunologically cold tumors and even in the hot ones, tumors literally melt away. And that is something that we've never seen with immunotherapy, particularly in cold tumors.

And importantly, we are seeing this across multiple cancers. Our BOT/BAL program now includes more than 1,200 patients treated across 9 tumor types. And across those studies, the continuous emergence of data is not merely response rates but the durability of these responses.

And Dr. O'Day points this out repeatedly because responses can be transient. But when responses become durable, then you basically can live with your disease for the long time or the long term and you could be cured. So these types of outcomes have been historically very hard to achieve, particularly in cold tumors.

And of course, this matters scientifically. It matters clinically. And above all, it matters for the patients the most. It also reinforces a central idea so-called cold tumors, which represent, as we talked about, the great majority of cancers are not beyond the reach of immune control. They have simply not been engaged by the right immune mechanism, which is what we specialize in, and we are changing that reality.

So with all this momentum, 2026 is an important year for us, but most importantly, for the patients. An important year for patients because our access is expanding, an important year for us because we are streamlining that access, prioritizing regulatory filings in the U.S. and Europe and moving with urgency on commercial product readiness, which is critically important, by the way, for approval for both BOT and BAL.

And when you see the remarkable effect of BOT/BAL in patients, it would be heartless not to make access a high priority for patients. The broader role of immunotherapy is expanding. But the more important question is whether the patient population benefiting from immunotherapy expands with it. And this is what our mission is. That is our highest priority now. That is the opportunity in front of us, and that is exactly what Agenus is built to pursue.

Now to build on that, you're going to hear from our colleagues, and I'd like to turn this back to Stefanie, who will be speaking with our Chief Medical Officer, Dr. O'Day, and also other members of our senior team, and how those data are shaping our development strategy, starting immediately. Stefanie?

Great. Thank you so much for that, Garo. And Steven -- Dr. O'Day, it's a pleasure to have you here with us and me getting the opportunity to have this one-on-one dialogue. And we've really built this session today because we've received a tremendous number of questions, both through this forum in past webcast, but then just in other forums. So hopefully, this will shed some light on some questions that we've been receiving.

But let's start off a little bit to talk about that clinical progress with BOT/BAL. So to start off, Garo was just talking about, in general terms, the really broad data set that we have for BOT/BAL. As a clinician and from a clinical perspective, what stands out to you most about the data set thus far?

So thanks, Stefanie, and it's great to have the opportunity to sort of weigh in here as the Chief Medical Officer of Agenus. I think Garo really set this up beautifully.

And as background, I want the audience to know, I've spent 30 years in the clinic prior to joining Agenus at the forefront of the checkpoint revolution in melanoma. And we took in refractory disease, patients that were destined to die in 6 to 12 months, almost uniformly. And with targeting not the tumor, but the immune system by unleashing first -- the first checkpoint CTLA-4 and then the second checkpoint, PD-1 and then in combination, we took advanced melanoma refractory patients with brain, lung, liver mets with 6 months to live. And with ipilimumab CTLA-4 alone, we cured 1 in 4 patients and with the combination, half of the patients.

I got to watch this extraordinary paradigm-shifting revolution of immunotherapy. What's more, this was relatively short exposures of immunotherapy in a very advanced disease setting and the patients who benefited were treatment-free and long-term survivors and eventually, we know cure. So that's the setting I saw. Unfortunately, as we move these drugs out into, as Garo described, cold or poorly immunogenic tumors, we did not see the same immune recognition. And this was the fundamental limitation of CTLA-4 and PD-1 first generation.

I became involved with the Scientific Advisory Board at Agenus, and I saw the next-generation CTLA-4 botensilimab and its mutational Fc engineering, the promise to unleash these T cells in a more potent way against cold or poorly immunogenic tumors. I was the primary investigator on the Phase I first-in-human trials, and I started to see very similar patterns to melanoma, but in tumor types that had no business responding, MS stable colorectal, refractory ovarian cancer, sarcomas, and this really prompted me to want to join Agenus and really drive this forward.

So I've been in the clinic with melanoma with first generation. I've been in the clinic with botensilimab and balstilimab in this next gen, and I've watched the paradigm moving where it's never been before. So to get back to your original question, what is the BOT/BAL data showing us? We've treated over 1,200 patients across a number of tumor settings, as Garo has mentioned. What are we seeing? And why does it impress me? Well, what really stands out is the consistency and reproducibility of our clinical results.

In oncology, particularly in immunotherapy, isolated exceptional responses can occur in a data set. However, when meaningful clinical activity repeats across multiple data sets across multiple tumor types and matures with time into more durable benefit, confidence in the benefit of the therapeutic intervention is significantly heightened. And that's why I am in reviewing this data to date.

With BOT/BAL, we are seeing consistent, meaningful clinical activity in tumors that have historically been resistant to checkpoint blockade. Importantly, we see this activity translating into long-term survival, including treatment-free survival, a hallmark of effective immunotherapy and a hallmark of the melanoma IO revolution. This is highly unusual for these heavily pretreated populations of poorly immunogenic tumors.

That combination, the breadth of our data, the consistency of our data, the durability with flattening of OS curves over time, it's reproducibly is what makes these data sets compelling.

Thank you so much for that, Steven. And thank you, too, for just sharing a little bit about your history because I think it's so relevant and to share the context of what never thought was possible in melanoma and now setting the stage for hope for additional tumors as we move forward.

So you talked a lot about durability. Can you maybe just share and expand upon that a little bit more about what you're seeing in terms of this long-term outcomes in that regard?

So durability with checkpoint inhibitors, particularly CTLA-4 as a hallmark feature. And why is that? Less so with PD-1 except in very highly immunogenic tumors. But CTLA-4, the hallmark is durability of response and long-term survival plateaus.

And this is because CTLA-4s, when they're working, either in hot tumors historically or now in colder tumors based on botensilimab's engineering are causing an expansion of T cell repertoire through the Fc engineering of botensilimab. This tightens the synapse between the antigen-presenting cell and the T cell, this critical synapse that actually drives T cell recognition of tumors.

So tumors that are more hidden to the immune system, which is the vast majority of these cold solid tumors, get away with not being recognized. But by making the Fc-enhanced portion synapse sticky with botensilimab's engineering, it's forcing the T cell to spend time to recognize tumors that are poorly immunogenic. And once they're recognized and they expand their T cell repertoire, you're able to get durable responses, long-term disease stability and long-term survival in some of these patients without additional treatment. And that's what we've really seen in this.

So it's a one-two punch. But the foundation is not the PD-1. The foundation to cold tumor recognition is a CTLA-4 that expands the T cell repertoire with memory and potency. And then the PD-1s are like pouring gasoline on the fire and drive these T cells and prevent them from exhausting. You can't eradicate cold tumors with PD-1s. They simply are not the fuel. CTLA-4 and botensilimab is providing the fuel to cold tumors and PD-1 is driving it further. It is a one-two punch and the combination is essential.

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

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

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

Well, I think it's critical because it's directed to the immune system not the cancer. So the fact that we have sort of a tumor-agnostic mechanism. Now certain tumor types clearly may benefit better than others even in an immune-directed approach. But the fact that we're seeing remarkable consistency in our pan solid tumor data of over 400 patients that we presented at ESMO at an oral plenary session this year, the consistency was remarkable.

And this included MS stable colorectal cancer, ovarian cancer, hepatocellular cancer, non-small cell lung cancer and sarcomas, among others. But the consistency in this refractory setting of seeing deep durable responses in approximately 20% of patients with prolonged stable disease and most importantly, survival plateaus emerging after 2 years and approximately 40% of patients alive at 2 years. This is really groundbreaking because it's pan tumor.

In this large database, we also saw responses in liver mets and non-liver mets in patients who had failed IO as a first line of therapy and who were naive to prior IO therapies. Again, consistency across tumor types and disease settings.

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

So I think to set up the BATTMAN study, the work that we've done in the last 5 years, both in the Phase I setting with a large expanded cohort of MS stable non-liver met population as well as the Phase II setting global trial, we've shown that we have demonstrated contribution of components, single-agent activity, and dose selection, which has been aligned now with regulatory bodies. This is obviously a huge amount of important regulatory work that sets up a registrational trial.

And we've now really opened the BATTMAN trial, and this is obviously the next logical step. It is critical that we design and test this in a randomized Phase III setting with survival as the signal, and that's what the BATTMAN trial do. It focuses on refractory MS stable colorectal population, both the liver met and non-liver met populations, and it's powered to address both. We think that there's clearly a benefit in the non-liver met population.

We also feel strongly that there is a benefit in the liver met population based on our pan tumor data as well as our limited data to date. So we're going to look at the broad refractory MS colon patient population that has failed all available therapy. Obviously, that's the subgroup in the Phase I and Phase II trial that are producing 20% response rates and durable survival plateaus and median survivals of approximately 20 to 21 months. So that is the setting that's been derisked for the BATTMAN trial and it's being compared in a global Phase III trial to the best supportive care.

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

Yes. So when we did our initial Phase I trial, we obviously started to see a stronger signal in terms of objective responses in the nonactive liver mets, meaning population that either had treated liver mets or never liver mets. We did treat a small group of active liver mets. These were advanced patients in a Phase I trial with heavy burden of disease. We did see disease stabilization, some tumor shrinkage, but they didn't meet the RECIST criteria response, although the median survival of that group outperformed historical controls.

So -- and then across more broadly, our 400-patient solid tumor program, we're clearly seeing RECIST responses and deep durable responses in active liver patients. So yes, liver met patients have more challenges with IO, but we think there is effect there. And in the CCTG large previous CTLA-4 -- first-generation CTLA-4 PD-1 trial, despite having no objective responses, they essentially had a trend in survival even in that small randomized Phase II trial. For those reasons, we think that all patients with metastatic colorectal cancer that have failed therapy should be -- have the opportunity to see the benefit of BOT/BAL in a survival analysis.

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

Yes. Well, I want to reassure people, we are absolutely focused on the data we've collected in colorectal cancer in the refractory disease setting and driving the BATTMAN global Phase III trial to completion and hopefully successful registration. But as you know, from the data that we've presented over recent years, we have broad signals in other solid tumors in the refractory setting.

But as Garo mentioned earlier, the future of the next generation of IO is both a next-generation of IO is both -- a next-generation of CTLA-4 that does what first generation didn't, which is to drive T cell priming and memory and deep responses in cold tumors combined with PD-1. And we're really -- and the earlier the disease setting, the better. And this is the melanoma paradigm, again, that I want to refer to. In melanoma, we started in the very late-stage, end-stage melanoma setting. We moved to first-line metastatic setting with the checkpoint drugs.

And the real progress in recent years has been to watch the neoadjuvant setting explode in melanoma with curative therapy in almost 2/3 of patients with large primary nodal disease. And that's because having an intact primary tumor is the perfect reservoir to educate and expand the T cell repertoire. Now you have to have an active CTLA-4 in colder tumors. We have that in botensilimab. You have to have an active PD-1 that drives these expanded tumors. We have that in balstilimab.

But we also have very important data in both a U.S. study and Italian multicenter trial, the NEST and UNICORN trial, showing that just a very limited 6 to 8 weeks of 1 dose of BOT and 2 to 3 doses of BAL followed by surgery results in complete or near-complete responses in approximately 40% of patients in 4 to 8 weeks. So this data is compelling. We hope that it will be published in the near future. And this will drive us to look for opportunities for a derisked Phase III randomized trial in the colon cancer setting.

Why am I enthusiastic about that being derisked? It's because these pathologic responses, which are approximately 40% in the data that we have to date in a cold tumor have translated historically in hot tumors to very consistent and robust EFS data. And in our data sets, both the Italian and U.S. studies, we show deep pathologic responses. We show clearing of ctDNA. And most importantly, we have not seen recurrences to date in the data reported to date in terms of follow-up, in terms of events, free relapses.

So all of this is aligning to a very powerful ability to impact and potentially deescalate therapy as we go. And going forward, we obviously have other tumor types we're going to continue to update across our solid tumor program as well as melanoma, which we'll be updating at conferences this year. So a lot of additional data in addition to the neoadjuvant data.

So that's exciting. So a lot of exciting data that set the foundation in 2025, and it sounds like without giving too many specifics, a lot of exciting potential data thus to come in 2026. So with that, thank you so much, Steven. This has been a really engaging conversation and a lot of insight and background about why we're so feel positive about the potential impact that and could make for patients moving forward.

So with what we're seeing clinically, it's now beginning to translate into real-world interest from physicians seeking access to patients pursuing the treatment through international pathways. So to build on everything that Steven just walked us through, we are originally going to have Kamal, our Head of Medical Affairs, walk us through more what this looks like in practice with some more specificity around the named patient programs and the French AAC. He unfortunately is out on medical. He's ill today. So Garo is going to be jumping in to walk through some of the details about these programs.

So to bring Garo back in, maybe Garo, you could start off in explaining how the paid named patient program actually works.

Just first off, patient access historically has been in the context of either clinical trials or we had a very robust compassionate use program. And clinical trials obviously are now limited to Phase III trials that are meant for registration with the exception of several ISTs that are mostly sponsored by institutions, but those are small trials.

And the compassionate use program, we had to terminate those sadly. Why? Because there was an explosion of requests for compassionate use. And as the explosion of requests occurred, it became untenable for us to deal with the cost of doing that. And the cost was both administrative costs, mostly external costs that we hired companies to do that with as well as the product costs. So volumes drove us to basically eliminate that program.

And with the grace of the French government, we had the AAC program that was administered in France. And that is a program where [indiscernible] who meet the criteria for colon cancer, for sarcoma and for ovarian cancer have access to BOT/BAL with the full reimbursement by the French government. But in addition to that, we also instituted a paid named-patient program. And the paid named-patient program can be administered in countries that allow it.

And those include, for example, Britain, U.K., Switzerland, Brazil, Argentina and several others. And what those programs allow patients to do is if the doctors request BOT/BAL and they're willing to pay out of pocket for the cost of BOT/BAL, then they have the opportunity to be treated with BOT/BAL. And we're seeing now both programs, the AAC program growing in numbers as well as the paid named-patient program growing numbers.

Now I just want to make sure that the world understands we're not promoting anything here. It is strictly based on requests that come in. And those requests come in from physicians, word of mouth or knowledge as well as patients.

Great. Thank you, Garo. So just to kind of then summarize because there could be some confusion, right? There is the French AAC program that has -- is being reimbursed by the government, but also in countries that allow outside of France, the named-patient program allows individual patients to be treated, again, across multiple tumor types as well as the French program is covering both the metastatic MSS late-stage colorectal cancer as well as certain sarcomas and platinum-resistant ovarian cancer.

So there are 2 different programs, but they offer patients different pathways still while the development is ongoing to receive access of BOT/BAL, which has been initiated by the physicians themselves. So you touched upon this a little bit just now, but can you share maybe a little bit more because we've had a lot of questions about the global interest and what that looks like to date and what that tells us?

So what's interesting is that we're getting a substantial number of inquiries from as we've stated before, 30 different countries, 270 inquiries. And this is through the end of March, which is basically today. And this is happening because sadly, patients are desperate for treatments, desperate. And even patients who are not desperate for treatments would, in some cases, prefer chemo-free options.

And that's what, of course, BOT/BAL offers. It's a chemo-free option. And so the demand is growing. There's no question about it. We will qualify -- I mean, quantify this on our next earnings call in terms of percentages, not in terms of numbers because we don't want people to calculate the cost of the product. there are sensitivities associated with that. And there's also competitive concerns associated with that.

But what's interesting to me is that physicians from the U.S. are calling us and saying, we have XYZ patient, and she or he would like to be treated with BOT/BAL, where can we do it? And so we provide the referrals, but we don't tell the physician or the patient to be treated with BOT/BAL because that would be promotion. And that is not the intent of either the French AAC program nor the out-of-pocket paid named-patient program.

So we're very encouraged with the trend that is developing. And what's also important is that up until about a month ago, we did not really have a formalized effort in medical education. So typically, as you know, companies that are doing clinical trials have a medical education department. But because of our previous budget cuts, we had pretty much eliminated that and Dr. O'Day and some of his colleagues were providing medical education. But in the last month, we have formalized our efforts to put into place a medical education department as well as medical affairs.

And the importance of this will be not just educating patients and doctors on the data that's been published. And as you know, we have published extensively in peer-reviewed journals, and we have also presented extensively at the major conferences. So with all of that, we are delighted that we have a number of professionals in place now who can educate people. And that is going to be a very important part of our undertaking.

And the same department, the medical education and medical affairs department will also be in charge of collecting real-world data from the experiences that we have with patients under both the AAC program as well as the named patient program. So that collection, both from a regulatory perspective as well as an educational perspective will be a very important part of our undertaking going forward.

That's great. Thank you so much for that, Garo. And I think one of the third element that we've spoken about a bit too is not just on the education and certainly the real-world experience and that data helps in so many different ways, but particularly ensuring patient safety and that physicians that may be new to BOT/BAL get experience but understand how to dose it, how to manage any potential side effects and making sure that the patients receive the best outcome possible and understanding how to do that appropriately.

So I know that the team has been fielding a lot of patient safety-related questions so that they can ensure that the patients are at the forefront and retain the best experience possible. So as we think about just a little bit more in closing, you mentioned some of this, Garo, about beyond access and the clinical insights and the real-world data how should we be thinking about the broader impact of these programs and really what that potentially means for patients now helping to receive access to these treatments in addition to the real-world experience that physicians are receiving?

So certainly, for French citizens or residents, the French government is underwriting the cost of treatment. And that's a very, very important thing to do. And French government actually and the French regulatory system has been among the most sophisticated in the world when it comes to oncology as well as when it comes to early adoption of immunological treatments for oncology. So that's one piece of it.

Now with the paid named-patient program, I think given the fact that patients will constitute a wider group of people or patients that may have different stages of disease or may have even different cancers, that kind of data is going to augment the phenomenal data collection that Dr. O'Day and his team have engaged in, in the last years. And I think the collection of that is going to have very, very important implications for us from a regulatory perspective because the totality of the data, I mean, for example, when we had our Berlin pan-tumor presentation, at that time, the presentation was in over 400 patients across 9 different tumor types.

And what was remarkable about it is that there was a narrow band of activity threshold for patients. For example, if you looked at survival at 2 years across all of these indications, it was somewhere between 39% and 41%, which is remarkable, which substantiates the point that I made earlier that we're not going after a specific cancer. We are really training the immune system to fight cancer. That is the key to all of this. And so this broader activity is going to be something that doctors are taking notice of.

And there are patients, by the way, not insignificant numbers of patients that when they hear about the attributes of immunotherapy and the well-known shortcomings of chemotherapy and other toxic treatments. They go to their physicians and they ask them, immunotherapy is available for XYZ, why can't we have access to it. And so these are very important questions that both the regulatory authorities and the medical community need to wrestle with because after all, it is not just the standard of care that dictates how patients should be treated.

There's also a patient preference issue. And it's between the patient and the physician that they need to make these decisions. So we're very, very, very optimistic and also really fulfilled by the fact that at least through these programs that we offer, paid named-patient program as well as the French AAC program, at least patients and physicians have some say.

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

Thank you so much to everyone that has joined us today and engaged. We've had a tremendous number of questions that have been submitted, so I'm going to try to paraphrase questions for our leadership here. So if you don't hear your specific question, it's only because we're trying to manage over the 30 questions that have been submitted.

So with that, there's a lot of questions related to regulatory path and our approval strategy and potential endpoints and data. So Steven, I'm going to ask this question to you first, I think you can jump in here, so can you walk me through what's the most realistic regulatory path for BOT/BAL is across U.S. and/or Europe? And if there's an opportunity in for an earlier submission for a conditional use of approval?

Sure. So obviously, the main focus is the data we've generated in the Phase I and II trial, the contribution component, the selected dose and the Phase III registration BATTMAN trial that has been reviewed by FDA and EMA regulatory bodies as potentially registration-supportive. So that is obviously our main focus of a regulatory pathway.

Having said that, we continue to watch this Phase I and Phase II blended data mature. We continue to see an occasional late response that's durable and the survival plateaus continuing to evolve. And we are looking at the patient population within this group that has failed all standard therapies. And we look forward to continuing to interact with U.S. and European regulatory authorities in the coming months about this evolving, maturing single-arm data with the hope that it could be considered as a more accelerated pathway, knowing that we have a supportive Phase III trial that is actively accruing patients and generating the data that will be critical to full approval.

I would just add that, obviously, the other pathway that is of great interest to us is the neoadjuvant setting in the colorectal space, colon cancer, in particular, based on our Phase II data in the U.S. and Europe. And we're actively reviewing that data and moving forward with planning to a pivotal registration potential trial with traditional EFS as an endpoint going forward.

We think that will have tremendous potential to impact, as Garo said, the large group of locally advanced colon cancer patients, which includes young patients that are diagnosed and require surgery and chemotherapy that can be debilitating. And despite the best surgery and chemotherapy in these high-risk locally advanced colon cancers, 25% to 30% will eventually recur and most of those will die with metastatic disease.

So if we could impact that by curing them earlier with better immune drugs and deescalating eventually chemotherapy in patients who may not need it, that would be a tremendous arc to the story from late to early stage in colon cancer.

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

Thank you, Stefanie. So one thing I think to look at is that we have 2 different types of programs. One is the named-patient program. And the people who express interest in that come from both a mix of patients and physicians. In order for a patient to actually receive BOT and BAL through the named-patient program, they need a physician who will send in the request, but we do get a lot of requests actually from patients who we can then help them understand the pathway.

The French AAC program in terms of the paid access has only been open really for -- opened in the last quarter of last year. And in that quarter, we saw a lot of interest, but there was also building awareness about the program because the access program had already been open. Colorectal cancer was approved through ANSM as an access program. Subsequently, ovarian cancer and sarcoma were also added. And so all of those are now available in France for physicians to request access for their patients.

We saw actually $3.2 million in realized revenues in the fourth quarter of last year across both the named-patient program and the French AAC. And we're seeing an increase in the interest in France, I think, probably as physicians speak to each other and there's greater awareness about the program.

In terms of how this impacts us for the commercial side, there are 2 things. One is that physicians are getting broader experience with BOT and BAL. And we have our medical affairs organization on the ground in France now to be able to help physicians understand the best way to manage patients, ensure that they're being safely managed. And that's really important because as we transition at some point to commercial access for BOT and BAL, the more physicians who have already used BOT and BAL and understand how to treat patients appropriately, that will make things a lot easier for a commercial launch.

So it's really a unique program in France that the French government recognizes that this early access is a way to actually benefit patients not only before the drug is approved, but also afterwards because physicians who have more experience are also going to be able to treat patients more appropriately in the -- as Garo mentioned, the real-world data from this program will also be helpful, both for regulators, but I also think for the discussions that we have with payers, having that real-world data really demonstrates that the BOT and BAL are performing as has been seen in a clinical trial.

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

Well, I think the first thing it tells us is that there is already awareness of the data with BOT and BAL that is driving this interest in -- for French physicians for the named-patient program, we do see there's a lot of awareness. So awareness is always important in the commercial launch.

Secondly, I think the question might also be getting at the economics in terms of things like pricing. And our pricing for BOT and BAL is at a point where we anticipate that this would be reasonable for our commercial pricing. We want to make sure that we're not undercutting our future potential pricing on the commercial side, but come in with something that is recognizing the value that BOT and BAL delivers in terms of the full benefit, everything that we're seeing in the clinical trials and how that translates into long-term benefit.

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

Yes. Well, there's 2 elements to this. One is the competitive landscape or the options that patients have in late-line colorectal cancer. And in that setting, there are already 3 approved drugs in the late-line colorectal cancer setting. There may be more coming. If you think about it from a patient benefit perspective, the more options there are, the better. And then is where does BOT/BAL fit into that. Our initial indication with the BATTMAN study is in this late-line setting after patients have exhausted available therapies. How that's used in the real world, this is where once the drug hits the market, physicians will start to figure out where does this fit in their treatment paradigm.

Secondly, as Steven talked about, we have data now in the very early disease setting. So in the neoadjuvant setting, we're seeing really encouraging data with BOT and BAL. And that we hope is going to lead to a registrational study in that early disease setting where really there have been no significant advances in colon cancer for essentially the last 20 years. The last drug approved in the adjuvant setting for Stage 3 colon cancer in not MSI-high is essentially oxaliplatin or Eloxatin. And so we think that there's a really tremendous opportunity to be able to improve on event-free survival, overall survival in that setting. And that would be a real game changer for these patients and certainly would be a situation where we don't see any real competition at the moment for BOT and BAL in that setting.

The second part of the question is really around other immunotherapies, other CTLA-4s that are in development. We have a tremendous advantage with BOT and BAL in that this is a very unique molecule. It was designed, as Steven described, with -- to be engineered to improve T cell priming and activation and generate T cell memory. Those modifications are fairly unique to botensilimab. So there are other immunotherapies that are looking at different ways of modifying CTLA-4 or other types of constructs, but they are distinct from what we've seen with botensilimab.

And so not only do we have the advantage right now of having a bigger data set so that we've been able to see the effect of botensilimab across multiple cold tumors, but we also believe that we have a molecule that we're going to be able to advance not only in colorectal cancer, but ideally be able to take across to other cold tumors where we've seen significant data.

Great. Thank you so much for that, Robin. So with that I think we have one last question for Garo. I think we're almost top of the hour. And so Garo, this question just came in a little bit late, just later in the day today after we started the call. And it's something that you've been talking about internally as well.

And the question actually is related to, we had so much strong data that's been presented over the course of 2025. We have spoken a lot about potential milestones or catalysts. What's ahead for us in 2026 and the execution that we're focused on delivering? However, the market doesn't seem to be responding to the value that we believe that we have in BOT and BAL and what that could offer to patients in colorectal cancer and potentially in the future beyond. What is your thinking and why do you think that's the case?

Well, let me just address this with some of the facts. And the facts are, as you stated, Stefanie, there is a disconnect between the progress we're making, and this is real tangible progress with patients and the value the market assigns to Agenus. Now of course, part of that disconnect is simple. Taking BOT/BAL all the way to approval, which we're getting closer and closer to, we believe, scaling it.

By the way, we have done most of the scaling already. And by scaling it, I'm talking about significant quantities of commercial-grade product. We've done really a phenomenal job of advancing that and commercialization, which I'm hoping that will not require very much based on the demand that we're seeing or the requests that we're seeing from physicians and patients. Of course, to be competitive, you need to have a bit of a commercialization effort. But all of these things require capital as well as getting through the details of the clinical trials.

So that's a real reality for us, and we don't hide from it, but we're working on solutions to it. We've already taken major steps to do exactly that, strengthening the company, expanding reimbursed and paid access is a part of that, advancing our Phase III trial, pursuing the regulatory paths that can move BOT/BAL much closer to patients and commercial reality quicker. I think that's very important. So this is not a story of promise without a plan. It's a story of proof and discipline to carry out the proof across the finish line.

Now we've had a very challenging period. I mean it is a miracle that we've gone through, persisted through this challenging period while maintaining the integrity of making sure that BOT/BAL is made available to patients expeditiously while making sure that our GMP production for both BOT and BAL, commercial-grade production is not compromised. And yes, of course, our shareholders matter in this process, not as spectators, but also as owners.

We want to have our owners who understand the magnitude of what is being built here and who recognize that lasting value is created when clinical impact, regulatory progress, access, manufacturing readiness, and capital discipline come altogether. And we've done some very creative financings in the last couple of years to be able to meet our challenges. We're not quite there yet in terms of the magnitude of capital that's going to be required, but we have actively pursuing programs. We have been, to do -- to make sure that, that gap closes as soon as possible.

So we're not going to let a temporary valuation disconnect define Agenus. We're going to close the gap with the data and execution and the results that market can no longer -- we don't want the market to have an excuse to ignore these important advancements. So that's what I think about it.

Thank you for that very transparent response. And thank you to both Steven and Robin for joining in the live Q&A and for everybody that submitted questions. We're going to close the Q&A session for now but for any questions that we did not have an opportunity to answer, we will be sure to carry forward into future webcast.

With that, Garo, I'll just turn it back to you for any type of closing remarks that you'd like to make before we close the official call today.

By the way, I apologize for the fact that Stefanie's broadcast quality voice is crackling because of some technical glitch that is not ours. I assure you but it is the system that's providing this for us. But even with that glitch, Stefanie, you came across very clearly.

So what you've heard today is not a collection of separate updates. I hope not. It is one story coming together that is the clinical data, physician interest, patient access, operational readiness. I mean, these are not trivial feats to be able to pull off. Those are no longer separate work streams. They are reinforcing one another, and that's what we're doing.

This is why 2026 matters to us. This is a year where we have to execute on all of these fronts. And what do I mean by that is the patient access program, the French AAC, reimbursed AAC, and paid named patient program. We have to execute on at least one filing in a major geography, at least that.

And you may say, well, didn't you fail in your previous filings? We haven't. We haven't, not on BOT/BAL. What we've done is a very rigid FDA opining across a virtual meeting that we should not go for accelerated approval. Well, since then, we have collected a significant amount of additional data. The data has matured, and it's been, as Dr. O'Day says repeatedly, we know that data is durable. In other words, the responses have not only gotten better, but some stable disease patients that were not yet that official -- across the official response threshold.

Now they've become responders after 2 years. I mean that speaks to the immunology's power in controlling cancer and controlling tumors. And execution on the regulatory engagement, of course, requires both urgency and discipline. And execution on the broader strategy to extend immunotherapy into cancers and patients that have historically been left outside of its reach.

As access programs expand within the proper regulatory framework, which we're doing, we're also beginning to see early pre-commercial income in certain settings like the AAC and named-patient program. That is not a story, but it is a sign that physician-led demand is translating into real-world requirements and use. We do not see this as a single milestone story. We see it as the building of a durable foundation because success is not defined by one readout or one indication.

Success for us is defined by whether more patients live longer and live better because the immune system was finally engaged in the right way. And certainly, I'm delighted that we have the right tools. And in fact, we have tools beyond BOT/BAL that we have put on the shelf for now. And as soon as we have the plenty fullness of resources, we will bring them back because each one of these programs and each one of these leads have a very sound reason why these molecules were designed and why they were taken into the clinic. And we have taken at least 5 other molecules into the clinic.

But as I said, they have been put on the shelf for now. So that remains our standard, and that remains our focus. And let me close with this. We're not here to participate at the margin of immuno-oncology, as Dr. O'Day indicated and Dr. Robin Taylor, who is one of the world's greatest experts on CRC.

We are here to change what is possible for patients who have been left out for too long. That is the work that we're doing. That is the opportunity. And that is exactly what Agenus intends to do. With all the obstacles we've encountered, we continue to pursue this mission and our expectation is that we will deal with these obstacles very expeditiously in the next 6 to 12 months.

So with that, thank you very much, everybody, and our team and our participants, and thank you, Stefanie.

Good afternoon, everyone, and thank you for joining us today. I'm Stefanie Nacar, Chief Communications Officer at Agenus, and welcome to our first stakeholder webcast of 2026. Today's discussion comes at a meaningful moment for our company, one shaped by important progress across patient access, clinical development and operational readiness as we enter a pivotal year for Agenus and for the patients we serve.

Before we begin, a brief reminder that today's discussion will include forward-looking statements. These are subject to risks and uncertainties that could cause actual results to differ. So please refer to our SEC filings for additional detail. Today's program is designed to reflect the full arc of momentum we are seeing globally from manufacturing and execution to expanded patient access to the clinical evidence needed to support regulatory pathways.

You'll hear perspectives from leaders who are directly shaping this progress. Garo and I will discuss recently closed Zydus collaboration and what enables operationally for Agenus, an expert clinical perspective on the expansion of France's reimbursed AAC program, including its relevance for sarcomas and insight into how growing physician and patient interest is reshaping our medical affairs infrastructure to support access responsibly and at scale.

Following these discussions, Agenus' leadership, including Dr. Steven O’Day, our Chief Medical Officer; Jose Iglesias, our Chief Medical Affairs Officer; and Robin Taylor, our Chief Commercial Officer, will join Garo for a live Q&A session.

Questions may be submitted at any time during the call to [email protected]. So thank you again for joining us today. And with that, I'm pleased to introduce our Founder, Chairman and CEO; Dr. Garo Armen. Garo?

Thank you very much, Stefanie, and thank you, everyone, for joining us today. We've had patients and families, physicians, researchers, partners and shareholders, of course, all of them are our stakeholders. We appreciate your time and your continued engagement with Agenus. And all because Agenus is on a very important mission, and we'll be talking about the details of that during the course of our session today.

As we enter 2026, we're doing so with a greater clarity. And that means -- clarity means lack of uncertainty. Certainly, some of the uncertainty that we experienced in the second half of last year with delayed closing of one of our important transactions. So with the recent closing of our collaboration transaction, which involved the sale of our facility in Emeryville, as well as our sale of equity at a significant premium to market price. With Zydus Life Sciences, Agenus has strengthened our ability to go about our business. This collaboration secures long-term U.S. best biologics manufacturing capacity for us because it's the facility that we built and it's the team that helped build that facility and operationalize some of the wonderful capabilities of that facility.

That will allow us to supply clinical and authorized access programs and support future commercialization, all with the same expert team, as I said, that we built. And just as importantly, it provides the capital that we need in order to be able to have a level of resilience to be able to execute our strategy with a high level of discipline and focus. And we've already started doing that in the first weeks of this year. As you know, we've talked about this, and I don't think the constituency that looks at us understands the full power of our accelerating momentum for patient access.

This started in last September with a surprise to the world of France's reimbursed AAC program. This is a program where every French citizen who is eligible for access to BOT/BAL can have access to it with the French government providing full reimbursement for it. And what began with colorectal cancer in this program has now, in the last few weeks, expanded to include sarcoma and ovarian cancer. Even though colorectal cancer is the largest indication, sarcoma and ovarian cancer patients who have exhausted other means have a very significant potential benefit from BOT/BAL. And we, of course, published and presented this data in a major setting in -- at ESMO GI in -- I'm sorry, ESMO in Berlin. It wasn't ESMO GI. It was a big ESMO conference in Berlin, Germany. It was an important plenary session presented by Michael Gordon, who was one of the participants in our previous webcast program.

These decisions namely patient access, reflect more than regulatory flexibility. They reflect urgency and a recognition that innovation must reach patients who are in need, while the confirmatory trials continue. They're very important consideration because as you know, confirmatory trials can take a long time. And while we're pursuing those as well, access to patients before, based on the data that we have generated, significant data for that matter, is very important. So the urgency that we feel, the urgency that patients feel is well founded.

When we speak about historically resistant cancers, we're talking about very specifically microsatellite stable tumors. And microsatellite stable tumors are in the form of many different types of cancers, and they represent more than 80% of all solid tumors. And importantly, more than approximately 95% of colorectal cancers.

I just want to note that, for example, with colorectal cancer, you may have heard in the headlines that there are products such as PD-1s and PD-L1s that have shown some very impressive activity in colorectal cancer patients. But remember, those are less than 5% of the patients. The other 95% of patients targeted by our BOT/BAL are the kinds of cancers that don't respond to these other currently approved products. So at the same time of all of this, the societal burden of colorectal cancer is accelerating. Just last week, many of you may have heard that American Cancer Society and Journal of the American Medical Association, JAMA, reported that CRC, unfortunately, is now the leading cause of cancer-related deaths in people under 50. We were expecting this to happen by 2030, but unfortunately for patients, and for the overall population, reaching this milestone is now 4 years ahead of expectations.

This is not just a medical challenge, it's a societal crisis. And some countries, including France, are recognizing both the urgency and the potential value of immunotherapy and responding to it. And lastly, we have the BATTMAN randomized trial. It's an important trial for us, of course. And this is a trial that is going to be launched very, very soon. It is a trial rigorously designed for a global Phase III study in the MSS, metastatic colorectal cancer, a population, as we talked about, long considered beyond the reach of currently approved immunotherapies. Of course, the level of engagement we're seeing from investigators and cooperative groups reflects a shared understanding that we're very hopeful about the quick enrollment of the randomized trial.

The early efficacy from a large Phase I and Phase II trials is driving this. When I talk about large Phase I and Phase II trials, we're talking about close to 500 patients worth of data that has been generated and now this will be tested in a randomized setting, which is next on the roster for us.

Now looking ahead, taken together, these developments shape our priorities for 2026. Expanding appropriate patient access through authorized pathways, a very important initiative. You're going to hear a lot more about that during the course of this session and beyond, preparing for global regulatory filings informed by both clinical trials and real-world evidence.

Now previously, as you know, we've had our challenges with the U.S. FDA in terms of filing for accelerated approval in the U.S. Well, there are also changes in the regulatory environment in the U.S. So we're going to diligently pursue filing in the U.S. for accelerated approval once again. And in Europe, things have been a bit more optimistic, of course, with the progressive way of thinking in Europe.

We've had meetings with the European regulators, and they have been a lot more receptive for conditional approval possibility than historically what we have faced in the U.S. Advancing BATTMAN with urgency and rigor is a very, very important priority as well. And to be able to accomplish all of this, we're scaling up, as we speak, our medical affairs capabilities. And this is going to support growing physician and patient interest and responsibility. Our medical affairs team is represented by Dr. Jose Iglesias today, and you're going to hear from him, both during the webcast session as well as during our Q&A.

So unquestionably, the role of immunotherapy is expanding. There's no question about it because chemotherapy and some of the other toxic therapies are archaic treatments, and we're confident that they will be either displaced completely by the new generation of treatments like immunotherapies or they're going to be used as adjunctive treatments to immunotherapy in the future, which is fine. And our responsibility to patients must expand with the expanding immunotherapy usage. And with that, let's begin.

Well, Garo, welcome. I'm very excited to actually be on this side of the fence talking to you today about a very exciting closure that we just had a few weeks ago with Zydus Life Sciences. We originally announced that deal back in early June of 2025. And finally, we went through a long process of getting that deal closed. Can you say a few words about that?

Well, this is a location that will allow us to have a definition on the next steps for our company, our treatment, our partners. And as you know, transactions take a long time. People don't realize that. They think that we come to an agreement, shake hands, the agreements are drafted, and here we go. It doesn't happen that way. Of course, there's extensive negotiation. And as you said, with Zydus, we really started negotiating well, well over a year ago. And then we came to a point of announcement last June. And of course, our expectation was that after the announcement would come to an expeditious closure, usually, transactions between 2 companies are governed by Hart-Scott Rodino Act, which is an antitrust regulatory act. In this particular case, it was added to that with the national [indiscernible] clarity that needed to be explored. And regrettably, that took about 6 months more.

I think we're going to get to talk a little bit more specifically about CFIUS, what you just mentioned and what that means. But maybe let's take a step back first, for those of our audience members that may not be as familiar with the deal or just joining us recently. But as you mentioned, you -- and the organization started conversations with Zydus Life Sciences approximately about a year ago, and certainly manufacturing is the heart of this transaction and this collaboration. Tell us a little bit about why Zydus Life Sciences and why this transaction and this collaboration is so important right now at this time of Agenus' evolution?

Their needs and our needs had to really match up. This is a company that has a culture. It has the absolute right intentions for the people that they're serving, which includes, of course, their patients and their employees. Zydus is basically a company that has made its fortune in the generics business. It's a $10 billion company in terms of market value. A lot of their operations on the generic side of things is in the U.S., but they didn't have a manufacturing facility in the U.S. No biologics manufacturing and as you know, a number of high value-added biologics, particularly in the oncology field, are coming of age now in the biosimilar area, meaning a number of very high value-added biologics are going to now be introduced as biosimilars in the U.S., of course.

And to do that, you need to have a U.S. manufacturing facility. And so this is what it provides Zydus with. Our pipeline is, of course, driven by biologics and in our case, our lead programs, BOT/BAL, are 2 antibodies that we aspire to manufacture in our West Coast facilities. And the beauty of this transaction for us is that it will provide us with the capital that we need right now. And it will also give us the luxury of being able to use this facility for manufacturing with the team that was also the key players in manufacturing of our product.

As we have been testing BOT/BAL across more than 9 different tumor types across different settings of disease, both in the earlier settings through some of our investigator-sponsored trials as those as well that are in the later-stage disease, like the BATTMAN study that we'll be enrolling patients shortly. Your vision was to have a fully integrated operation in which we could serve patients faster, more quickly, control costs, housing manufacturing really from the beginning part of drug substance to supply to fill and finish and labeling all underneath one controlled setting. Manufacturing tends to be one of the most challenging aspects when you launch a drug to make sure you understand demand that you have enough inventory in place. Can you share with us a little bit about your vision for Agenus West and what you and the team were able to foster and build which was really the interest mark from Zydus Life Sciences to really utilize those facilities as their flagship locations for their CDMO business in the U.S.

You have a treatment that may be in high demand upon approval. You want to make sure that you don't find yourself of not having appropriate supplies of the product, that is the cornerstone of this treatment. And I've learned this lesson from many years ago with my affiliation with Immunex when for a wonderful arthritis product that was introduced. They couldn't produce enough and so they had to put patients on a lottery. So that has been impregnated into my head. And so many years ago, I thought that we wouldn't really want to find ourselves in such a predicament should our product be improved quickly and the demand for it should skyrocket. And that's why we want to have our own manufacturing facility. And so the Emeryville facility, which is a commercial facility, who fills that dream for everything is [indiscernible]. And so with this transaction, we'll be able to meet our needs and meet the demand down the road with a partner who has the same vision that we do.

There are honorable people that are in the business of serving the patients, and they have retained our entire team. This is a superstar team [indiscernible]. They were key in designing the facility, bring the facility up to where it is today, and they will be continuing with the leadership of our Chief Manufacturing Officer, Al Dadson, who will be now a Zydus executive serving both Zydus and Agenus. So it meets our capital requirements and our operational manufacturing requirements. So it's the best of all worlds really.

I'm not sure if many people outside of the immediate industry understand that even for large pharmaceutical organizations, many times, the drug substance that you need to create the treatment is produced in one location in one continent and then gets shipped to another facility and another continent for actually making the treatments themselves. And in other cases, it's been shipped to a third location for fill and finishing and labeling before it even gets sent to the different pharmacies around the world. So that is a lot of exchange of hands, a lot of transportation, a lot of operations. And for you to have the foresight to think about doing this within the U.S. on U.S. soil, particularly given where the industry is now with tariffs of exporting pharmaceuticals. Share with us a little bit more about the confidence that provides and the element of the deal in which Zydus is going to be the exclusive manufacturer for BOT and BAL throughout for clinical trials as well as for our French AAC program, which now is covering reimbursement for 3 different tumor types as well as our paid named patient program.

These are critically important questions, and we foresaw those things many years ago because as you said, we had drug substance being produced in Seattle. It was being shipped to Vetter Germany and then being shipped back to the U.S. and then back to a warehouse. Every time this happens, it affects costs. There are risks associated with shipment. And it also affects timelines. Imagine our product visiting multiple continents if it can be made in one location efficiently. And that was the reason, fundamental reason why we built the Emeryville facility.

You spoke about your visit right out to India during this process, and it was upon presenting some of our data to the KOLs in the region that the partnership actually expanded. This collaboration expanded to now include the ability for Zydus Life Sciences to develop and commercialize BOT and BAL in India and Sri Lanka because of the data that they had seen and so that took a little bit of an additional component, which was a wonderful, I think, recognition of the data that we had presented previously. Tell our folks here on the line today a little bit more about that from Zydus Life Sciences perspective because they may only be thinking of them as a CDMO, but they actually have hospitals, clinical trial operations within that region of the world that could help also enable additional development of BOT and BAL. Can you share a little bit about that with us as well.

You mentioned they have hospitals. In fact, they have oncology hospitals as well. In fact, they have a hospital that also provides patients with free treatment. And so this is a very noble company. It's a very noble company, and we're delighted that they have these capabilities in India that you spoke about, hospital capabilities as well as clinical research organizations that can streamline the development of a product or generation of clinical data. We visited with their CRO. We visited with their hospitals, several hospitals. And we also visited with the company. Over a dozen physicians, oncologists came from all over India to Ahmedabad to meet with us. Things got done in 1.5 days without any bureaucracy, and this is what we need to implement in our country.

When you and the team were out in India, a lot of the bureaucracy was kind of put to the wayside and real conversations were able to be had and alignment and an understanding was had in days time. Then upon returning, closure -- announcement and then final closure of the deal seemed to take a very long time. So earlier, you had mentioned this point about CFIUS. Can you describe a little bit about what CFIUS means? And why this became relevant for this collaboration at this time and why now it's so important that we're able to move forward?

So over my career, I had always heard about Hart-Scott-Rodino, HSR, and that's very well known. Of course, the government is in the business of making sure that there is no monopoly. And that clearance for us took literally 30 days because there was no issue. I've never heard of CFIUS, but CFIUS has been in existence for a long time. It's a government agency that is sort of supervised and overseen by the Department of Treasury. Department of Defense now is Department of War and also the Department of Commerce. And it's expressed purpose is to make sure that when a transaction takes place between a U.S. company and a foreign company that, that transaction doesn't pose a national security threat. A very important consideration, but the government is not really a specialist in health care per se. And so when this review got started, similar to Hart-Scott-Rodino, we thought it was going to be a relatively straightforward thing.

And then the government shutdown for 40 days within that time frame as well, right?

There was a perfect storm. So we had CFIUS officials, very good people, doing their due diligence, and it's a back and forth educational process of course because you don't expect these officials to know much about Agenus or much about Zydus. So there's an education that goes on about both companies. But to the credit of CFIUS officials, these people worked through Thanksgiving, through some of the shutdown, through Christmas and through New Year's. All of this resulted in an expedited closure and expedited closure meaning it could have extended more.

So wonderful news that the closure came, and now we're able to move forward with many of the plans that we had set out for 2026. So tell us -- as we look ahead into 2026, Garo, can you tell us about how that -- this collaboration and the closure enables us to effectively move forward with the execution of those priorities in 2026?

It's not a secret, Stefanie, that we came through a 6-month period where our financials were very challenging. No question about it, very challenging in spite of the fact that we have a treatment like no other in our industry. I'm a CEO that has worked for no cash compensation for an extended period of time. It is done because of a high sense of responsibility to the patients. Now we have more financial means to attend to our priorities, given the data that we've generated, data that has been presented at major conferences. It's been published amongst the most prestigious journals.

Priorities for 2026 are very clear. Number one, we've seen a growing interest, I must say substantially growing interest in our named patient programs, namely the paid named patient programs in France and outside of France. It is our moral responsibility to make sure that, that demand is met honorably and with compliance.

Number two priority of the company in the next 6 to 12 months is to make sure that we're on a path to file, both in the U.S. and in Europe, for the registration of our product. Even though the old FDA oncology division has not been helpful in endorsing an accelerated approval filing, we just heard from another company today that they are revisiting this, and they're going to go ahead and file for approval even though the FDA -- the previous FDA oncology did not. And the third priority, of course, is to do our randomized trial.

Thank you, Garo, and thank you for your time. I know that we're on to many other interesting conversations today talking about the French AAC expansion and the sarcoma data as well as later on talking more specifically about the need to expand our medical affairs infrastructure because of the incoming interest from both physicians and patients for utilization of BOT/BAL and the appropriate pathways. Thank you.

Thank you very much, Stefanie. Well, as we heard, the Zydus collaboration represents far more than a completed transaction for us. It reflects a year of deliberate -- even with the delays, a very deliberate planning to ensure that when scientific momentum accelerates, execution does not become a constraint, and that's what we've done. And so -- it must be also matched by clinical insights and responsible access, particularly for patients facing cancers, as we talked about, where options have been historically very limited.

And that brings us to France's reimbursement AAC program. And of course, that expansion includes sarcoma. Sarcoma represents a very challenging cancer, one of the most complex and underserved areas in oncology. It is biologically heterogeneous, often aggressive and has limited benefit from first-generation immunotherapies, and to help us understand why recent AAC expansion decision matters and what the emerging data may mean for patients, I'm pleased to speak with Dr. Robin Jones. Dr. Jones is a leading sarcoma specialist globally and an independent clinical investigator. And I'd like to now turn it over to that discussion.

Thank you very much for joining us, Dr. Robin Jones. I was remarking before you joined that you are not only a brilliant physician, but you're a physician who cares about patients, which is a very special attribute in today's environment where physicians are so busy and patients perhaps don't get as much attention and love. And as we know, one of the areas of greatest unmet need in oncology today, sarcoma. Dr. Jones is a specialist in sarcoma. He has been a leading sarcoma specialist at Royal Marsden Hospital in the U.K. and is widely respected for his work advancing new treatment approaches for patients with rare and difficult-to-treat cancers.

Of course, sarcoma is amongst the top on that list. And sarcomas represent a very big unmet need in oncology. They are rare, they're biologically complex, where treatment options become extremely limited once patients progress and where immunotherapy has historically been of little impact. He has closely reviewed the BOT/BAL sarcoma data and was an author of the peer review manuscript published last year in the Journal of Clinical Oncology as well as a broader pan tumor Phase I data presented at ESMO 2025 just a few months ago, which included patients with sarcoma as well as 6 other tumors.

Given his frontline experience treating these patients and his independent perspective on the data, we felt that Dr. Jones was uniquely positioned to help us understand what these results may mean for patients? And why recent decisions to expand reimbursed early access in France are so important because they include sarcoma.

So Robin, thank you very much again for joining us. If I may start with some opening questions. Many people aren't as familiar with sarcoma as other tumor types. Everybody knows what breast cancer is, lung cancer is, kidney cancer is, colon cancer now. Can you tell us what sarcoma is and why it remains one of the most complex and difficult cancers to treat.

Well, thank you so much for the invitation, Garo, and it's a real pleasure to be with you today. So to start with, sarcomas are tumors of connective tissue, so the bits that join the body together. So that includes bone, cartilage, muscle, fat, et cetera. And the word sarcoma is derived from the Greek word sarco, so flesh or fleshy substance. And because of this, because they're tumors of connective tissue, the first point to make is that they can occur anywhere in the body. And this makes them very difficult to diagnose and you've already alluded to 2 other major challenges in terms of diagnosing and treating sarcomas. And the second is that sort of rarity, i.e. that they account for about 1% of adult cancers. And then the third point is that they're very heterogeneous. So there are over 80 different types of sarcoma each with its own different biology and clinical behavior.

So those 3 things together, the fact that they can occur anywhere in the body, the fact that they're rare and the fact that they are very heterogeneous and lots of different subtypes makes them extremely challenging to diagnose and treat. And superimposed on this is the fact that they can affect anybody from the age of -- from infants to people in their 90s, make them incredibly challenging to treat and diagnose.

Many years ago, Robin, we were told that certain sarcomas can respond to immunotherapy because they may be ideally suited to do that. But the first-generation immunotherapies have not really done a very good job with that. But what does the current treatment paradigm look like for sarcoma.

Garo, in terms of the majority of soft tissue sarcomas, the current treatment paradigm for local disease, so localized tumors consists of complete surgical resection with or without radiation. The role of pre and postoperative chemotherapy remains under discussion, although over the last 10 years, there has been a shift towards using more preoperative chemotherapy in particular. But in many ways, the sort of major unmet need remains the treatment of metastatic disease. And for a lot of soft tissue sarcoma subtypes, this really hasn't changed. It's still a one-size-fits-all approach for most patients with multifocal metastatic disease where we use chemotherapy -- older chemotherapy drugs such as doxorubicin and ifosfamide.

There are salvage -- schedule salvage treatments that are effective. But as I say, it's still very much a one-size-fits-all for many soft tissue sarcoma subtypes. And there's a huge unmet need. As you mentioned, the first-generation checkpoint inhibitor trials have been, to a certain extent, disappointing for most sarcoma subtypes, apart from notable exceptions such as alveolar soft part sarcoma, potentially undifferentiated pleamorphic sarcoma and cutaneous angiosarcoma as well.

So just the fact that you're citing all of these different sarcomas is confusing enough. And if I heard you properly, you said, even though there are standards of care, one-size-fits-all, there's a wide variability in terms of outcomes. And of course, once patients recur or the disease becomes metastatic, I'm assuming that the treatment can be all over the place. Why is there a high level of interest in, for example, BOT/BAL in the treatment of resistant or recurrent or metastatic sarcomas?

So you're absolutely right. For patients with symptomatic multifocal metastatic disease, the current treatment options are extremely limited. As I mentioned, the chemotherapy options can help some patients, but there remains a huge unmet need for well-tolerated treatments that drive durable benefit. And I think the -- as we discussed at the ESMO meeting in Berlin, the data from the early-stage BOT/BAL trial, the sarcoma-specific data, very promising in that respect both in terms of the safety of the combination, but also the provisional efficacy data. So I think that's got a lot of sarcoma experts interested and keen to explore this combination in sarcomas and particularly in angiosarcoma.

BOT is a CTLA-4 targeting anybody, but it does a lot more than just targeting CTLA-4. Can you also tell us a little bit more about why do you think BOT is showing the kind of activity that hasn't been seen before in a challenging tumor like sarcoma?

I think the major point regarding the publication, the data published in the JCO is that the activity of BOT, I think, is probably superior to the other agents out there. And the fact that it seems to improve the efficacy of immune checkpoint inhibition, particularly in immune cold tumors such as sarcomas. And the majority of sarcomas are particularly immune cold. And I think it's that activity of BOT in these immune cold tumors that is a crucial factor in the success that we've seen so far with the combination, particularly in leiomyosarcoma.

And that's a type of a sarcoma that really doesn't respond to much of anything, particularly immunotherapy. And so when you see these kinds of responses in a very difficult sarcoma and the durability of these responses, once there is a response with an immunotherapy agent, that response is more likely to be durable. So how much of you and your colleagues' sense of the data is driven by that durability phenomenon, the tail of the curve that shows any responses that you see can be long lasting. So how do you interpret all of that in the context of your experience?

My experience with the combination has been very favorable. I've had patients derive durable benefit from this treatment. And I think as you've pointed out, the context is really important. Many of the other treatments that we have to treat, sarcomas can actually result in a response or stabilization of disease. But again, crucially, it's that durability that is an issue in terms of the treatments can work for a period of time, but they're nondurable and when we had the trial opened in the U.K., I was impressed, as I mentioned, with the -- not only the efficacy and the durability of benefit with the combination, but also the exceptional tolerability of this particular combination.

Now most recently, the French authorities granted BOT/BAL, a reimbursed use in CRC, colorectal cancer. We all know the colorectal cancer is a major problem today. And in fact, I spoke to 3 patients over the weekend, and we're getting these unsolicited inquiries, and these inquiries are translating now in increasing number of reimbursed patient treatments in France. French authorities are quite sophisticated when it comes to oncology. They're also very sophisticated based on our previous experience when it comes to immunotherapy. So how does it affect you and your colleagues in sarcoma to have the French authorities provide government reimbursed allowance for sarcoma now. After CRC, we have sarcoma and ovarian cancer. What does it say in terms of your confidence that even the regulatory authorities are making a move in the right direction with these small steps.

Yes. I think this is great news and great news for patients. I have very frequent e-mails, letters from oncologists all over the U.K. asking about access to BOT and BAL either through a trial or expanded access programs. And I think for French patients, this is fantastic news and opens the door to another treatment option, an effective treatment options. So I think it's really, really good news. And I hope that other regulatory agencies. Other countries will follow suit and in time, we'll be able to access the combination in the U.K. as well. But the bottom line is, I think this is absolutely great news.

What can we expect that would be the best outcome for patients and their physicians, particularly in your field?

That's a fantastic question. I think in the sarcoma community, we're all very excited about the activity of BOT/BAL, and we hope that we can proceed with a registrational clinical trial so that more patients around the world will be able to access this combination. As you and I have discussed, it's such an unmet medical need. And I'm really, really optimistic that we can collaborate and develop this clinical trial and lead to registrational approval for the combination.

Thank you very much, Dr. Jones. As you said, expanding access is not simply about availability. It's a sense of responsibility, sense of duty to patients. And as reimbursed and authorized access expands, particularly across multiple tumor types, it brings with it a responsibility to ensure that patients are treated thoughtfully, physicians are appropriately supported and real-world data are captured in the process. This is especially critical as interest grows well beyond France.

As we said, we're getting inquiries now and we're treating patients in real time with out-of-pocket reimbursement driven by physicians seeking options for patients who have few remaining alternatives. And some of these patients, unfortunately, are desperate, many of them are. Meeting that demand requires an appropriately structured infrastructure, a disciplined approach, and of course, clinical leadership that is dedicated for this purpose. And to discuss how Agenus is scaling its medical affairs organization to support this growing interest while maintaining scientific integrity and patient safety, I'm pleased to be joined by Dr. Jose Iglesias, our Chief Medical Affairs Officer. Jose?

Gracias.

Welcome to our forum. We have been doing -- as you know, we have been doing these webcasts, discussion sessions. I think this is our fourth or fifth time, but they're very informative, and I am delighted that you're joining us because you're a newcomer to the company, but you have 30 years of global experience in oncology. You're a physician yourself and you've also been involved in immuno-oncology drug development. And most recently, you had senior positions at a number of smaller companies. But prior to that, you were Chief Medical Officer at Abraxis. You were also a Vice President of Clinical Development at Celgene. And so -- you've also authored, I believe, more than 70 peer-reviewed oncology publications. So that's no small feat, and you've earned your medical degree in Uruguay, then you've done a fellowship at the Weitzman Institute, the famous Weitzman Institute in Israel.

You've been at Duke University, and University of Toronto. After this career, what brought you to Agenus. Why did you decide to come to Agenus?

Well, where do I start? I mean there are several factors, Garo. First of all, the innovation and the science. I mean I was always attracted and science was actually what drove my career all along. When I discovered the developments that Agenus was conducting in immuno-oncology, that really caught my attention. And when I dug into the science, all of a sudden it looks like I was not too familiar with it. I was really impressed. The world of immuno-oncology is dominated by a number of immune checkpoint inhibitors. But when I discovered the uniqueness of botensilimab or BOT for short, as we all know it, it really opened my eyes to a very new domain. I mean the activities are shown in tumors that normally do not respond to immuno-oncology. That was a very powerful magnet for me. And thinking of the implications that it could have, many patients have tumors that are without the reach of immuno-oncology. So providing a solution and a hope to these people is extremely important.

Thank you. Now to get more specific, I had the pleasure of listening to your presentation to a group of doctors recently. What is the most compelling nature of the data that you cite from a physician's perspective as well as a patient's perspective.

We have a large database of patients. As you know, more than 1,200 patients have received this innovative therapy and the results have been striking, not only in metastatic disease, which is where with the bulk of their work started, but in new areas like neoadjuvant therapy or treatment prior to surgery. And every physician I talked to or have discussed the data with have shown a lot, a lot of interest. I actually get statement I'd say, "Oh, I can't wait to get my chance on how soon can I treat my patients with this" because it is a significant advancement in immuno-oncology.

I mean for a time -- immune checkpoint inhibitors have been around for several years, but none to this time has presented this degree of innovation and promise like botensilimab has.

So if you can give us some sense of what you're heading up at Agenus. And some of the ways with which patients and doctors can be treated with BOT/BAL with existing programs.

In France is the authorization of compassionate access. And this is an initiative that is fully reimbursed by the French government. In addition to that program, there is the opportunity for patients who live outside of France and are not eligible for not being French citizens to participate in the program through cross-country health care arrangements like the existing Europe is they are reimbursed by insurance companies in their country of origin or if that's not possible, they can also provide self-pay for the program.

So the therapy is not denied to people who need it. And I think that's a very important spirit to exert in a program like this. And not having just one way to access a drug but several routes to make this treatment available. Medical affairs is supporting all this, of course.

France government is paying reimbursing for the use of the product for French citizens. And there are other countries you said where the product can be made available with special insurance or out-of-pocket pay and -- are you seeing traction since you joined us in terms of at least tangibly going through the process of governments reimbursing and patients paying for product through other means? And beyond France, where are we seeing activity, if you will?

Well, let me tell a little bit about France at this moment. We have 60 total inquiries from physicians. But outside of France, we have several countries in Europe and also in Latin America providing access to these patients through the named patient program. And again, this can only increase with time as the knowledge increases. Publications and conferences have divulged a lot of knowledge that have actually generated all this interest. So we are actually receiving comments and requests from physicians from several countries. France is, of course, the main one because the program started there, but we are hearing from other parts of the world, as I mentioned, Latin America and other countries of Europe as well. So we're very pleased with hearing this interest and as a result of that, we are beefing up our medical affairs division to cope with this increased interest from physicians.

So tell us, now you've started building a medical affairs department.

Well, as you know quite well, we are already quite emerged into the process of building medical affairs. I mean this increased demand and interest has to be met with resources because otherwise, everybody loses. I mean the patients that are waiting and the physicians that are also waiting to start this treatment as soon as possible. So we have hired a Vice President of Medical Affairs who is based in Europe, is based in Switzerland but is French and with strong connections to the environment.

He's an oncologist. So in the process of hiring right now medical scientific liaisons, or MSLs, for short. Some other people call them regional medical liaisons, or RMLs. But they are professionals with PhDs and MDs that actually have participated in these kind of activities of liaising between companies and sites and patients before. And they are the direct conduits for all kinds of requests and initiatives that originate in sites to actually maintain a constant dialogue with them. And that is ensured not only just to know what's going on at the sites, but to make sure that every request for compassionate access is properly assessed, evaluated and authorized.

There are some eligibility criteria, some selection criteria that need to be met. And these criteria are very strict and also at the request of the French government, we need to observe what happens with these patients, collect data and report it, which is of great importance because the data that comes from clinical trials, like the ones we have embarked in the large Phase III BATTMAN study, those are very selective populations, very strictly chosen from the patient that comes through the door every day.

So they are not representative of the general population. This program, the compassionate access program provides what is called the real world experience. This data is absolutely invaluable. Regulatory agencies, including the FDA and the European Medicines Agency are increasingly looking at the value of this real-world data. And for that to happen, as you can imagine, there has to be compliance from the sites. There has to be vigilance from our side, not only in terms of data compliance and data entry, but pharmacovigilance. I mean we need to know how these patients are doing safety-wise, we need to know how they are doing efficacy-wise, and that information will be supplementary to whatever we file with regulatory agencies in every part of the world.

One of the other reasons that we are expanding the medical affairs division because as people may have known recently the European agency, the French agency authorized reimbursement for 2 other indications that were not the original ones. The original one was colorectal cancer, and the 2 new ones are ovarian cancer and sarcomas. So there is an increased number of patients beyond colorectal cancer that now have the opportunity to receive this innovative treatment. And again, we're very happy at the vision of the French government to have increased access for the French population. So all this translates into a lot of work for us, and we need to have a good and robust medical affairs division to actually face this program and make it work.

Thank you for that. So it's our responsibility. It's our privilege actually to make sure that patients are served. What is the best outcome from a patient's perspective?

So our hope and desire is that patients with late disease who have exhausted all available therapies, as the program requires, can have prolonged time free of symptoms, not free of disease, but free of disease progression. So increasing the time to progression and ultimately increasing survival. When you are a cancer patient and at this stage, every minute counts. So prolongation of life is important to meet milestones and at the same time, with the quality of life. There's no point in increasing life if you have to suffer the pain of chemotherapy complications or radiotherapy.

BOT/BAL is chemotherapy and radiotherapy free treatment, which you can imagine after patients have been bombarded with multiple things during the journey of the disease, arriving at a point where that suffering could be at least helped or removed in addition to prolonging enough time to be with their families and at the same time, not suffering from the tumors that they carry. That's a satisfactory outcome for us and for any physician that cares of oncology patients. They are more than Kaplan curves. They are more than confidence intervals. They are more than p-values. These are things that are imponderable in terms of science, but they are very measurable in terms of human outcomes.

What do you see, Dr. Iglesias, as the medical affairs role in making sure that what is available in France for patients also becomes available throughout the world for patients that need it. You cannot treat a patient in the U.S. either with government pay like the AAC program in France or out-of-pocket. And so patients are not allowed to make a choice. If a patient in the U.S. wants to be treated with BOT/BAL, they have to travel to a different geography. Can you imagine a patient that is suffering from cancer, you're going to have to travel to the U.K., Switzerland, France or South America to get treatment. I mean it is unconscionable. So what can we do besides formal approval? Of course, we're going for formal approval. That's a very important part of our agenda. But as soon as possible, how do we make the treatment available to patients as expeditiously as possible without enduring any additional hardship? How does medical affairs play a role?

That's an excellent question, Garo because there are 2 prongs to this. One of them is what we can do, and there is what the countries individually can do. Talking about the latter, I would wish that more countries follow the example of France that they have the illuminated challenge in order to recognize the value of the data and act accordingly like the French government has done for their citizens.

Now from our side of medical affairs, education and physician contact is absolutely key. And that can be delivered in many ways. I mean, in France through the medical scientific liaisons and ourselves, as we mentioned, and in other places, we take advantage of course of conferences and meetings. There are lectures, there are invited symposia where data can be shared and discussed with physicians. New data always needs discussion.

I'm hopeful that the new professionals, leaders of the health care system in the U.S. now may be much more patient-centric. So I'm hopeful that perhaps these changes may happen quickly because cancer cannot wait, cancer doesn't wait, doesn't take a day off in its efforts to grow. So this will be critically important for us. Any final comments from you?

My enthusiasm is being fueled every day.

That's a consistent theme: Scientific momentum, patient urgency and operational readiness, of course, are converging, and they must move forward together. Expanded access programs provide immediate [indiscernible] for patient in need. Clinical trials like BATTMAN provide the evidence required for lasting change even with bureaucratic regulatory organizations and medical affairs ensures that both are executed responsibly, ethically and with patients at the center.

Taken together, these efforts reinforce why 2026 is such an important year for patients and for Agenus. And why the work ahead matters so deeply for everybody?

With that, let's turn to your questions and continue the conversation. Stefanie, back to you.

Great. Thank you so much, Garo. And thank you for all of those that are still staying with us on the line for some of the live Q&A. And thank you again to our doctors, Steven O'Day, Dr. Iglesias and Dr. Robin Taylor for joining us for the Q&A. So without further ado, let's jump in and get started. I actually have received a number of questions via [email protected], so please keep sending them forward. And I do have some questions as well that we didn't get the opportunity to answer during our last webcast. So if they don't get answered today, we will be sure to address them as soon as we can.

So the first question here is actually going to be for Dr. Steven O'Day. So the first question for you, we've commented a number of times that BOT and BAL have been studied in over 1,200 patients either BOT alone or in combination with BAL in over 9 different tumor types, collectively from studies that Agenus sponsored or investigator-sponsored trials across different stages of disease. The question that came in was how broad can BOT/BAL be applied? And can you maybe share some just high-level overview of the tumor types that we have studied BOT/BAL in? Obviously, there's a lot of specifics related to biomarkers and diseases tend to be a number of diseases within one tumor type. So this is a very general question, but this particular person unfortunately, has had a lot of experience with family and friends with a lot of different tumor types and was very curious just about the expansiveness of our development program with BOT and BAL.

So thank you, Stefanie. It's a great question. So why is BOT/BAL impacting so many tumor types? With traditional oncology where you're attacking the tumor specifically through targeted therapy or chemotherapy, it's much more specific for disease. Here, with the immune system, we're actually not targeting the cancer specifically. We're targeting T cells and activation to these very important primal checkpoints, CTLA-4 and PD-1. And botensilimab, which is the next-generation CTLA-4, is really the magic of the combination that is driving these T cells to recognize tumors more broadly, even tumors that stay hidden to the immune system historically. And this is the large proportion of solid tumors.

So it's not surprising to me that when you have an effective CTLA-4 like botensilimab and a PD-1 that is its companion and you're activating and expanding these T cells against multiple neoantigen targets that were not restricted in tumor types. And I think our data and our large Phase I data, particularly the more than 400 patients that we presented in a plenary session at ESMO this year, really speaks to the consistency of the data across these tumor types. And the French government, as Garo and Jose have recently just talked about, has really recognized not just MS-stable colorectal, but sarcoma and ovarian, 2 other of the 9 different disease types that we're showing these consistent.

Yes, I think that's really important, and it's a very helpful description and a way to take a look at it because I think everyone historically has thought very specifically about treatments targeting certain tumors themselves, and this is really activating the immune system to combat the cancer. So for those of you that are more interested, there's publications that are listed on our website, if you want to take a look more about that across a number of different tumor types as Steven just described.

I think our Phase I included colorectal cancer, ovarian cancer, hepatocellular, lung. There's been investigation in sarcoma as well as melanoma and in some of the ISTs, there's even been triple-negative breast cancer and others. So we're very excited about the breadth. And with the data that Dr. O'Day has referred to previously at ESMO that Phase I showed a lot of consistency across many tumor types, which supports the explanation that he just shared. So thank you for that explanation, Dr. O'Day.

The next question here that I've received, I'm going to pitch this over to Garo first. And then if others on our panel want to join in, it has to do with our named patient program. And the international access programs are expanding. We've heard about the additional tumor types that France is now including in their protocol. Can you share as well what signals this might be providing to Agenus in validating this as a potential global pathway or expansion pathway to other countries? And are there other countries that are enabling the similar pathway, either through a paid named patient program or a specific pathway like France, which is uniquely reimbursing that from a government perspective.

Thank you, Stefanie. By the way, you mentioned the -- our website being a resource. Just for everybody's benefit, we have a wonderful, brand-new website. which is very patient-centric. So we welcome everyone to visit our website and see the ease with which information has been available now since the launch of this website, which is only about 2 weeks ago, I think, and that it is improving with additional comments coming in.

But more directly addressing your question, as I mentioned earlier, France happens to be a very sophisticated regulatory agency. They have been sophisticated in oncology reviews. They've been also very sophisticated in understanding of immunology. And we're very grateful that they considered this an important treatment for patients and that they have not only allowed access but also are providing reimbursement for patients, which is a very significant commitment. Now beyond France, there are other countries such as the U.K., Switzerland, some of the South American countries like Brazil and Argentina that allow for out-of-pocket pay or pay through special insurance that patients may have.

Now we're -- with the expanded medical affairs team, we're attempting to expand those geographies where not only patient access may happen, but possibly reimbursement by governments may happen as well. And those include some of the Middle Eastern countries as well as some of the Asian countries. And since Dr. Iglesias has arrived at Agenus, those are being pursued with rigor and all with a very high sense of responsibility for patients' sake. It is an important consideration for us to make sure that patients who need treatment and had badly needed treatment like BOT/BAL, either for end-stage patients that don't have any other alternatives or even, in some cases, for earlier-stage patients that they have a path forward. And so that's something very important for us to expand.

Thank you, Garo. And I don't know if we had a follow-up question that it relates to specifically the French AAC program. And now with the expansion of the 3 different tumor types, is there a number that we expect to treat. I'm not sure that we can answer that specifically, but we know that interest continues to come in. Maybe very broadly, you could just comment on that and talk to the preparations that the organization has to be able to fulfill requests as they come in.

A couple of thoughts on this. Number one, when we were interviewing -- I mean, taping for this show, which was less than 2 weeks ago, Jose mentioned in his tape clip that we've had 60 inquiries. Now I just want to caution everybody to understanding that not every inquiry translates to treatment and reimbursement. However, in France, a reasonable proportion of these inquiries are translating to reimbursement and treatment. So he mentioned 60 inquiries have come in. Now the total number of inquiries that we've had are more than double that. So this is happening in real time. And just to make sure that there may be concern out there, we're expanding in medical affairs, and we're expanding in a way where it costs us money. One of the reasons we terminated unpaid named patient or compassionate use programs is because we're a small company. We have already spent billions since inception 31 years ago. And it's not really feasible for us to provide product for free going forward. That's the reason why we converted our compassionate use programs to paid named patient programs or government reimbursed programs like the one in France.

So with that in mind and with the ramping up of our medical affairs team, based on the current trend, I expect that our expenses associated with medical affairs will be many times covered by the revenues that we get from paid reimbursement programs. So I just want to make sure that, that is a clear understanding by the viewers. And that's not because we're a greedy company and clearly, we're not going to become a highly, highly profitable company like the major pharma companies. But this will go some ways in terms of reducing our burden, if you will, financial burden.

Thank you, Garo. Let's see, I'm looking at the question that we had received last time, but we were unable to answer. I think this is probably one of the closing questions. So post Zydus, we had mentioned a couple of times in 2025 what our annual cash burn target was going to be and what we were trying to do to enable a real focus on our investments and our financing to be focused on enabling broader access and registration for the company. So can you maybe share a little bit of guidance now that the Zydus deal has closed and a lot of overhead related to manufacturing facilities in California, what is our cap rating burn rate anticipated now for 2026?

So just once again, for everyone's understanding, we have reduced our cash burn, operating burn very significantly in the past 2 years to the point where our current operating cash burn, not counting revenues coming in from, for example, the paid access programs, not counting those in because it would be premature for us to plan for that. Our operating cash burn is approximately $50,000 -- I'm sorry, I wish it was, $50 million a year. I wish it was $50,000, but it isn't. So it's $50 million a year operating cash burn.

Now at the closure of the Zydus transaction, we filed this, our cash position was a little over $60 million. So the question may be from shareholders, how do you get from $91 million to a little over $60 million in cash on the balance sheet. At the close of the year, we had essentially no cash. I mean it was down to the bone, as they say. And with the Zydus transaction, there are a number of obligations that we have had to meet simultaneously with the closure of the transaction. They included, for example, purchasing the equipment from the leasing company that goes along with the manufacturing facility. It included some of the closing costs. It included some of the monies that we owed third parties. And so -- and it also included an escrow, $7.5 million of the proceeds received went into escrow for a period of time.

So net-net, we ended up with over $60 million. And with an operating cash burn of $50 million with potentially revenues coming in, not counted in that projection, we think we'll be able to manage our affairs with our operating burn for the balance of this year and perhaps into next year.

Great. Thank you for that clarification. And Robin, this last question is going to be for you. And this might be a little bit harder to quantify. But the question is given all the tumor types that we've investigated BOT/BAL in, one of the questions here is, how big is the potential slice of the pie, so to say here, from BOT/BAL and I know that's going to be really hard, right, because we're in so many different tumor types, and there's lots of different ways to take a look at this. But I think perhaps maybe how we could describe this or maybe that you could address, particularly looking at the example of colorectal cancer and how much MSS disease is in colorectal cancer versus how it's being addressed today and how prevalent MSS is in solid tumors, just to give an idea of the potential application, if it were to work in different tumor types, really how broadly MSS disease is across solid tumors.

Thank you, Stefanie. Well, let's start with colorectal cancer because in colorectal cancer, there is a small proportion of colorectal cancers that are hypermutated. They're called microsatellite instability high. It's about 5% of the metastatic setting, and it's about 15% in early-stage disease. So for those patients, immunotherapy is very active because there are lots of mutations is like melanoma or lung cancer. But for 95% of the patients with metastatic colorectal cancer, they don't have that high mutation burden. And to date, immunotherapy is not being particularly active. PD-1s are clearly inactive. First gen CTLA-4 has had some level of activity, but not to the extent that botensilimab does. And so we have this opportunity beginning with the Phase III in the late-line setting to be able to provide patients with really -- the first really active immunotherapy in this setting.

That's one setting. But within colorectal cancer, we already have data now generated in combination with FOLFOX and Avastin, which is the first-line standard of care. We have a study ongoing at Duke University, looking at BOT/BAL alone prior to chemotherapy. And then finally, we have remarkable data in early-stage disease from 2 different investigator-sponsored studies in colorectal cancer, both demonstrating that one dose of BOT and 2 to 4 doses of balstilimab can generate pathologic complete responses. Those patients, in the data that was reported last year at ASCO GI, there would be no recurrences of any of the patients who had been treated with the combination. So colorectal cancer is a very large tumor type. Just within colorectal cancer, this is a multibillion-dollar opportunity just talking about the late-line setting and that early-stage neoadjuvant setting. Adding in the frontline setting as well, where there's a big possibility expands that even further.

And then you started the question by talking about, okay, where else outside colorectal cancer is there potential. And we've already seen this in our Phase Ib. We've seen that there is significant activity in other tumor types, ovarian, hepatocellular carcinoma, lung cancer. And so there is this potential to expand into many other tumor types. If you think about where immunotherapy has been active. It's been in tumors that are more mutated. They're classified as warm tumors. That only constitutes essentially about 1/3 to 40% of tumors. The rest have not been particularly responsive to immunotherapy, and that's a wide open space that we certainly like to explore. So where is the potential for botensilimab? It's very hard to estimate because it is so broad.

Thank you for that. I know that, that was going to be a little bit challenging question to quantify, but I think you did a fantastic job in describing MSS tumors and where we are. So lots of development opportunity. Right now, we're being very focused and prioritized, but lots of interest out there as well. So with that, I wanted to thank everybody for staying a little bit longer. We know that it's important to be able to answer some of the questions live. So with that, I'm just going to turn it back over to Garo just for some closing comments before we close out this webcast for the first of the year in 2026. Thank you all.

Thank you, Stefanie, and I want to thank our colleagues for joining us today and everyone else who joined us today on the call. As my colleagues said, it's remarkable to see this consistency of data across different tumors across different continents for clinical trials have been conducted, different types of studies and of course, different stages of disease. And that's what is so revolutionary about BOT/BAL and it is so encouraging that now regulatory agencies such as France are having not only a patient-centric attitude, but also putting a significant amount of money to reimburse for treatment. And what we've discussed, of course, reflects a shift in how we think about cancers. And how long have -- we've considered beyond the reach of immunotherapy, particularly in MSS disease as Robin and Dr. O'Day and Jose made references to.

Patients, there's no question. Patients are asking for better options. They're asking for potentially curative options and options that are not laden with poisonous traditional treatments like chemotherapy. Physicians are seeking responsible pathway to treat these patients. And some countries as we said France are demonstrating the urgency to act. As we move through 2026, we remain committed to advancing BOT/BAL with rigor, expanding appropriate access with discipline and working with regulators, clinicians and partners to bring meaningful innovation to patients who deserve them. We appreciate your continued engagement and look forward to sharing updates as the year progresses with these conversational, very interactive programs. Thank you very much.

[Audio Gap] '25 Stakeholder Webcast where we bring together scientific leaders, clinicians and patient voices to discuss the progress and global momentum surrounding the BOT/BAL immunotherapy program.

Before we begin, a quick reminder that today's discussion will include forward-looking statements. These are subject to risks and uncertainties that could cause actual results to differ. Please refer to our SEC filings for more detail.

Today's session brings together 3 distinguished guests offering scientific depth, clinical insight and lived experiences in colorectal cancer. First, we'll hear from Dr. Christopher Lieu, Professor of Medicine at the University of Colorado Cancer Center, where he'll discuss the evolving role of immuno-oncology in colorectal cancer, particularly in MSS disease. And he'll also share a remarkable case from this practice that demonstrates the potential of deep and durable responses.

Then we'll have Dr. Jonathan Loree, Medical Oncologist, Associate Professor at the University of British Columbia and the Senior Investigator with the Canadian Cancer Trials Group. He will provide an operational update on the global Phase III BATTMAN trial, including rapid site engagement, broad international enthusiasm and key drivers on trial momentum heading into 2026. And finally, Dr. Benny Johnson, Senior Medical Director at Agenus and former GI Oncologist at MD Anderson Cancer Center, will share his family's personal experience navigating early onset colorectal cancer, a journey that shapes his dual perspective as both the clinician and the caregiver.

Following these discussions, Agenus leadership, including Dr. David -- excuse me, Dr. Steven O’Day, our Chief Medical Officer; and Dr. Richard Goldberg, Chief Development Officer; along Benny Johnson, Senior Medical Director will join Garo for a live Q&A. As there were some pre-submitted questions related to biomarker development, Dhan Chand, our VP of Research, will also join for the Q&A as well. Questions may be submitted at any time to the e-mail [email protected]. So thank you again for joining us today.

And with that, I'm pleased to introduce our Founder, Chairman and CEO, Dr. Garo Armen. Garo?

Thank you very much, Stefanie, and thank you, all of you for joining us today. Based on our previous experience, we have patients, caregivers, advocates, clinicians, regulators, policy leaders as well as investors and everyone else who is committed to advancing the future of cancer care. Now we've decided to have these sessions with some frequency for 2 very clear purposes: Number one, we want to make sure that we keep you abreast of the latest developments concerning BOT/BAL, particularly, but also concerning the company; and secondly, we would like you to hear the points of views of a broad range of experts in the field. And that's what we've done in the last 3 sessions. And that's what we will continue to do with frequency in the future. And so these are not quarterly meetings, but these are meetings that will be presented to you with a higher level of frequency.

In 2025, the BOT/BAL program reached a number of important inflection points. Clinical data now span more than 1,200 patients treated across 9 tumor types from the most refractory settings to earlier localized disease. These findings continue to reinforce the fact that a clear trend is emerging in a significant number of patients. Immunotherapy may hold far more potential, including particularly cold tumors than previously believed and this has surprised a number of experts, but the data is clear. MSS colorectal cancer is among the clearest examples of this. For years, this disease was considered largely unresponsive to immunotherapy. By the way, when we talk about MSS colorectal cancer, this accounts for well over 90% of colorectal cancer patients in the U.S. and across the world. So this is the substantial chunk of colorectal cancer patients.

But this past year has brought forward new signals with our experience, certainly, in both refractory and earlier stage settings, as I mentioned before. We're seeing meaningful responses, and these are durable responses, and we're seeing them consistently across multiple centers around the world. And of course, one of the concerns is that if your data is only from 1 or 2 centers, perhaps there's the risk of cherry picking. But we are now talking about dozens of centers in 3 different continents. These findings clearly challenge the long-held assumption and that opens the door to new possibilities for patients with chemo-free treatment options.

For all of us at Agenus, this work is deeply personal. As you'll hear from the interview with Benny Johnson, who is also here live today. Every patient and family navigating this disease reminds us that why progress must continue with a high sense of urgency. Today, you'll hear from 3 leaders, as Stefanie talked about, who reflect the scientific, operational and human dimensions of this work. Dr. Lieu will share how expectations for immunotherapy in CRC are evolving. Now these expectations were nonexistent other than for MSI-high tumors, which account for about 5% of all CRC patients. He's going to share a case from his practice with a hepatocellular carcinoma patient. And I'll let him, of course, describe his experience with this, which is a remarkable outcome.

Dr. Loree will describe the extraordinary global mobilization behind the Phase III BATTMAN trial. This is our Phase III potentially approvable trial, a level of alignment driven by strength of early-stage clinical signals and the urgency felt by investigators worldwide. And of course, Dr. Johnson, our very own Dr. Johnson, will offer a deeply personal perspective as both a physician and a caregiver, reminding us that behind every data point is a family, a patient whose life is shaped by the options available to them. And we're very proud of the fact that we're expanding those options, particularly chemo-free options for them.

As we move into 2026, our priorities are clear. We will expand patient access to BOT/BAL, including through France's reimbursed AAC pathway and Agenus paid Name Patient Program available in approximately 30 countries that allow self-pay or pay with special insurance that has a patient's ability to access and none yet approved treatment. Number two, we will advance the BATTMAN global Phase III program with speed and rigor. And number three, expand our neoadjuvant studies that are now beyond CRC, where the potential for cure is the greatest. These efforts are essential if we are to bring meaningful innovation to patients in years. And I hope, in some cases, it will be in days and months, but not decades.

I want to thank you, Dr. Lieu, Dr. Loree and Dr. Johnson for joining us today and for your commitment to patients. So let's begin our program. Andy?

I've been in the oncology space for 31 years, formerly through [indiscernible], but we did not get to know you until BOT/BAL. And so you are a very accomplished physician with varied interests and you've been at MD Anderson for your fellowship, I believe. And now you're at [indiscernible]. Now when I look at your institution's background [indiscernible] it lifts everything under the sun for the treatment of cancer. And I'm not talking about your research interest, of course, but the institution, but it doesn't talk about immunotherapy because -- partly because, of course, it's understandable immunotherapy is relatively new. Why do you think that is? And what is it going to take for us to get around the historical barriers to embrace new treatments? What do you think is the issue with MSS colorectal cancer, which constitutes about 90%, 95% of the patients today?

That's right. MSI-high colorectal cases have gotten a ton of press, which is phenomenal, right? I mean like for that 4% or 5% of patients that are MSI-high to be able to offer them single-agent immunotherapy or, in some cases, double immunotherapy and to have -- I mean, what I think are outstanding outcomes, I mean, that is exciting, right? We see that in the metastatic setting. We see that in the neoadjuvant setting, into curative setting, particularly with locally advanced rectal cancers. But just like you said, 95% to 96% of our patients with metastatic colorectal cancer will be microsatellite stable. And of course, the issue there is that when we've done studies with pembrolizumab or nivolumab or even nivolumab and ipilimumab, in this subset of patients, the 96% of patients that are microsatellite stable, we know that the responses have been virtually 0, right, for lack of a better term. It's just really not been effective.

And the reason why is because when you look at MSI-high cancers, I mean the T cells are there, you can even look inside the tumor and their lymphocytes, right, that are infiltrating into the tumor. But when you look at microsatellite stable colorectal cancer, it is the perfect definition of an immune desert. There are no T cells. It seems like there's very little upfront immune activation. And so the way I describe it is that for microsatellite stable colorectal cancers like having a dance floor, but nobody is on the dance floor, right? You're turning up the music louder and louder, but there's nobody dance because there's nobody there.

To use the same analogy, in MSI-high colorectal cancer, it's like you have the dance floor, and there are a ton of people already there. You just got to start the music. And it really just shows you there's a very, very distinct difference in the tumor microenvironment between the majority of our patients, microsatellite stable, and our patients that have MSI-high colorectal cancer.

What you're seeing in the small group of patients who have MSI-high colorectal cancer is nothing short of a miracle, right? So then how do we repeat that miracle?

Yes. I think we were very fortunate at the University of Colorado to be able to be involved early in drug development for BOT/BAL. And I think that when we initially started the Phase I, I think there was some healthy skepticism in terms of what we may or may not see. Just based off of the mechanism of action, we just kind of wanted to see, okay, well, what are some of the responses that we're seeing with this combination. And I think one of the things that really just impressed not only me but our entire team, our entire Phase I unit were some of the responses that we're seeing and what we are talking about are really kind of 2 things. Whenever patients have really refractory cancers, you really want to focus on response rates because that's a very, very early endpoint. But our patients just feel better, right, when they have less tumor burden. And so when we are seeing dramatic responses, that's always exciting. Patients are excited. They're feeling better, CT scans are looking better and you can show them, right, the difference before and after, and we were seeing that with BOT/BAL.

And then the second thing is the durability of response. It's no fun at all for any patient or any provider to have a response that lasts for 2 months because 8 weeks after you start treatment, you're super excited and then like literally 16 weeks after you started treatment, everybody's super, super upset and sad, right? And so it's response and it's the durability of that response because if you see great response to a treatment, and it goes on for a really long time, I mean that's the win, right? And so when we started seeing that early, early, right, in the drug development of BOT/BAL, it was unbelievably exciting.

I had a patient with severely refractory hepatocellular carcinoma, liver cancer, and immunotherapy is actually used upfront for the treatment of metastatic liver cancer, HCC. And so this patient was started on atezolizumab and bevacizumab, she didn't respond at all. She started on a second-generation tyrosine kinase inhibitor that targets VEGF, we tried lenvatinib, that didn't work. And by that time, she had this mass that was in her abdomen that literally you could feel and with each subsequent therapy, the immunotherapy, the targeted therapy, even the other Phase I clinical trial, we saw continued growth of this tumor. It was causing a ton of pain. So she reported kind of continuous 7 out of 10 pain that's really unacceptable. And we also knew that -- I mean if this thing is going to continue to grow, eventually, it's going to block the bowel or I mean, even potentially protrude out of the skin. And so usually, in that case, as oncologists, we're going to recommend hospice because we expect in the next couple of months that maybe there would be a really, really unfortunate or bad outcome.

And I think my patient kind of understood that as well. But she was eligible for BOT/BAL. We put her on the Phase I. And really, I mean, this is the last Hail Mary attempt. We knew if this didn't work, we were absolutely going to send this patient to hospice where the life expectancy really would be measured in months. And just after a couple of doses, you can actually feel this thing in her abdomen, her pain went from a 7 out of 10 after like literally 4 weeks it went to 0 out of 10. It was unbelievable. Her AFP, alpha-fetoprotein, which is a tumor marker that we measure in the blood, it was literally 200,000, right? Normal, you don't want that thing to be above single digits, right? And that had completely normalized after 2 months.

One of the most dramatic responses I've ever seen in my entire life. And the thing that was so gratifying about it is the patient just, her pain was gone, right? When you look at the imaging, all that was left was like the shell, right? Kind of what I assume is just byproduct or scar tissue. The amazing thing about this patient is that she was going to hospice, 2 years later after being on the BOT/BAL study, she came off study because that's protocol, and she hasn't required treatment for her cancer now in over 2 years. And this really kind of shows you, number one, exactly what we're talking about, response, patients feel better.

Number two, the durability of response. And for all intents and purposes, with a normal AFP, a normal scan, no treatment in 1.5 years to 2 years, when we're effectively talking about cure of a disease that would have probably given her only a couple more months to live. Really just one of those things that you'll never forget as a physician, and it's just an honor to be part of it, a life saved and literally a life cured. And there are stories like this across all investigators that have had experience with BOT/BAL.

Wow. Now that is a wow. It is nothing short of a miracle to see something like that. And yet when you talk to individual patient case studies with regulators and regulatory experts, the typical response is that it's an anecdotal case with traditional treatments like chemotherapy, not only often do you require continuous therapy for the patient in order for the response to persist. But you also have to deal with the toxicities associated with traditional treatments -- more is sometimes resulting in more responses, but more is also resulting in a lot more toxicity.

When you think about chemotherapy side effects, especially if you say like, okay, well, chemotherapy is going to decrease white blood cells. You imagine when you stop chemotherapy that there will be at least somewhat of a recovery, right, of those counts because you're taking that kind of poisonous toxicity off the table. One of the things with immunotherapy is that when you activate somebody's immune system, you obviously hope it attacks the tumor by golly, it really did, right, in this patient. But you also have immune activation in other areas as well that can cause side effects.

For this patient, she actually developed adrenal insufficiency, right? And that is a known side effect of immunotherapy. So that requires her to take a daily small amount of steroid and she'll tell you, right, time over time that she would trade that a million times over for the cure that she's received. But the toxicity balancing that toxicity and the efficacy of the drug is something that we all do as investigators, as physicians. And here, I would say the trade-off is pretty clear, right? You're cured, you do have to take this medicine. But it's kind of one of those things where is it worth it? For her, she will tell you that she's living her best life, right? And so I don't think that she really has too many long-lasting toxicities besides the fact that she does have to take the medicine.

So how does a physician like you who has also served on ODAC, FDA's Oncology Advisory Committee, reconcile all of these anecdotal cases that are miracles for patients?

Well, I think from a regulatory standpoint, it's difficult, right? I mean what we -- the paradigm of how we traditionally look at progression-free survival curves and overall survival curves is really changing in the setting of immunotherapy. And I think that the FDA is really trying to maneuver this change from what we typically see with chemotherapy and even targeted therapies with some of the long-lasting impacts that we see with immunotherapy. And so -- and it's not an easy job because whenever you look at these curves, we know that there are some patients that are just not going to respond at all to these drugs.

And then on the flip side, there are going to be patients like my patient that -- where that curve is just going to keep going, right, kind of forever. What we call the tail of the curve. And really what that means for people who aren't familiar with looking at some of these kind of survival curves is we have to keep in mind that whenever a survival curve drops, I mean those are patients that are passing away from their cancer. And there should be -- that should be a sobering thing whenever we look at it. But at the same time, when you look at these curves, and the drop-off stops and then there becomes this tail of the curve where people are just continuing to live and live and live, which again suggests either 2 things that the disease is under incredible control or that there's a cure. We, as physicians, as investigators, as patients, even as regulators, are going to have to really determine where that tail of the curve is and what that means for our patients.

So do approvals start to happen because we see that like, say, what if 20% of the patients that enroll onto a study are essentially either have durable responses or cured? Well, that's something that needs to be considered. And there have been treatments that have been approved based off of this long, continuous either cure rate or continuous response curve or durability of response.

How do patients react or even embrace when you explain the prospects of being treated with immunotherapy versus the traditional treatment?

I think that there's always a lot of excitement from our patients whenever they're offered anything other than chemotherapy, right? And I think that there is a knowledge that immunotherapy isn't going to work for everybody, but it's the idea that there's a chance of a durable response that I think really gets everybody excited. Again, it's up to us to make sure that we provide access. Number two, make sure that we provide the right clinical setting. But number three, one of the most important things is to really just find out who those amazing responders are and offer those patients the drug to make sure that if they do experience any side effects, it's well worth it because the responses are going to be so much higher, we have to identify the patients that are going to have that durable response. And I think that, that's a lot of the work that's coming up for all of us.

Well, thank you very much. You probably always do that for your patients, but for your extra time that you've devoted to us this morning, and we will see you soon.

Absolutely. Thank you for this opportunity.

So we thank Dr. Lieu for his very insightful discussion, which you experienced with Dr. Lieu having served on the FDA Advisory Committee, he has a substantial amount of regulatory experience and the ability to decipher data in ways that other investigators may not have. And Dr. Lieu is new to you. We haven't featured him. And we expect that many others in the next months will be here talking about their experience with BOT/BAL. His remarks underscore a meaningful shift underway in oncology. As clinicians observe responses in diseases like MSS colorectal cancer, typically unresponsive to not just immunotherapy but poorly responsive to other treatments, particularly in the metastatic setting. And the fact that we have to move very quickly with a high level of urgency. This sentiment is growing. It's increasingly clear that immunotherapy will play a role in this and other disease settings. The question now is how quickly can we bring these advances to patients?

So few people have had a closer view of this momentum than Dr. Jonathan Loree. Dr. Jonathan Loree is one of the lead investigators for our CCTG trial that has gotten underway actually, working with the Canadian Cancer Trials Group, that is the full name for CCTG, and partners across Canada, France, Australia and New Zealand where the trial is going to be conducted, and the patient recruitment is going to take place. He has helped drive one of the fastest-moving global trial efforts we've seen. His perspective reveals not only the scientific promise but also the operational readiness and enthusiasm from investigators around the world.

And let's turn now to that discussion.

Hello, Jon. Dr. Loree, thank you very much for being with us today. The first time we met, I believe, was almost 3 years ago at ASCO. You and Chris had come to meet with us with our team. And you made a very, very strong case as to why CCTG, along with the interest of your colleagues in Canada and elsewhere would be the best candidates to enroll patients in this trial.

Yes. The Canadian Cancer Trial Group had recently finished at the time a clinical trial evaluating different immunotherapy compounds, durvalumab and tremelimumab in a trial called CO.26. This was a Phase II trial, and it was weakly positive, but it wasn't something that moved to a Phase III trial. And we thought that this is a population that really there is an opportunity for there to be benefit for immunotherapy. But then when we saw the data with botensilimab and balstilimab, it really stood out as something that was exceptional and different. And when we thought about the Phase III trial and something that should move forward in the same population, they really stood out as the agents that would be ideal.

We had a strong track record in Canada for that trial, the CO.26 trial, and we worked very closely with collaborators in Australia, New Zealand and France in a number of trials across our cooperative groups. And so we've got a strong track record in shared history. And so we knew that this was something that we were excited about the science, excited about the possibility of progress for our patients. We have the capacity across our networks and a shared history that we can really do this trial efficiently and do it at a level that was going to be important to move this as something that would evaluate it properly for moving into the clinic.

Typically in colon cancer, you don't really look at immunotherapy as an option. Jon, what is the sentiment from the field? Your core circle of hospitals and investigators, what are they thinking? And what's the level of early receptivity?

There's been a sense of awe really at seeing what immunotherapy can do in microsatellite instability-high colorectal cancer. We've seen just how dramatic that effect can be. But when we see patients in clinic, who don't have microsatellite instability high, we felt a little bit like we're failing them. People are excited about the possibility of doing that in the 95% of colorectal cancers that are not microsatellite instability high. And so that's led to a lot of hope and enthusiasm for this to be something that is a new option for patients and not just an option that's an incremental step, but something that can really make a big impact for our patients.

Jon, patients are looking for a an option that is different than the traditional toxic options.

The field is excited about this, and the preliminary data looks really good. I'm excited about the BATTMAN trial being something that we're doing in a way that is going to give us the data showing that this combination improves overall survival. And one of the key priorities when working with the Canadian Cancer Trial Group is we're designing this trial also to make sure that not just is it positive from a regulatory perspective, but when it gets to a health technology assessment that payers across every country are going to have the data that they need to make their decisions on reimbursement. And I think that's really important. We need to plan for not just the trial now, but also planning to make sure that we have all the data elements that are there and required to make it so it's something that can move into the clinic.

You mentioned the cytotoxic component, and that's really important. Patients when they're at the point that they would enroll on BATTMAN, they've been on cytotoxic chemotherapy for a couple of years. And they're getting tired. They've had a lot of the cytotoxic side effects that build up over time. And having something different, it's a world of difference for what their quality of life means. And it gives them a chance to spend the quality time with their loved ones and doing the things that they want to do. And so I think that's also really important, having that different mechanism, so that way they can recover from what they've been through.

And not only do you have to address their needs to have a longer life, but you said a better quality of life.

Yes. That's a major thing that patients tell me in clinic is that they want to live longer with their cancer, and they want to live well and they want to be able to do the things that they used to do before their cancer diagnosis. And having that long curve, that's amazing and super exciting, but also being able to see patients in clinic and have it be a good visit, a visit that's about kind of the successes that have happened and less about the toxicity, I think that's a really impactful opportunity with something that has not those cytotoxic side effects, as you mentioned.

Now what about the prospect of having patients be treated with BOT/BAL, for example, for a reasonably short period of time, and having results without necessarily the need for chronic continuous treatment because, as we know, with traditional cytotoxics, if you stop treatment, often the disease comes back very quickly. So you have to continue on treatment. And of course, there is the cumulative toxicity of that treatment.

Yes, that's what really excites me in clinic to have that as something that's a possibility for the patient sitting in front of me, and it excites them as well. And those -- that time off therapy is a really important metric because that's the time that people can travel, they can -- they're not tied to coming into see me continuously. It lets them prioritize the things that they want to do. So I think you highlighted a really impactful benefit of something that if patients have a durable response that they can enjoy those other aspects of their life and not be tied to the chemo center.

I love those appointments when somebody comes back and tells me about the trip that they just had and this amazing thing that they did and the grandchild that they got to hold because they were able to travel to someone because they didn't have to be here for everything continuously. Another thing that my patients tell me that they want is they want quality of life. And many of our surgeries and our treatments lead to impaired quality of life for bowel function, sexual function, overall health. Thinking about the surgeries that are required, sometimes requiring a lifelong stoma. And so the opportunity for organ preservation and for cancers to either disappear to a point where there -- it's a different surgery that might provide a better quality of life or maybe a nonoperative management is a possibility. And I think as people gain experience and understand kind of the effect of something that works on a typically cold tumor, they're going to be really excited about that, both patients and providers.

And are you seeing early signs of this amongst the exploration of your expansion to beyond your center in Canada, France, Australia, New Zealand?

Yes. I hear from investigators all over the world where are things at. We're excited about this. Can we be part of this? And so I think that the momentum is incredible. And that's quite an exciting thing to be a part of. And I'm very grateful also of all the things that have helped make that momentum possible. There's great collaboration, both with the clinical development team at Agenus. But with our clinical colleagues across these cooperative groups. We have this shared history that's really rich over the past 20, 30 years where we've done lots of trials together.

That's wonderful to hear, actually. So when we started the trial efforts, Jon, we said, well, how quickly can we gear up to get this thing started? And if you can give us a sense of what has really driven the speed with which we have arrived to where we are and the level of excitement that has driven the speed and how quickly your organization has geared up to put all the elements in so that the first patient in can be accomplished as quickly as possible?

You highlighted a really key word, and that's enthusiasm. I think there's a lot of enthusiasm amongst sites and the central offices and our patients because of the data that they've seen to date and because this is a group that really needs something new. We see so many patients who are still well and they run out of treatment options. And they need more things in our toolbox and they need different things.

We've talked a little bit about potential side effects that can happen from chemotherapy. This is a different drug that affects patients differently. It's durable. That's really exciting to providers. They've seen how good immunotherapy works in microsatellite instability-high colorectal cancer and the opportunity for that in the 95% of patients that don't have microsatellite instability high, that's huge. That gets people really excited.

And when you combine that with the Canadian Cancer Trials Group's experience running large trials working together with our collaborators at the Australasian Gastro-Intestinal Trial Group, AGITG and UNICANCER in France. There's this shared history where we work together. We know each other's policies. We know the things that are important for each site. We know the protocol kind of the key important pieces that need to happen to put a trial together that's successful, and we know each other and those relationships are really important. It's not just receiving an e-mail from someone that you don't know. It's someone that you've known for years, you've worked together, you have a shared history, and that's really important.

So you say, I've got this really exciting opportunity for us and people get excited about it. And it's really it's infectious, and that's been exciting. We've done a lot of groundwork. And so that groundwork has been important for getting our sites excited. There's one thing of all the operationalization that happens at a central office between institutions in different countries, but getting sites excited about this and telling them we've got a trial. It's going to be for your patients. These are the compounds. This is the exciting part. That's really important for kind of getting the system ready and priming the pump. So that way things are ready to go.

And when you combine all that together, that groundwork, the excitement, that shared history, it's really led to something remarkable as far as how fast things have gone. We've gone over a period of about 4 months from contract signing to protocol development, regulatory approvals in multiple regions to now us having sites asking, let's go, we're ready to activate. And that's really exciting. So we are moving very quickly.

That's powerful. That's very powerful. Thank you very much for that. And all of this obviously catalyzes a process by which we can achieve enrollment quickly and collect the data on the important end points. We appreciate your being a major driver of the BATTMAN trial, and we are very excited about working side by side with you to make sure that we complete enrollment quickly and that we also get the readout from the trial as quickly as possible for the benefit of our patients. Thank you.

Thank you.

So we thank Dr. Loree. His remarks highlight a critical reality. And as he said and others have said, patients around the world are looking for treatments that extend life, but also importantly, allow them to live without the burden of traditional treatments like chemotherapy, which could have lifelong impact on the quality of life.

The momentum behind the Phase III program reflects the need and the possibility of investigators around the world in their belief in such an outcome, and that is now within reach. Now it's also important to remember why we do all this work. Every data point represents a person, a family whose life is shaped by the options available to them. What stands out most in our work with CCTG and our global partners is the level of enthusiasm that is building, and that's very tangible. The kind that accelerates timelines removes barriers and aligns teams across many continents behind a shared purpose, improving the lives of patients with colorectal cancer and many other types of cancers, which were the subject of our ESMO presentation in Berlin about a month ago. And this, of course, brings this to our next segment.

Our next session is with Benny Johnson. Benny Johnson joined us a little over 2 years ago from one of the world's most renowned cancer centers, MD Anderson Cancer Center in Houston, Texas. And shortly after he joined the company, his wife was diagnosed with Stage III colorectal cancer. And here is Benny to tell us about his experience in having joined Agenus as well as his experience going through that process with his wife.

It's been a delight to have you at Agenus as a colleague. And before Agenus, if you can give us a little bit of a synopsis of what you did, more importantly, how did your daily life look every day, taking care of patients?

Yes. Before joining Agenus, Garo, I was actually an Assistant Professor in GI Medical Oncology at MD Anderson Cancer Center in Houston. So my focus was primarily colorectal cancer patients and anal cancer patients. As my career evolved at MD Anderson, I took on a particular interest in young onset patients and worked towards developing that program at Anderson. And so my clinic really became a clinic full of peers, if you will, depending on the day.

So about 2 days of clinic, 2, 3 days about with research trying to work towards clinical trial design and investigator-initiated studies.

Your decision to join Agenus, and how did your knowledge of BOT/BAL materialize even before you joined the Agenus? What was the critical driver for you?

Yes. As I mentioned earlier, a good amount of my time was thinking about investigator-initiated studies, but also finding the right collaborators, right sponsors to work with because when you see really exciting data, we want to partner with those companies early because we want to not only help them run meaningful trials for our patients to offer new therapies, this is the way that we move the needle forward for metastatic colorectal cancer.

And so the way that Agenus came to me was very interesting, one of my mentors, Dr. Michael Overman, sent me an e-mail and said, "Hey, there's a Phase II trial being proposed in colorectal cancer, and I really want you to lead this program and increase our interaction with this company." And that was really the excitement around that, as you know, and now that I know was the data from the Phase I study that was showing in refractory colorectal cancer patients, MSS which is 95% of our patients.

We were seeing response rates with an immunotherapy combination, BOT and BAL that we never really saw before in MSS colon, never seen it over 20% and then having durable responses. And the percentage of patients enjoying that and even potentially being cured, right? So I had the opportunity to be the Phase II PI. And then in my interactions with some of the clinical development team just in that space, there was an opportunity here at Agenus, and I really felt that it was continuing the same mission that I had to move the needle forward for the majority of metastatic colorectal cancer patients. And so I jumped on it. I think it was really just an amazing opportunity to be a part of this team.

So it wasn't just a job at another company that there was a greater purpose in all of this.

100%. I think we all want to find meaning in what we do. And the experiences that I had at MD Anderson were really formative for me. And then having the opportunity to then take a really powerful combination and think critically and work with a really talented team here at Agenus to push the boundaries and bring it to more patients sooner was really an opportunity that I wanted to dive into to have that experience to help many patients with colon cancer, not just the few that I see in my clinic but a global need and being a part of that.

So you join Agenus and then you get hit with a personal challenge. And of course, you come from a medically sophisticated family, including your wife. How does that factor into your decision-making to deal with that challenge?

I would say about 4 months after joining the company, this is when we found out that my wife was diagnosed with sigmoid colon cancer. And leading up to that point when we actually receive the diagnosis, we both knew something wasn't right. Her -- she had some symptoms of just GI symptoms that were new, change in bowel habits that were new, periodic bleeding. And we just -- we both -- without saying it to each other, we knew there was some urgency in getting to the bottom of this.

And so actually, Garo, for many weeks, the 2 of us actually never said what we were thinking aloud to each other. And I think that's because, as you mentioned, just having -- obviously, me having my background but even my wife, who saw -- who has a tremendous amount of background in primary care, understands these red flag symptoms. And one of the things about young onset colon cancer is primary care physicians still are learning that a young patient less than 50 years old, a 30-year-old, 40-year-old patient can actually have colon cancer. That's really not something that is on the top of their mind or their differential.

And so we saw that even as 2 health care providers, we saw this delay in diagnosis. We were told -- when she was found to have an anemia, we were told to just take iron pills for a couple of months and come back and reassess. When we told an OB/GYN that she was having this unusual pelvic discomfort she was told, "Well, now you're over 40, you just have different symptoms now."

It was just -- it was really sad and surprising to me that, that still happens to patients. We advocated for ourselves because we kind of understand that no, something is not right. But for the layperson, I think they would just believe their doctor and say, okay, I'll just do what you say, and I'll come back 6 months from now. And unfortunately, for some patients, that may result in advanced disease. So all that to say that we were able to move forward and she was diagnosed with a sigmoid colon cancer. And our lives changed immediately, immediately, you could imagine.

And you have children, of course, and that makes it challenging. So what factored into your decision to -- for your wife to be treated with BOT/BAL?

As you mentioned, I knew what was on the table, right? For a patient that has what we call clinical stage III disease, standard of care is to move to upfront resection, followed by anywhere from 3 to 6 months of adjuvant FOLFOX or CAPOX. So we're talking about 2 chemotherapies that have some side effects. But what was in the back of my mind was I've treated many patients just like that. And unfortunately, even with our best treatments, anywhere from 22% to 30% of patients will still recur within 2 to 3 years. And that statistic was in the back of my mind. And I wanted something more and what was available.

And you mentioned earlier, just the timing of it all to kind of have experience with BOT/BAL as a PI in the Phase II CRC program for advanced disease, but still nonetheless, seeing the responses there. And then joining the company to see some of the early published data that was available in the NEST clinical trial, a neoadjuvant trial of BOT/BAL for patients with resectable colon cancer.

So how do you take that mindset of, hey, there's this trial that's an option for you and also kind of knowing the standard of care and then present it to not only my wife, but my wife comes from a very educated family. I had to convince them too. Explain to them the novelty here, and the fact that we have one chance. We have one chance to do our very best. And at that moment, I think we felt it was the right decision for us. And ultimately, she decided that she was willing to do whatever it takes.

What happened? She gets treated. How many treatments did you have?

Yes. So she received one dose of BOT, 2 doses of BAL perioperatively. And then she went for kind of evaluation endoscopically. And we saw within 7 weeks that a very large sigmoid tumor had complete resolution endoscopically. So what we call kind of a clinical complete response. In that moment, her surgeon, we still decided as part of the protocol and standard of care to move on with surgery, and we were then able to confirm a complete 100% pathologic response.

And so this was just an amazing news for us. I think Lij often says that I really wasn't breathing when she started the clinical trial. And up until that endoscopy is kind of when I was able to exhale because I feel as though I was holding my breath for months. And so that was a really powerful moment for her, for me. And then it allowed so many things that I think she benefited from. I mentioned earlier that most patients would go on to get anywhere from 3 to 6 months. And young patients, there's this idea that we kind of need to give them everything. So she may have -- very well have received 6 months of adjuvant chemotherapy, but at the very least, 3 months, but it was -- it would have been 2 drugs.

But the fact that she had this amazing response, this 100% clinical complete response or pathologic response we were able to de-escalate her adjuvant chemotherapy to a single agent. So we look at it as an unbelievable win for our family that she was able to have this opportunity, be a part of a really novel immunotherapy combination that I think will eventually change the entire landscape for localized colon and rectal cancers. And then to be able to de-escalate her adjuvant chemotherapy is huge. These treatments come with a lot of long-term side effects. And for someone like her who's a runner, young kids, an 8-year-old and a 3-year old at home, peripheral neuropathy would have been crippling for her.

Here you are a colorectal cancer specialist. You join a company that has a remarkable treatment. Your wife comes down with cancer shortly thereafter, gets treated, you witness the outcome firsthand. How does all of this factor into your thoughts as a professional as you're building a career?

Right. I think the lesson here is this is not just an old person disease, right? Colorectal cancer is impacting -- can impact any of us. And the rising incidence in young people, it just brings it to the forefront to really see how close to home it hit. It was -- it really was one of the most challenging times of our lives, as you can imagine. Because even though I was taking care of these patients and walking with them and just how this huge admiration for what patients and families, especially our young patients were going through. Now I had a front row seat, and I got to admit, I didn't really want to have that viewpoint but I did. God decided for us to have that viewpoint. And I think where it leaves me now is I'm just so thankful, as I mentioned before, I've been able to see BOT/BAL on all sides of the development, if you will, as an investigator, now here at the company and developing it further. But Lij's story is one of many other stories as we see the mature NEST data that will be published soon. This is an amazing story that's not just impacted her as a one-off. It's a powerful regimen that is impacting many other patients with very similar results.

And so I think moving this it drives me to move it for an available therapy for all of our patients, right, to really change where localized colon cancer is going, right? Currently, we're still using the same therapies we've been using for over 20 years, and I think it's time to move that needle. And so watching -- having this front row seat has provided a real passion for me to do whatever it takes to move it forward and to innovate, right, to innovate therapies for our patients. Because honestly, Garo, if you have Stage III disease, and you're doing everything you can at the best centers with the best oncologists, the best surgeons, and we're still having a 22% to 30% recurrence rate, it's just not enough, right? Because that percentage impacts one family, right?

So as you said, it's not just one patient. It's now scores of patients that have experienced some remarkable responses. And if you were to explain to a patient knowing what you have gone through, this optionality, how would you paraphrase the advantages of having BOT/BAL?

I'd really say we want to do everything we can to train your immune system to fight your cancer. And if we have drugs now that are able to do that, that is the change, right? It's not just a matter of giving therapies early, right? So for instance, there's data now that if you give your standard chemotherapies like FOLFOX, like CAPOX before surgery, the response rates are still very low. It's not what we're seeing when you give novel immunotherapies like BOT/BAL before surgery. So it's a significant difference. It's to give them their best shot and also to use their immune system to their advantage to fight the cancer in a way that will really result in lasting change and cure.

If your wife looks back at her experience, how does she tell her own story in terms of her own experience versus, for example, what you would have expected when she was first diagnosed?

But I think looking at it now, as you mentioned, an abbreviated course of therapy, having her surgery and then being able to de-escalate chemotherapy to a single-agent drug for about 3 months, the benefits of that, I think, have been so impactful for her because now she's not thankfully having to deal with chronic chemotherapy toxicities or having a risk of developing peripheral neuropathy from oxaliplatinum because she was able to avoid the drug altogether. And that's been huge for her because now she's kind of back at what she was doing before, looking for a new job, getting back to running, which she loved, being fully available at the kids' school and being able to take care of both of our children. And so doing all the things that she loves again, and I think being able to avoid some of these therapies played a role in that, for sure.

And so she's thankful. She's very thankful. And then both of us, as I mentioned before, last year was kind of a year where we just needed to survive. And this has been -- and this year has been one where we were kind of, wow, last year really happened, and we're unpacking it. And one of the things she said is I'm just so thankful that I was able to receive this therapy and now be done with therapy a lot sooner on the back end. And she has no long-term side effect profile, which is really, really unique. And I think just something we are so happy for her to have that opportunity.

And based on your experience, certainly as an important member of our clinical team, we've treated over 1,200 patients across 9 different types of cancers, treated patients in the last line setting as well as in the earlier stage like the case of wife. And it's a chemo-free option. And so the question is young patients want something a little bit more innovative and luckily, for your wife that innovation was available for her setting in time to benefit her. What's the chances of all of this happening you joining the company 4 months later, your wife comes down with it. By then, we have generated data that has convinced not just you and your wife, but your family to allow her to participate in this trial. And here we are, a beautiful outcome. And that's what we really want to have for all patients as soon as possible.

We are doing tremendous work in -- with really some amazing investigators all across the globe. And the excitement from oncologists here in the United States, but also globally just kind of speaks to the data and speaks to the novelty and the potential to really transform solid tumor cancers, right? And so yes, it's a miracle. I think about just the fact that I'm here, like you said, it's not a coincidence. And I get to be a part of this wild ride and work with an amazing team that is focused and dedicated. Even though we're a small team, each of us has these stories and has the patient in the back of their mind or the family member that's been impacted. And we realize the current standard of care is just not enough. So what can we do? So Agenus has this amazing pipeline. This amazing drug in BOT/BAL that we will bring to the finish line. And I think that's our goal. And then patients benefit. And so that's why we're here, and I'm truly excited to be part of the team.

Thank you very much for that, Benny, and we're delighted to see that your wife is -- had such a phenomenal outcome.

Thank you, Benny. Benny is with us today, along with members of our technical, medical and commercial team to field questions. But we appreciate your transparency, Benny, and sharing such a deeply personal journey with us. Your family's experience reminds us of the importance of the urgency as you stated, of patient access to a treatment option like BOT/BAL. Taken together today's discussion reaffirms the importance of our mission. Number one, patients need better options. Two, the path forward is becoming increasingly clear.

With that, we'll now turn to your questions and continue the conversation with our leadership team. Stefanie take it away from here.

Great. Thank you so much, Garo, and welcome to our Chief Medical Officer, Dr. Steven O’Day, he is with us as well as Chief Development Officer, Dr. Richard Goldberg, and welcoming back Benny, Dr. Benny Johnson. And we also have other members of our team that we added based off of the questions that we were receiving. Dr. Dhan Chand is with us as well, our VP of Research. And I believe that we were able to get our Chief Commercial Officer, Robin Taylor, I. think he was trying to come back through travel. So thank you all for joining us today.

With that, I'm going to jump right in because I'm noticing the time, but we did have some questions that were submitted from our call in October that we didn't get to. And I'm going to give these questions to Dhan. Some of these questions are related to our partnership and our collaboration with Noetik. So we announced that quite a couple of months ago and there were some questions related to, is there anything that has come out of that? Or can you share with the status of that work that's being done with Noetik and their AI platform?

Yes. Thank you, Stefanie. So this is Dhan Chand, Head of Research at Agenus. So our collaboration with Noetik is focused on identifying biomarkers that can predict response to BOT/BAL. And while these studies are still ongoing, I'm very excited by the early results that we're seeing because now we can distinguish or starting to distinguish at the molecular level responders from nonresponders. And as you can imagine, as this data matures, it will empower us for patients that are most likely to benefit from BOT/BAL.

Now we do expect to share these findings with the broader scientific community as the data matures. So stay tuned. We're hoping to have that shared as early as next year.

Thank you, Dhan. And while you're on the line, there was another question that I think would be appropriate for you to answer as well is that, is there any plans in looking at other specific biomarkers that may come out? Particularly, there was a specific question about c-MET inhibitors or potentially eGFR. Can you comment on any specific biomarkers or work related to that as well?

Great question. We're definitely exploring a range of biomarkers to help with [indiscernible] most likely to benefit from BOT/BAL. But what's been really interesting is that we're seeing clinical activity independent of your traditional biomarkers, which fits BOT's unique mechanism of action.

Now regarding c-MET and eGFR, specifically, these are well-established biomarkers in lung cancer, but it's less well known for its role and response immunotherapy in colorectal cancer. So while our focus right now is on colorectal cancer and prioritizing biomarkers for that patient population, we'll absolutely continue to explore other biomarkers as the development of BOT/BAL and other indications mature.

Great. Thank you so much for that, Dhan. So let's switch gears a little bit here. There was a question that was submitted related to the priority voucher program. And Dr. Goldberg perhaps you could answer this question. So of course, we can't comment necessarily on where colorectal cancer sits in the priority list for the FDA. We don't have specifically those insights per se. We know that colorectal cancer has been something that has been top of mind in a lot of communications coming out of the administration and the FDA. But can you share with the audience just what our plans are for submitting a voucher and with the status and if we've actually tried to take part in that program or not.

Sure, I'd be happy to. So when we heard about the director's voucher program. We were very excited about it. He came out with statements that he hoped to shorten the time to getting drugs that satisfy an unmet need into the hands of oncologists and patients as well as other physicians as quickly as possible. And so we immediately submitted an application to be considered for the voucher program for BOT/BAL. Unfortunately, we weren't 1 of the 10 drugs that were chosen but then we were heartened again when an announcement for a second group of drugs and applications to be examined. And so we immediately, again, submitted our application for the voucher program. The voucher process is actually a very brief 2-page application process. So I also sent an e-mail to Marty Makary, the FDA Director, adding a few details about what we've been explaining to you today. We haven't heard back. I don't think anyone's heard back about the second tier of applications, but we're waiting with bated breadth.

Great. Thank you so much for that, Richard. And I have a question here that's just been submitted for Garo. Let's see if we can get Garo back on camera. The question is related to Zydus and CFIUS review. And -- but if we could comment on how operationally the ownership transition of the manufacturing facility is progressing? And also, there's a question here about on the BOT/BAL supply and if we have that secured for the Phase III trial?

Sure. So with regard to CFIUS and Zydus transaction, as you know, we had a number of unforeseen events, amongst them was the government shutdown for a period of time that basically put some of the key workers at government in various departments in hibernation, but we've come out of that. And we're hopeful that a decision by CFIUS will be made very soon.

Now with regard to the Zydus team, we have been working very collaboratively with the Zydus team all along. In fact, as you know, they extended a $10 million loan to us to make sure that their commitment is very clear and it continues. We continue to work collaboratively with them. We will continue to work collaboratively with them post the closure of the transaction. By the way, once CFIUS clears the transaction, we expect in less than a year -- I'm sorry, there was a big slip. In less than a week from the CFIUS clearance, we'll be able to close the transaction. We're geared up for it with a meeting with the team yesterday, actually, to make sure that everything is lined up so that we can advance it to an expeditious closure. And as you know, after the transaction, we will be a very big beneficiary of the collective resources of the Agenus team that's in existence as well as the Zydus team that's coming into place.

Now with regard to supply, we have a substantial amount of BOT supply in the form of drug substance. And that drug substance could be converted to drug product very, very quickly. However, we have separate from this drug substance, which could be enough to treat tens of thousands of patients, and you can extrapolate from that what the potential revenue is upon approval of BOT/BAL.

But aside from that, we have ample supply to conduct the BATTMAN trial in the form of drug product that is undergoing right now labeling and packaging. So that portion of it is secure. In fact, we have shipped the first batch of product to Canadian pharmacies where we expect the first enrollment to take place prior to France, Australia and New Zealand.

Thank you for that very thorough answer, Garo. The next question here, there's actually been a lot of questions that are coming in. So thank you all and please continue to send them in to [email protected]. If we don't get to them today because I'm already looking at the time, we'll certainly be able to get to them at future webcast.

But the next question here, I'm going to share this question with Dr. O’Day, kind of 2 questions here. One is that we have a number of really important investigator-sponsored trials that are running. This particular question is which ones do we think that we should be watching the most closely in terms of new incremental data set? Those that have a really high unmet need, particularly those that might be beyond colorectal cancer because we know that we've been focusing a lot on colorectal cancer, but we have some neoadjuvant studies as well as some other data from our Phase Ib study as an other. So can you share a little bit from your perspective on any of those ISTs that we should be watching closely. Steven, I think you're still on mute. Perhaps, can you double check? Thank you.

Can you hear me now?

We can. Thank you so much.

Okay. So we have 4 major ISTs at major centers around the world. The NEST in the UNICORN ISTs that are colorectal based and then a pan-tumor IST and with Myriam Chalabi at the Netherlands and then a new rectal dedicated IST at Memorial Sloan Kettering with Andrea Cercek. These are compelling...

We lost Steven. I think maybe Dr. Goldberg you can continue on this.

Right. So I can take off where Steven left off. So these 4 studies are looking at the use of BOT/BAL in the neoadjuvant setting. So similar to the setting that Benny's wife received the drug for. And what we're seeing in initial studies are broad activity across colon and rectal cancers as well as other cancers where adjuvant and neoadjuvant treatment is commonly given. So we're excited about data coming from the Netherlands in triple-negative breast cancer. And as a consequence of this, we're putting together future potential indication granting studies, Phase III studies particularly in colon cancer.

We also had a meeting with the FDA previously in August for rectal cancer. And it makes sense that the real power of these immune-activating agents is going to be in patients with lymph nodes intact because the source of immune cells, in many cases, is the lymph nodes and lower tumor burden. So we're really bullish on the potential to make a real difference here. And that follows in the pathway that Dr. Cercek blazed with her initial trial in MSI-high rectal cancers where 100% of her patients had complete responses in the MSI-high setting. But of course, we're treating mostly patients in the MSS setting here, although some patients have been treated with MSI-high tumors, and we've seen similar dramatic activity to what she's reported in her initial trial. So stay tuned. We're very hopeful that this will change the paradigm in the management of colon cancer and potentially other cancers.

Thank you so much for following up on that, Richard, and it looks like we have Steven back. A follow-up question. So perhaps I don't know, Richard, if you have the insight of this, there were some questions specifically the neoadjuvant or early line studies. Is there any update or any indication that [indiscernible] about when we might be anticipating having any of that data shared in publications or at upcoming congresses in 2026?

So at this point, that data is maturing. We did have an update last spring that was in the public domain. The trial at Sloan Kettering is accruing very quickly, but the data has to mature and patients have to complete their treatment before we have more knowledge of that. The data in the Netherlands Cancer Institute Group is expanding as they're accruing more patients across the various indications. So it probably will not be until ASCO of next year that we would have an update on these data. So stay tuned.

Great. And we'll be sure to keep everybody posted when we do have a better idea of those abstracts of that data being available either through manuscripts or through congress presentations.

Given the time, I want to be really respectful of everybody's time, I'm actually going to turn it back over to Garo to close out the call. We do have a number of submitted questions that we didn't get to, but just like what we did this time, we will keep them together and make sure that we do address them at the next opportunity or our next webcast or our earnings call.

So with that, I am going to turn it back over to Garo to close out our call and thank you all for joining us today.

Thank you very much, Stefanie. And I also want to especially thank our participating clinicians as well as our team and all of you who have joined us today. What we've heard through this session from Dr. Lieu, Dr. Loree, Dr. Johnson and members of our team points to a profound shift which is underway in not just colorectal cancer, but in all cold, warm or hot cancers. This scientific insight that immunotherapy can work in those types of cancers, has very important global implications in the way we manage patients. We've discussed the personal stories, patients who have experienced this, the patients' family members. And all of this reinforces the fact that there is an unmistakable truth, patients urgently need better options. And we are closer than ever to delivering them.

I mean, who after all, would not want to have a chemotherapy, a debilitating treatment-free, mutilating surgery-free option. And potentially, this is what we're heading towards. This year, we've seen encouraging signs across multiple fronts. Consistent clinical activity across refractory and earlier stage settings and that story is growing. Our global Phase III trial has been launched with unprecedented collaboration and speed with one of the leading organizations, CCTG, and the principals, including Dr. Loree, who you heard from today. Stories of real patients and families whose lives have been changed by across this -- by access to this innovative therapy. And these are not abstract accomplishments. They are reminders of what is at stake and what is possible.

As we enter 2026, we're committed as a company and as a team to continuing to advance the BOT/BAL program with the highest sense of urgency as an organization with a highly dedicated team. And the highest priority for us is to make sure that we provide every single patient who can benefit from BOT/BAL, the opportunity to be treated through either a government paid program like the French AAC or through a self-pay program or through private insurance paid program. And of course, we will engage closely with regulators with a near-term emphasis on ex U.S. regulators in pursuant of approval.

To all of you, patients, clinicians, advocates, partners and shareholders, we thank you. Your engagement strengthens our ability to success and our ability to make sure that patients and their families have access to less toxic treatments and patients, of course, would desperately need less toxic and more effective treatments.

We look forward to our future sessions, updating you on the progress that we're making in months ahead. Thank you very much. We wish you and your families a healthy, happy and joyful holiday season.

Good afternoon, everybody. I'm Stefanie Nacar, Chief Communications Officer at Agenus. Welcome to the October Agenus Stakeholder webcast, where we'll be discussing efforts to bring treatment options to cancer patients around the world. But before we dive in, a quick reminder that today's discussion includes forward-looking statements. These are subject to risks and uncertainties that could make actual results differ. Please check our SEC filings for the details.

Joining Dr. Armen today are 2 internationally known leaders in the field of oncology and immuno-oncology research, bringing deep expertise and insights from both the U.S. and Europe. Dr. Michael Gordon, Chief Medical Officer at HonorHealth Research Institute in Arizona, will be sharing highlights of the pan-tumor data evaluating Agenus's immunotherapy combination, botensilimab plus balstilimab, also known as BOT/BAL in refractory solid tumors that he presented just this past weekend at the Annual European Society for Medical Oncology Congress in Berlin.

We will also hear from Professor Alexander Eggermont, Professor of Clinical and Translational Immunotherapy, who is also a treating oncologist in France, about his perspectives on what the inclusion of BOT/BAL in the French AAC program means for patients in France that are impacted by colorectal cancer. After the discussion, Agenus leadership, including Dr. Steven O'Day, our Chief Medical Officer; Dr. Richard Goldberg, Chief Development Officer; and Robin Taylor, our Chief Commercial Officer, will join Garo for a live Q&A. For the listeners that have joined for us today, please submit your questions to the e-mail [email protected]. And we'll be sure to share that again at the end of the discussion to make sure that you guys engage and submit your questions. With that, I would like to introduce Agenus Founder, Chairman and CEO, Dr. Garo Armen.

That's okay. Some people call me Garmin, Stefanie. Hello to everyone once again. At today's briefing, we will discuss 2 of our most exciting global developments in cancer. That may give some hope to an earlier growing number of cancer patients. When I say earlier, I'm talking about younger patients that are increasingly coming down with things like colorectal cancer, which is quite alarming. As you know, BOT either alone or in combination with BAL, which is our PD-1, has been studied in more than 1,200 patients across more than 9 different types of tumors across late-line settings as well as in earlier settings.

When we say earlier, of course, we're not talking about very early-stage disease, but in the neoadjuvant setting, where patients have significant burden of disease before surgery, and we have seen some absolutely remarkable results in those patients in both colorectal cancer, in rectal cancer as well as in our all-comers trials. What's truly exciting is the consistent efficacy data that we see across various tumor types, including those traditionally considered as cold meaning resistant to immune response, and those constitute the great majority of cancer patients.

And the exciting news is that the data presented to date demonstrates the responses improve when you go to earlier stages of disease. As I mentioned, for example, as we go from the very late line Stage IV patients that have exhausted all treatments to the neoadjuvant setting where patients still have significant disease burden, we see remarkably improved rates of responses. Last week, at the ESMO Congress in Berlin, updated data was presented from our Phase I study which, by the way, when you say Phase I, this is one of the largest Phase I studies ever because we have nearly 1,000 patients in just the Phase I cohort of our studies. Dr. Michael Gordon of HonorHealth Research in Scottsdale, Arizona, presented the data. And of course, this was in front of a substantial audience. And I was able to connect with Dr. Gordon before his presentation at ESMO for a brief discussion about the data. And let's now turn Andy to that discussion that was taped with Dr. Gordon.

[Presentation]

Thank you very much for joining us, Mike, here. Dr. Gordon is an extraordinarily experienced and talented investigator treating physician. And he has done a significant number of trials over the years, even though he's young by age, these include a whole gamut of solid tumors. And I've had the pleasure of knowing him for a number of years now, probably over 20 years, Mike, when immuno-oncology was a field. And all of a sudden, of course, the field has sprung up and become a very, very key component of treating cancer patients with a very different quality of life profile than the typical agents that we know.

I'd like to first recognize the decades of work that has advanced the IO revolution and reshaped cancer care. Today, about 60% of patients have access to approved IO therapies sometime during their cancer journey. Responses remain concentrated in immunogenic or the so-called hot tumors and only about 11% of patients have an objective and often a durable response to approved IO therapies. Therefore, the need for novel treatments to extend the benefits of IO to more patients is urgent.

Thank you for that. Now you mentioned some very important points here. The first-generation IO compounds have been sort of impacting the low-hanging fruit, which we would term as immunologically active tumors. And now this is the next wave presumably, and it's a significant proportion of cancer patients that suffer from immunologically hidden tumors.

I think the most important thing is that we hit an inflection point and took a sharp turn north in terms of what's perceived as access to IO therapy for a greater number of patients. We've become very accustomed to those tumors that traditionally respond to immunotherapy, notably the hot tumors, which seem to get larger and larger numbers of options within the immuno-oncology field. But those cold tumors that have historically not responded to the commercially available drugs and therefore, somewhat suffer from the lack of durability of responses, we're now seeing that evolve and change with the data that we've presented here, I think, an impact that has been carried forward.

And perhaps the biggest element has been the absence of investigational therapies, drugs that can break through that glass ceiling that has been established and has limited perhaps our vision of what we need to do to transform care in the diseases that have not previously adopted the standardized use of immuno-oncology drugs. So when we look at things like microsatellite stable colorectal cancer, we see the fact that we are now across the spectrum from advanced disease to early disease, identifying robust activity, which I believe will ultimately chart a course for immuno-oncology drugs to potentially overcome those barriers that have been established by what I think we're going to show are misperceptions of the response of these types of cancers to immunotherapy.

The same is true for classical ovarian cancer as opposed to subgroups that tend to respond to immunotherapy. And of course, sarcomas, while a broad range of diseases have subgroups for which IO therapy is approved or endorsed, but we're beginning to see a more robust activity in diseases that had not been contemplated in that area. So I think that the data that we're presenting with BAT and BAL is going to be intriguing and will open doors -- the hard question and the challenge, as you well know, in drug development is, are there people -- are there companies courageous enough to step through those doors and push through with those unique opportunities to transform our understanding in this case of perhaps IO refractory or cold tumors.

The critical takeaways from our messaging, traditionally cold tumors respond to BOT/BAL with the robustness and durability seen historically with hot tumors getting classical immuno-oncology drugs. Response rates, durations of response and durability of response mirror those seen in prior studies. The adverse events are limited predominantly to GI issues such as colitis, and we believe that the aggressive management with short course steroids and early use of TNF-alpha agents will be able to overcome that toxicity and allow patients to, as best as possible, stay on schedule. We believe that patients with or without liver metastases both respond, though the patients without unquestionably have higher response rates. And critically, those patients who have progressed on prior IO therapy similarly have reproducible responses to BOT/BAL demonstrating that this combination regimen may be able to overcome the failure of classical or historical IO therapies. We're excited about turning a new page in IO treatment and having BOT/BAL be the leader or a leading opportunity to transform the care that we deliver. Thank you very much.

Thank you for all of that. So this exciting data presented by Dr. Gordon. Of course, we thank him for this and the rest of the investigators as well as the patient volunteers that contributed to this study, a very large study, I might add. As enthusiasm grows about BOT/BAL and the enthusiasm, particularly at this ESMO meeting was palpable. And that's because both the data as well as the fact that the French authorities, and I'll talk about that in just a little bit, approved reimbursement and the use of BOT/BAL in France for colorectal patients -- advanced colorectal patients. And this is the first validation that we've gotten. So the data generated and shared at leading international conferences so far have excited people. We're also encouraged by the global recognition, as I mentioned, affirming international confidence for the potential of BOT/BAL.

We had nearly 80 meetings in Paris as well as at ESMO in Berlin, and there was unanimous excitement about the prospects for treating patients with BOT/BAL. Now last month, the French National Agency of Medicines and Health Products Safety granted Compassionate Access known as AAC to BOT/BAL for patients with refractory metastatic microsatellite stable colorectal cancer, which is about 90% plus of the colorectal cancer patients. So it's the biggest chunk of colorectal cancer that is scaring people these days. Now the French authorization came in for patients that have exhausted all available options.

The inclusion of 2 investigational agents, including BOT and BAL is an extremely uncommon phenomenon and is a tremendous endorsement from, in this particular case, the French ANSM. And this, by the way, agency is one of the most sophisticated, not just in oncology, but in particularly immuno-oncology on the available data and the unmet need, which was the driver of this decision. Agenus has already supported patient access programs for BOT/BAL through various investigational access programs in France, the United States and other geographies around the world.

Some of the stories from those patients are remarkable stories and we will be sharing them when we can with you as we have in the past. But this recent announcement from French National Agency of Medicines is very meaningful because France will fully reimburse treatment with BOT/BAL for their citizens. And of course, this is a very, very important pivotal point, and it's a very important inflection point for us that have -- these patients have refractory MSS in CRC and have no other options left. And of course, this is the right thing to do because with patients that have no other viable options left, the data presented on BOT/BAL is quite compelling. French patients pay nothing for this program, and the hospitals pay nothing because the government fully reimburses for the cost of BOT/BAL.

Agenus is committed to making access to our investigational medicines available to patients with cancers at appropriate times and in the correct manner as we have done in the past. If you are a patient outside of France, please visit our website for programs that may be able to help you. And our website has a growing wealth of information on how patients may be helped. Last week, we were, as I said, in Europe, meeting with more than 80 oncologists from France and across the globe. Over the course of these meetings, it became clear that physicians on both sides of the Atlantic want more choices for their patients. It is very important, having choices for patients that have exhausted all other treatments or patients that have actually been confronted with horrible toxicity, mutilating surgeries, having them be presented with options is important for physicians as well as for patients.

For example, one of the doctors we met last week in France, Dr. Claire Gallois has treated 6 patients through appropriate access programs with BOT/BAL and is now initiating a treatment for her seventh patient. The stories we are hearing about these patients, her patients and others align with those that are palpable to us through publications that we have seen on BOT/BAL as well as in conferences that we've attended. And of course, we look forward to sharing more about these experiences as appropriate in the future. The French AAC program will not only allow Agenus to help more patients, it will also provide access to more real-world evidence, which will support the next steps towards gaining full approval for BOT/BAL. This is part of the program that is required in France, and we have made arrangements with the appropriate outside agencies to collect this data.

France has been at the forefront of cancer research, as I've said before, and this goes on for many decades in many ways, French science and medicines is the gold standard for the rest of Europe. As countries see more of their citizens turning to France for treatment, the questions will become unavoidable. Why aren't we doing the same thing in other countries? Patients in the United States will ask, why is this available to French patients and not to me. Of course, physicians and researchers in America will also ask why is French leading the way and not America? Of course, this is a very testy question, and we will work with the appropriate agencies in the U.S. to try to answer this in an appropriate way.

Last week, I also had the pleasure of speaking to one of the legends in the field, Dr. Alexander Eggermont, who was a pioneer in the field of immuno-oncology. And Andy, if we can go to that segment of the video now.

[Presentation]

And now we're joined by Professor Alexander Eggermont, Professor of Immunology, University of Medical Center in Utrecht. Professor Eggermont serves as Scientific Director of the Princess Máxima Center for Pediatric Oncology and holds the Joseph Maisin Honorary Chair of Oncological Surgery at Leuven. And importantly, he previously served as Director General of the prestigious Francis Gustave Roussy Cancer Institute and [indiscernible] Oncology at the University of Paris-Saclay. Recently, the French system under Accès Compassionnel AAC, a national framework administered by NS or ANSM, which is the French national agency for regulatory affairs.

Under AAC hospital use is now covering 100% of the cost associated with the use of BOT/BAL to start with, it's in refractory colon cancer. France is the first country to validate the use of BOT/BAL in this context ahead of the U.S. where the product was discovered and developed for the most part. What is the significance of this? And how do you see this affecting the future of access to effective oncology drugs?

The importance of this step cannot be underestimated because it is a program that identifies drugs that are still not approved by FDA or EMA, but that show very clear signals of exceptional efficacy. And so it's really a pleasure to see that there is a government-supported early access program for those drugs and make them already available and therefore, also speed up all sorts of study possibilities and create an environment where we can move fast and faster in patients who may have seen second, third, fourth lines of treatment and with very difficult tumors like MSS garden variety, colorectal cancer after 3, 4 lines of treatment.

So I applaud this initiative greatly. And I think it's actually a very good decision to recognize that with botensilimab, you have an exceptional anti-CTLA-4, exceptional in terms of capability to prime T cells to activate antigen-presenting cells to deplete T regulatory cells at the tumor side. And because of this point mutation, you don't have activation of the complement system, which greatly reduces the autoimmune side effects that we know so well of your regular anti-CTLA-4 and therefore, it's an exceptional next-generation anti-CTLA-4. And therefore, now it emerges as an agent that with far less side effects has much more efficacy even in the metastatic setting.

This is a clear case where not only the regulatory agency in France has reviewed the data, but they're basically putting their own money, the government's money where their mouth is in terms of endorsing the use of the product in patients. What does this mean for the French patients?

So what you will see, obviously, is that the French patients will benefit from this greatly because they have access to a unique combo with efficacy across multiple tumor types of which colorectal cancer is a very important one and a very frequent one. And therefore, it will start ringing bells elsewhere because I would predict that many European countries will follow this example because we have many discussions about equal access in Europe. And now that France has taken the lead with this program, it puts a lot of pressure on all those countries.

The French government got very good advice from a very vibrant immuno-oncology culture in France. And for once, they were not defensive, but they were exploratory and they were willing to give through their regulation now these type of drugs an early chance.

How does the French approval under the AAC program impact the credibility of the enormous work that has been done having treated 1,200 patients with BOT/BAL. What does it mean that French government -- French regulatory system made this provision as an endorsement of the efficacy. Of course, the French government elects cannot make a decision for the approval of any agent because of the EMA. But this is as close to an approval as we can get with the endorsement of a credible thoughtful regulatory body. So from your perspective, what does this mean for the typical oncologists to have this endorsement?

The oncologists more and more will realize their opportunity to offer a treatment, which otherwise would still take a while, right, to be approved in indication A, B, C. They will recognize and experience the extraordinary effect of your anti-CTLA-4 BOT as a driver, as a changer, as an immunosuppressive mechanism suppressor and as a further structurizing agent and discovered that in the tumors that we thought nothing would help anymore, right, in third, fourth line, et cetera, et cetera. There is still significant activity to be explored and observed in patient percentages that matter with a durability effect that matters. Yes, I cannot suppress my enthusiasm.

I have to test -- I have to give testimony of my enthusiasm how game-changing this program can be, not just for France, but for many other countries. And it will greatly lead to further advances and acceleration of not just discovering, but also leading to sufficient numbers of success rates that will lead to approvals on both sides of the ocean, of course, by FDA, by EMA. So I applaud really ANCA and I applaud the French oncology community for this early access program. I think it's fantastic.

So Professor Eggermont was one of the very early visionaries whose idea for immuno-oncology was testing it in the earlier stages of patients, namely neoadjuvant patients before they went into surgery. And I've learned a great deal from his vision because he was a first comer to this idea, and he continues to lead the way. Now as we accumulate more data and find appropriate ways to enable access for more patients globally, we're clearly building the momentum to bring BOT/BAL to patients who are waiting for alternatives to chemo, radiation and surgery. We just heard some fantastically positive news from one of our centers with an investigator who was doing a trial with BOT/BAL in patients who are candidates for chemo and surgery. And because of the efficacy or I should say, responses that this clinician is seeing, she is submitting a change in the protocol to exclude potentially chemo in patients who are showing profound responses.

And when you see developments like that, it excites you because our many years of effort in advancing immuno-oncology is now starting to bear fruit for the purposes of improving quality of care and outcomes for patients. And with that, my team and I would be happy to take questions, and this will happen through Stefanie Nacar, who has done a fantastic job of moderating questions in our last session. Stefanie?

Great. Thank you so much, Garo, and thank you for all that attended the call today. Please be sure to submit any questions or comments directly at [email protected]. So with that, as questions are coming in, we did receive some questions. The first question, I will pitch this over to Dr. Goldberg as there's a question about the Phase II study. And when can we anticipate additional efficacy data, particularly some of the secondary endpoints and like overall survival being presented and being available.

So we have more mature data in the Phase I study than we do in the Phase II. But we are expecting to get follow-up data for 2-year overall survival from the last few patients that were enrolled in the Phase II study in the next few months. Once we've had an opportunity to reflect on that data and put it in perspective, we'll be communicating that to the academic world, to the treatment world and to the investment world.

Great. Thank you so much for that, Dr. Goldberg. Garo, here's a question for you because certainly, the company was very excited about an announcement back in June that we made about a collaboration and a partnership with Zydus Lifesciences. And there's a couple of steps to that process in closing that, both related to the manufacturing center out in California as well as other elements that really enable BOT/BAL to be studied and brought to market in India and Sri Lanka. Can you give an update related to where does that stand? And where are we within the process of actually closing out that particular deal?

Well, it's a -- you'd like to answer that question in the following way. As Stefanie mentioned, this deal was signed several months ago. And the milestones that we have achieved is essentially every step other than what is called a CFIUS review, which is a review that ensures that a transaction with a foreign company does not jeopardize any national security issues. And of course, we don't think that what we're doing in our efforts to cure cancer patients does jeopardize, but it's a process that we need to go through. And the other step was what's known as Hart-Scott-Rodino, which I'm delighted to tell you again that has been cleared.

So the only step that we're waiting for is CFIUS. Now to make matters a little bit more complicated, we had the government shutdown because of the disagreement about the budget several weeks ago and that got in the way. But I'm hopeful that in the next few weeks, that will be resolved. But in the meantime, certain elements of the government are still functioning. We have submitted the data that they required. They need to formally accept that. And post the formal acceptance, the decision will be made about CFIUS. So I'm hopeful that this will get done in the next weeks to a few months, and it will be over with. But in the meantime, Zydus was very, very gracious to extend us a long to take some of the pressure off the expenditures from the facility that they will be purchasing. And that has been transacted. And so some of the pressure associated with those payments from our West Coast efforts is now borne by that loan. And so we're making progress.

Thank you so much, Garo, for that further clarification. I know it's kind of a unique situation on the CFIUS review that is a little bit newer given where the partnership is and those organizations. So I think it's very helpful. While we have you up there, there was another question. You had made a comment a little bit earlier within the discussion about one of the protocols changing and then potentially eliminating chemotherapy as an option. There was a question if you could just clarify a little bit more what cancer and as well as what setting that was in just for further clarification.

So I don't want to lead too much because we don't want to take the wind of the investigator who is very excited about this outcome. And it'd be inappropriate for me to provide more details because I know that our audience is very smart and particularly with AI in operation these days, they can type in a few lines and identify the study and the investigator and would like to make sure that we don't violate the confidence of the investigator.

Okay. So more to come very soon and very quickly, I anticipate. Wonderful. So there's a question that was posted as well. In our last webcast that we had back at the end of August, we had Dr. DeVito on the line to talk a little bit about his study, the BB-OPCO. The question is, when do we expect to hear more about progress on that study? And that study was actually in frontline colorectal cancer, not in the neoadjuvant setting. But perhaps I don't know if Dr. Goldberg, you or Dr. O'Day, just from conversations that you've had with Dr. DeVito, if you know when he expects or anticipates to present some of that data at any upcoming conferences.

So Stefanie, maybe I can jump in there. Yes, that study continues to accrue and has a lot of excitement around it from patient advocates, patients and other clinicians. And we expect those results to be presented sometime in 2026. The exact timing will depend on the maturity of the data.

Great. I know that we're all looking forward to seeing that. So we'll be sure to notify everybody when we hear about when he plans on presenting that data for sure. This next question actually is going to be for you, Rob. Given all the excitement and the availability of BOT/BAL through the French AAC program, there was a question here about what is -- what are we charging as this is a reimbursed situation within French -- France. Can you explain a little bit about what that looks like and how it potentially could or will not impact future commercialization in Europe?

Sure. Thanks, Stefanie. We've not disclosed the explicit pricing publicly. But what I can say is that we have a price in France that is consistent with basically our ability to both price and ensure market access in the future in Europe, not only in France, but across other countries in Europe as well.

Great. Okay. Thank you for that. Another question that we have here, which I know that people were very excited about on our last webcast, we had Chris O'Callaghan from the CCTG Group. That is really our collaborating partner of our Phase III BATTMAN study in Canada. We are doing a lot of work, and the team is working diligently to initiate that study and open that study as quickly as possible. Dr. Goldberg, can you provide some updates on when do we anticipate that starting? Or when do we anticipate potentially patients being able to consent or begin enrollment within the study?

So I have some exciting news about that. Working with the Canadian Clinical Trials Group has been a real pleasure because they are incredibly responsive and have put our need to get this going first. So the study has now been approved by the Canadian authorities. It has actually been approved by IRBs in 3 of the larger provinces in Canada. The drug availability has been worked out. You have all these details that you have to manage like labeling and shipping the drug. So that has all been taken care of. We had our first investigator meeting at ESMO with attendees from the 3 continents where the study will be done, Canada, France and Australia, New Zealand. And we fully expect the first patient to be enrolled in November, latest December of this year.

Great. So more to come. We'll be sure to make that announcement when we reach that milestone as well. So we're very excited about patients globally being able to participate in volunteer in the study and get access to BOT/BAL as well. So the next question here, Dr. O'Day. There's been a lot of focus, particularly on colorectal cancer, as we understand, is the most advanced tumor type for our program. But with the data that was just presented at ESMO in the pan-tumor setting, we're also getting some questions related to any updates on pancreatic cancer data as well as anything else related in RCC?

So pancreas and RCC, there were patients in the large Phase I trial, a small number of patients on those. We have not reported any Phase II data yet in pancreas or RCC, but those studies are ongoing. But what I will say is really bringing back to heart what Mike Gordon, the presenter at ESMO for the 400-patient pan-tumor Phase I. What's really remarkable about this study is it really points to the mechanism of action of BOT and how it's been designed to prime better, to deplete T-cell -- T regulatory cells and to reactivate and repolarize the microenvironment. This very important foundation of botensilimab has made it an agnostic target in the sense that it's immune T-cells and other immune cells that affect the microenvironment. And really, what we saw with over 400 patients was compelling and consistent data.

Mike spoke to this as well as [ zalifrelimab ] with response rates that are deep and durable and survival rates at 2 years of essentially 40% with emerging plateaus beyond that. This has been not produced before in cold or poorly immunogenic or even IO refractory tumors and even liver metastasis. So these themes are what are propelling doctors across the continents that there is a differentiated CTLA-4 that paired with an effective PD-1 is really expanding the reach, and that's the excitement that's been generated.

Great. Thank you so much, Steven. I have another question here as they keep coming in. So please continue to submit your questions to [email protected]. And Dr. Goldberg, we just spoke a little bit about the excitement around the BATTMAN initiation. Certainly, with data that was presented at ESMO, there is a question that has come in related to data in MSS CRC from the STELLAR-303 study versus the non-liver met data set. I know it's been really just moments and the team necessarily probably hasn't had a chance to completely debrief, but would love to have your perspectives on that? And do you see it informing any probability of success for our BATTMAN study? So that was the first part of the question that was submitted.

So it's not really our place to comment on the efficacy of another company's trial. There are plenty of talking heads out there that are busy commenting and you can find those on the Internet as well as you can listen to the commentary by the person that reviewed the abstract and presentation at ESMO. What this does for us is to feed our enthusiasm about having a Phase III trial compared to best supportive care in the fourth-line setting in colorectal cancer with 2 IO drugs, a primer and an effector. And we believe that, that synergistic combination is uniquely effective and that BOT is uniquely effective compared to competitor drugs. Stay tuned. BATTMAN will be accruing shortly, and we hope to have data to support our enthusiasm within the next several years.

Thank you, Dr. Goldberg. I actually have another follow-up question to you. I know that as questions come in, we are kind of bouncing around a little bit between disease settings and different lines of treatment given the broadness of our clinical studies that are ongoing, either through the company itself or through investigator-sponsored trials. But this question here is, what are our thoughts on any late-stage development in the neoadjuvant setting? Certainly, there's a lot of data that's been presented from the UNICORN study and the NEST study at ASCO GI last January as well as the NEOASIS study in pan-tumor neoadjuvant setting. Can you share a little bit more about the guidance or the development path for neoadjuvant in rectal or colorectal cancer?

So we believe that BOT/BAL will be used to best advantage in early-stage disease. And the notion that we could avoid chemotherapy radiation and extensive surgeries in patients is very attractive to patients and to their physicians. We are seeing dramatic improvements in tumors that are treated with just 3 doses, 1 BOT and 2 BAL and then patients have been taken to surgery and many of them have had complete responses. Some of this data has been presented at AACR at the ASCO GI Symposium. The data is still being collected. Patients are still being enrolled, but we are expanding our enrollment to include MSS rectal cancer patients. And we are in the process of putting together a clinical trial in the neoadjuvant setting in colon cancer, which we will be requesting FDA commentary on once the government is open and they're back in business.

Great. Thank you so much. And I think we have maybe a moment for one last question. And Robin, this question will be for you. Given the French AAC program was just announced just a short while ago. But is there anything that you could share to date? I know that there's a lot of administrative processes right and things to put into place before patients can be receiving BOT/BAL in France through the AAC program. But if there's anything to share about any uptake or any current interest or what we anticipate, that would be fantastic.

Sure. Well, one of the things I can share is that we have already received order for BOT/BAL through the paid AAC program. One comment is that, remember, this is Compassionate Access. The physicians who are requesting access for their patients in France request access has to be approved by ANSM. And then the patients have to be also approved in terms of their medical eligibility by Agenus by our clinical team. So this is a program that is open to all of the patients who are under the French health care system. It is, I think, very encouraging that it is reimbursed by the government of France. And I think this is a very unique program. It's great to see how progressive France is in ensuring access for patients early on when they see that there is a positive clinical benefit for patients based on their assessment of the data. And that's -- those are the only programs from which they will grant Compassionate Access.

All right. Stay tuned, more to come. So we are actually a little bit over our dedicated time, and there's still some questions that we were not able to answer. We will be sure to collate those and make sure that we address them during our next webcast or our next engagement with you all. So with that, I want to thank all the viewers for attending today and for all of your questions and for Dr. Armen as well as Dr. Gordon and Dr. Eggermont for their participation. I know that they wanted to be here live, but due to ESMO engagements and responsibilities and the time difference they were unable to do that in person. So we thank them for taking the time to share with us their thoughts in advance. And we look forward to sharing more with you all on our next webcast. So thanks for joining.

Thank you.

[Audio Gap]

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, 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.

And 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 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 [email protected].

And with that, I'll turn it over to Garo to start our webcast for today. Garo?

Thank you, Stefanie, 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 is on track to be the #1 cancer killer for people under 50 by 2030. That's around the corner. And that's insane.

For metastatic patients who failed first and second line, today's approved drugs give you 6 to 11 months. That's it, 6 to 11 months. These aren't numbers, they're lives, families broken, future stolen. And here's the truth. The system is failing them. The current paradigm clings to paperwork. It rewards drugs that give weeks, but BAL is shown 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 8-year-old child with metastatic colon cancer. That was unheard of. It was denied because of bureaucracy. Think about that. An 8-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 chemoradiation, surgeries, colostomy bags, infertility, bankruptcies. Now I want to show you a story millions have seen. Andy, please play the video of Tanner.

[Presentation]

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 today, 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 rub 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 are 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, 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 III 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, 1 dose of BOT and 2 doses of BAL, tumor is gone in 7 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 the miracle of the immune system, an absolutely 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 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 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 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 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 the hot tumors to the majority of cases with the 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 things like high fat, low fiber diets. It may be things were 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.

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. And 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 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. And that made 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 and had an opportunity to see what was happening, not just with BOT/BAL, but with other companies who are advancing other drugs. And the most promising combination in my mind was what I was seeing with BOT/BAL. And 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.

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, 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-high, which is some of the so-called other 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 BAL is going after. Now there's been confusion about MSI-high because we've seen drugs like PD-1 drugs or PD-L1s 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.

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. And we studied it, as you mentioned, across more than 1,200 patients with 9 different tumor types, including colorectal cancer. And recently, we updated our data from our Phase I study of 123 patients with MSS colorectal cancer. And these are late-stage patients. They've either had 3 lines of therapy or 4 lines of therapy. And in the cases of those with 4 lines of therapy, there's nothing more to do other than best supportive care. And 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 are still maturing of 21 months.

And this is way more than the 10 to 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 are years past getting oxaliplatin still have the sensory neuropathy that's the scourge of treatment with that drug. And 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 cancer. So when you give a medical treatment before surgery, we call that neoadjuvant therapy. And 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 seeing that in patients with robust immune systems that haven't been damaged by exposure to cytotoxic drugs that the responses are even more dramatic. Just like you saw in that patient's colonoscopy where the colon cancer disappeared with just 3 treatments. So the preliminary data that we're seeing with BOT/BAL, everywhere we look, it's active. And we hope that, that will really translate into lives saved.

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 have a pretty good sense of the toxicity profile and the transient nature of some of the toxicities that we're seeing. 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 remark, 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 is this hang up? And 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.

Well, 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, 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 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 hope to accomplish this with IO regimens without the side effects of traditional chemotherapy-based regimens is why BOT/BAL 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 Clinical Trials Group, they had approached us with an idea for a study for 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 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 move at the same pace as the science. We believe that the regulators need to reflect upon and update the approval process.

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 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? Just to start.

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 has led to a lot of unfortunate failures. But I have always -- 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 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.

And I think there's a real appeal to patients as well with immunotherapy 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 me surviving chemotherapy or something like that. And I think that's extremely meaningful to people. So 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, I should say, an orthodox trial because the standard 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 and what...

Happy to do it.

Yes. Thank you.

Yes. So this is referring to BB-OPCO or botensilimab and balstilimab optimization in colorectal cancer. And as 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 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.

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 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. 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 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 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 really like aligns with exactly what he wanted. He is 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 in people in the hospital or where we have to do desensitization because it randomly at the ninth dose or something, it can happen any time, leads to a terrible infusion reaction or some of the other things like diarrhea during chemotherapy with irinotecan while it's infusing, it can even happen. So a lot of these things are very different with BOT/BAL.

And so that's why this trial was developed. And 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 too. And moreover, one thing that I think is really fascinating here and I think when we -- I hope that when we look back on this in 5 to 10 years, Garo, that we say like, 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 and like 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 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 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 like oxaliplatin infusion reactions. So it's very important to me that patients have this option. And if they have it as early as possible, especially in a disease setting like Stage IV CRC, which we know is typically incurable that may change. And 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.

So 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. Mike 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...

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.

And 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. And of course, Richard Goldberg said that the FDA requirement today is randomized trials that have 4-, 5-, 6-year readouts. And of course, we're trying to change that. And 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 really is based on precedence, based on an old generation of drugs rather than embracing new innovative drugs. How would you do that?

Yes. Why are we so wed to the mustard gas, I guess, is the phrase that I always say, this is -- 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. So 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.

And I think that there is a patient population that you can select for to try highly promising agents like botensilimab out as first line obviously under a consent and a protocol and with the plan like what we have for BB-OPCO, which is where we give BOT/BAL, we scan at 6 weeks. We monitor circulating tumor DNA, et cetera. We monitor patient symptoms, and we can rescue with chemotherapy and add it on if we need to. But 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 like a very basic scientific standpoint, like 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 like 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.

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 them?

Yes. It was incredibly difficult. I mean I know you've heard the story, but I'll repeat for everybody on the call is that in the 2022 SITC hot topic session I saw the BOT/BAL data and like leapt out of my seat and I 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 give it first, give people a shot at it. And I immediately wrote the trial like after that, like on the plane home, just started like crafting it and my -- the knee-jerk response from almost everybody with a few select people is 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 what 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, it's the sticktoitiveness of like 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 like, 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 1.5 years, and we were extremely fortunate because I kept trying to apply for different opportunities and finding different grants and everything else. And Gateway, which is the clinical trial research foundation 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 are essentially told that you must scan these patients at 6 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. But frankly, we have an amazing GI oncology research group, 9 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 $0.25 million from Gateway. Let's go. And that's what happened in 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 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 10x over again even if it took twice as long.

And Gateway is happy so far.

They're thrilled. They just invited me to a gala to speak, and they're saying like 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 BB-OPCO start to pop up over time. And I think you'll see at least 2 or 3 of our patient stories show up on there, including the 30-year-old with lung metastasis, I mentioned before.

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 to do 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 heads and tell us that, then I have a couple of additional questions for you.

Sure, Garo. Well, 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 we have a -- 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 literally 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 2 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. And we were excited by that. And serendipitously, we became aware of your work with BOT and BAL around that time. And quite frankly, your results look even more impressive for those agents. And so 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 doublet IO therapy works in these patients and that's the reason we approached Agenus. And we are very excited as we embark on opening up our CO33 or BATTMAN trial.

And when you talked about the other trial, Chris, I suspect the reason that it worked, but it wasn't [ blown away ]. Is it because the molecule didn't have the turbo charging capabilities that BOT perhaps brings to the party?

Well, 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. They -- the Phase I and Phase II studies that you have done really outstrip the results that we saw in our combination trial. And so 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. And now the question is if we use the best immunotherapies that we can get our hands on, can we show that, that works even better.

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? And -- 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.

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 and 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 3 regions around the world that want to enroll patients on this study. 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 2 of our lead investigators in provinces, the major provinces in Canada, Ontario and British Columbia, got their ethics submissions in within 6 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.

So when we go through with this, we've talked about enrollment time lines. 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 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 time lines?

So 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. And 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, is 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 million to 40 million, and we triple that or more than triple that by engaging Australia, New Zealand and France, our -- 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 834 patient sample size, that is a pretty expeditiously recruiting trial.

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 is -- 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 seem 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, 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 all ridiculed 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 there are -- 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.

I'm so happy to. And what a perfect segue, given what you've 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 Therapeutics. So the invariant natural killer T cells, as you've mentioned, they're rare cells. They are 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 2 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 pandemic. That immune -- 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 could 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 anticancer or antitumor 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 the 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 in 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 nondilutive grant financing to advance these cells in these disease settings.

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?

Well, 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, in pneumonia models and actually restored immune function and improved oxygenation in the lungs by repairing cells within the lungs. So the agency cleared in 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 or biologic threats.

So what we showed is that in our clinical trial now published that we -- that when you administer just a single dose of about 1 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. So there were 2 opportunities for us in those settings that show 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 and that was really illuminating for us. So 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.

And we could administer the cells, and they do not plug 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 was -- 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 by a warfare. We have shown and will be publishing relatively soon some very important data on the effect of the iNKT cells in a typical 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. And 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. In the way that we could use the iNKT cells and because they have a common receptor, common in all of us, we can 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. It's very important.

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've 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 stand-alone 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 is -- also it is an owner of this entity, Agenus owns about 48% of MiNK. And 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. So we're now pushing [indiscernible] actually. So we are -- 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, and it speaks to Dr. Nick DeVito's point about life with chemotherapy in the same patient versus life with an immunotherapy. So if we can roll that video, Andy, that would be...

[Presentation]

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 are -- do their best treatment options as quickly as possible. I mean, waiting 4 or 5 years for randomized trial readout before patients get widely access to drugs like BOT and BAL 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 Corporation, 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. And 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 2 to 3 weeks. And after that, we should very expeditiously be able to close the transaction. So I will end my talk, and 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 4 participants, please do so. Stefanie Nacar is going to be moderating the question-and-answer period. So go ahead, Stefanie.

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 missed the beginning of the call, you are able to submit questions either via text or on -- via e-mail, please text (510) 323-5188 or you can send an e-mail 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 the study?

Sure. Thank you very much, Stefanie. So 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 trials organization, and 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 Agenus has agreed to support of 834 patients really requires an international effort. And thankfully, we have cultivated a long-standing and productive collaboration with other groups like ourselves around the world, specifically the Australasian Gastro-Intestinal 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 3 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 grant of them and have been for 45 years. And 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. So we are a solid, stable organization able to conduct and fund the trials that we do.

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.

Yes. 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 have been considered a cold tumor. And 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.

And the other 50% of the patients on our trial will be patients who will proceed with what are known as best supportive care measures. And 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. So that trial will recruit, as I said, 834 patients. We're projecting that recruitment to occur over a period of approximately 20 to 24 months. There will be a period of follow-up as we mature -- wait for the data to mature, and then there will be an analysis. And we're confident and cautiously optimistic that it will be supportive for registration of BOT and BAL internationally.

Thank you 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 delay? Why has the study since the completion of the Phase II been delayed by approximately 18 months? So maybe can you share some light on that, please?

Well, first of all, at last year's FDA meeting, about a year ago and change, the FDA was still insisting on doing a 3-arm trial. And even though we had brought in some of the experts that had experience with BOT/BAL and patients that had experienced with BOT/BAL to submit that doing a 3-arm trial would not be ethical based on the data that was generated. And 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 3-arm trial was not necessary, that a 2-arm trial would be the way to go. And so that delayed us by at least a year. And at this year's meeting with the FDA, one concession, an important concession they made was the fact that they agreed to a 2-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 formally 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.

Yes. 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 near term? And are there any other data reads out that were expected for the remainder of the year as well?

Thank you, Stefanie. 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 the [Technical Difficulty] of the -- 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 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 line, 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 speak 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 learn 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 took -- 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 4 to 8 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. And 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 1 dose of BOT and 2 doses a BAL, and we're seeing remarkable 40-plus percent of patients within 4 to 8 weeks are having complete or near complete responses. And then finally, Myriam Chalabi has taken the same approach at the Netherlands Cancer Institute across multiple solid tumors. And at AACR, she presented the first patients there, similarly high response rates, almost tumor agnostic. And 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 that 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 to 12 months and ongoing reporting of the data.

Yes. Thanks, Steven. And related to that studies and other neoadjuvant studies, is -- are we doing anything specifically to identify patients that have MSS disease. Certainly, we've also -- we -- 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?

Yes. 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 setting. 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-plus percent deep durable response in an end-stage sitting and maybe 40% to 50% as we move further as this neoadjuvant data. It would be wonderful to enrich even further to MSI-high type approaches. And so we are actively working both internally as well as external collaborations to really find ways to deeply enrich MS stable tumors so that more and more patients can have these long-term benefits.

Yes. Thank you, Steven, for that clarification, and while I have you on the line still, what's coming next at the end of -- between now and the end of 2025? 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 the year?

Yes, we're very excited about ESMO. We're going to be launching our BATTMAN 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 -- when 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 seen 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. And the real advantage is long-term survival without the need for additional treatment. We call it treatment-free survival. So 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 BATTMAN Phase III study, there's a question that has arisen. A lot of our studies has been in non-liver met patients. Can you describe any sort of stratification or inclusion in the Phase III trial related to those patients?

So certainly, Chris can also answer this. I think the short answer to this is in the original first-generation CTLA-4 PD-L1 study that the Canadian Group did, they saw a positive study in all comers. And obviously, non-liver mets are even more enriched for IO response, but there was a survival benefit across all comers, meaning liver and non-liver, and we have better drugs. Obviously, they had a 1% objective response rate in that trial with durva and treme with -- so 1% response rate, but still had a survival benefit, and we obviously have 20% or thereabouts deep durable responses in ours. So you can just imagine why we would want to look at all comers as well as our subgroups. And 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 D.C. 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?

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 that 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 asked, Stefanie, 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 rights to BOT/BAL, which is -- 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 let me, I will -- 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 have 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 endgame here, but I think we're getting closer. And I'm delighted that our external environment, including our regulatory environment, maybe moving in the right direction, and 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. So thank you very much.