Friends. We're here with the team from Agenus. We have Robin Taylor and Zack Armen. Thank you both for joining us today. We have a lot to pack into the next 30 minutes, so why don't we get started? Again, thank you for joining, and maybe you both can just provide a brief overview of Agenus, including your recent financing and what investors should be focusing on over the next 12 months.
Sure. Thanks, Alexa. Agenus has been a company that has been approaching leveraging the human immune system to deliver curative outcomes in cancer for the last 32 years. We were founded back in 1994, and the mission of the company has always been the same through many different chapters of our history. What we're really excited about today, and what we're going to spend our time on today, is to talk about our lead asset, which is the combination therapy of botensilimab and balstilimab, or as we call it, BOT/BAL, which we've now treated over 1,300 patients in both the metastatic setting and the locally advanced settings across prevalent solid tumor cancers like colon and rectal cancer, lung, ovarian, sarcoma, melanoma.
What we've seen are unprecedented results in what are called cold tumors, or the MSS population, which are typically the most prevalent portions of the population of these solid tumor cancers. That's what's given us not only the excitement for the potential of this therapy, but has also attracted investment. We'll talk a little bit about the transaction that we just closed two months ago. Just to explain what you're seeing here, this is an example of a patient who was actually in one of our neoadjuvant BOT/BAL in colon cancer trials, which was held at Weill Cornell Medicine in New York City. On the left side, you're seeing an 8 cm colon tumor that a patient was diagnosed with through a colonoscopy.
After treatment only with our drug, no concurrent therapies, no prior therapies, after seven weeks, you see when they went back in for their surgery, there was no tumor. This looks like a miraculous case. It's not necessarily miraculous in our mind. It's what we expect this therapy to do. It's what the translational data has all shown is what's happening with this drug, which is a proliferation of immune cells, both to detect, kill, and remember the tumor, which is how the drug was designed by our research team. We've seen this now, similar responsiveness now in dozens of patients in this setting. It's the basis for which we are moving into a phase III registrational trial in the stage II, stage III MSS colon cancer setting.
We have a line on that phase III trial design with the FDA, and that trial formed the basis for the transaction that we closed back in July. That was a $340 million PIPE financing. $85 million of those dollars were in upfront proceeds. Another $255 million are divided into two warrant tranches, the first of which is what we call a Series A tranche, priced at $4.02 per share. That will be triggered based upon our disclosure of the 60th patient enrolled in that trial, which we expect to occur in the second quarter of next year. The second Series B warrant tranche will be triggered by our public disclosure of the pathologic response rate data from that phase III trial, which we call the ROBBIN Trial. Not named after my colleague here.
That was actually going to be one of my questions.
Similar sounding. That path response rate data would be in the first 100 patients enrolled in the trial, 50 in the BOT/BAL arm, 50 in the control arm, and that we expect to be a Q4 2027 event. If both warrant tranches are triggered, we will have enough cash proceeds to get through end of year 2031. As you'll see from the timeline slide here, which we'll get more into. Alexa, we are planning to have EFS readouts on an interim basis in the second half of 2029 and on a full analysis basis in the second half of 2030.
The transaction was important for us because it obviously gave us the capital to go and start the trial, but we also think it's really valuable that it gives us the capital to fulfill the full needs of the trial, along with our company expenses through what we hope to be a full approval outcome.
Okay. We will definitely dive into a lot of those things in a bit more detail. Before we start, maybe you can just tell us what aspects of the story do you still think are most misunderstood or underappreciated by investors?
That's a good question. I will focus on the capital market side and I will let Robin chime in on more of the scientific and medical side. I do think that there's clearly an appreciation for the strategic rationale to move into this earlier stage setting. It's a bigger opportunity. It's a chance for us to really deliver curative outcomes in patients who are starting their treatment journey, and we think that impact could be in a larger population of patients that unfortunately are diagnosed in this setting every year. We think that maybe there's a bit of a lack of understanding of the size of the opportunity.
That comes down, obviously, to the number of patients, the pricing that we can garner, and the penetration rate that one would expect if we are able to deliver the clinical benefit that we expect to. We think that's part of it. We also think maybe the actual timelines and the catalysts that we have forthcoming in the trial, maybe there's a belief that those are not yet de-risked or there's a high degree of risk associated with some of those milestones. We don't know what the future will hold, but our team is heavily focused on executing this trial. It's the focus of all of our senior leadership and our operational teams. So we feel very strongly that we're going to deliver the trial with a high degree of precision and success.
Okay. All right, so let's get into the science and the data. So maybe starting with BOT and BAL, so how do these two drugs work together mechanistically?
So let's talk about each individually. BOT is a next-generation CTLA-4. The modifications to this antibody were based on observations that tighter binding to basically the Fc receptor create this tighter synapse, stimulating immune responses. BOT's been engineered with two-point mutations in the Fc region that create this tighter binding, and also one mutation that was engineered in that abrogates complement binding to improve the safety. That's actually an observation that some of the more long-term toxicities observed were first-gen CTLA-4. You could potentially eliminate those by eliminating the complement binding, and that's actually what we see. We see a much lower rate of some of these more difficult-to-manage toxicities like hypophysitis that you see with the first-gen CTLA-4. So BOT is a next-gen CTLA-4. BAL is a PD-1 that is comparable to other PD-1s, comparable to Pembrolizumab or Nivolumab. It was engineered that way.
Together, what we're seeing is that you have BOT to stimulate the immune system, create this priming, generate T-cell response, and generate T-cell memory. We're also seeing that BOT is causing a depletion of Tregs. So we're seeing both aspects. One is that you are amplifying the immune response. You're also taking away this immunosuppressive Treg environment. We see that not only in pre-clinical, in the clinic, but we're also seeing it now in these neoadjuvant studies where we can look at pre- and post-treatment biopsies. The first example of that was just reported in Clinical Cancer Research.
Okay, great. So you're evaluating these agents in microsatellite stable CRC.
That's right.
Maybe you can just give a brief overview of how that's managed today, and why has this subtype of CRC historically been resistant to checkpoint immunotherapy? Then I guess maybe explain the mechanistic argument for why BOT and BAL can convert this cold tumor microenvironment.
Yeah, that's a good question. If we look right now at the treatment of early-stage colon cancer, everything from stage I to stage III, this treatment paradigm you see here has essentially been unchanged for the last 20 years. The last new drug introduced into this treatment paradigm here is oxaliplatin, which was approved in 2004. Right now what patients go through is they have the diagnosis and then most patients will go straight to surgery and based on the pathologic staging, primarily based on the size of the tumor and the nodal status, so the node positive, node negative, they will then make a choice around the adjuvant therapy, which could just be observation if it was a small tumor, node negative, or it could be up to CAPOX or FOLFOX for up to six months.
Now oxaliplatin is an effective drug, but it's also neurotoxic, and so this creates this neuropathy. Some patients live with lifelong neuropathy because of this course of treatment. This is the standard treatment before immunotherapy came in. Immunotherapy came in with an observation that a subset of these patients, about 10%-15% of these early-stage cancers had microsatellite instability that created a very immune-sensitive tumor. Immunotherapy is very active in that population. That's really the standard of care for those patients. But the population we're focusing on is the other 85%, the microsatellite stable, where really this is the current standard of care, is going to surgery and then chemo.
Okay. BOT and BAL, they were originally viewed as a later line treatment opportunity. What data or strategic insight-
Yeah
What did you see that drove the pivot to the neoadjuvant setting?
Yeah. The late line data is very powerful for us in terms of both establishing the breadth of activity of botensilimab across multiple solid tumors, including colorectal and also the safety profile for the agent. During that time when we were evaluating BOT/BAL in this treatment setting, we were able to actually improve management of AEs. That is important as we bring BOT into the neoadjuvant setting because it also is how we are going to manage BOT and BAL in this early-stage treatment setting. But the data that really stimulated our focus on this early stage was from two different neoadjuvant studies, one called NEST which was run at Cornell.
Here in the NEST study, there were 26 tumors evaluated, 22 of them were MSS, and we saw a complete pathologic response in 32% of those tumors, a major path response in 41%, and a path response, which is a tumor shrinkage of 50% or greater in about 60%. Similarly, a second study being run by an Italian group in Milan and a network of 10 sites called the UNICORN Study evaluated BOT and BAL. It also evaluated BOT monotherapy in different cohorts, both microsatellite stable and MSI-high. I do not show you the MSI-high data here, but the MSI-high data are very consistent with what you see with other immunotherapy combinations as you would expect.
But in the MSS cohort what we see is a PCR rate of about 29%, so very consistent with the NEST study, a major PR of 36% and a path response again of around 71%. So nice consistency between these two studies. When you compare that to the historic data, a large study called FOxTROT looked at neoadjuvant FOLFOX in this treatment setting, only a 4% pathologic complete response rate. Then a small study with Ipi/Nivo called NICHE looked at 31 patients, 30 of them are valuable for tumor response and a 10% path CR rate, and overall path response at 29%. So what we are seeing is that we are seeing this consistency of results with BOT/BAL, and we are seeing that the data to date are better than what we have seen with historical precedents.
That was really the impetus for us to move into this treatment setting where we believe that we are going to see a dramatic effect. One other note from all of these studies is that there is a correlation between the depth of response and outcomes in terms of EFS. Across all of these studies, none of the patients who have had a pathologic complete response have relapsed. But I should say, the NEST study, which was just published recently, out of all the patients treated, there have been zero relapses among any of them, with the follow-up ranging from 24 - 32 months.
Wow.
Compared to historical, from the FOxTROT study, if you look at the control arm, at three years, 25% of those patients have relapsed.
That is really impressive, and we are going to get into the ROBBIN study in a few minutes, but perhaps before we do that, maybe you can just walk us through the safety and tolerability that was observed in NEST and UNICORN, particularly maybe the rates of immune-related events. Then maybe comment how those rates of AEs compared to what was seen with BOT and BAL in previous studies.
Yeah. The most common immune-related AE of interest for us with BOT and BAL is diarrhea colitis. We see in the metastatic setting, we see about 20%-30% of patients with diarrhea colitis. About half of that has been grade 3. That is with up to four doses of BOT. When we come into the neoadjuvant setting here, we are treating with one dose of BOT and two-four doses of BAL. The time to surgery has been in the range of four weeks to eight weeks, so there is a little variability there on NEST. UNICORN was fairly consistent. It was about five weeks to surgery. In NEST, we saw fairly consistent results that we saw a little bit of diarrhea colitis. There were a few cases of grade 3, but none of those patients had any delay to surgery.
The diarrhea colitis is managed right now with very quickly getting the patient on steroids and then quickly transitioning them to infliximab. That has been very effective in terms of suppressing that immune-related adverse event. Similarly, on UNICORN, we actually saw no incidents of grade 3 diarrhea colitis. In fact, there was only one grade 3 event that was with hyperthyroidism. That patient who had hyperthyroidism had a short delay to surgery of 10 days, but that was the only delay to surgery across either of these two studies.
Now, is there a certain level of these immune-related events that you actually want to see to show that the drug is actually working as it should be?
Yeah, it is an interesting question of AEs as a biomarker of response. The truth is, in the metastatic setting, we see that. We see the patients who have an immune-related adverse event, have longer survival. So there is this correlation between really what you are observing in terms of the immune system being activated, telling you that, in fact, because it is activated, it is probably going to be more effective. In this setting, we are not sure yet because there is a difference between the patients in this setting and the patients in the metastatic setting. Generally, you are expecting these patients will probably have healthier immune systems. They have not gone through multiple rounds of chemo. So, whether we see that correlation or not, too early to tell.
Okay.
As far as EFS goes, since the whole population had 0% recurrence, we cannot really find one doing better than the other from a survival perspective.
I see.
That is something we will keep an eye on when it comes to the phase III.
Okay. Now let us chat about the phase III. The ROBBIN Study, maybe you can walk us through the design of this study, which you said is expected to start dosing in the first quarter of next year. Maybe we can chat about the patient population, the comparator arm, primary endpoint, and how the trial is powered.
Yeah. This is an 850-patient study, randomized one-to-one for neoadjuvant BOT and BAL. As I said, it is one dose of BOT, three doses of BAL on a Q2 weekly schedule. The last dose of BAL will be at about four weeks, and then we will have about four weeks to surgery. This is based on the observations in the NEST study that that longer treatment interval resulted in an increase in terms of the depth of response, including pathologic complete response. That is what we are shooting for here around that eight-week interval. On the control arm, patients will get the standard of care, which is right now they go to surgery. That can range in time anywhere from two - six weeks. It depends on the institution.
At surgery, patients, based on the pathologic staging, will be the determination of the choice of adjuvant chemotherapy. For smaller node-negative tumors, they may only get observation, or they may get 5-FU or capecitabine. If it is a larger tumor, node-positive, then those patients typically get CAPOX or FOLFOX, as we saw earlier. It is important here that we expect, actually, in the BOT/BAL arm, that there will probably be a de-escalation of the use of chemotherapy. We may see a lower use of oxaliplatin, which is actually a benefit to patients because then you are reducing the risk of them having long-term peripheral neuropathy. In terms of the patient population, this is very similar to the FOxTROT study, high risk stage II, those are large tumors that are node negative, and stage III, which is basically node positive tumors. Patients have to be resectable.
In other words, at the time that the patient is enrolled into the study, the surgeon has to believe that they do not need any further treatment before they go to surgery. Very large tumors that are invading other organs, basically T4b, would not be candidates for this study because if those patients, the surgeon wants them to have neoadjuvant chemo, that is the only population in this treatment setting that typically would get chemo, then they would not be candidates for the study. They would go off on their own treatment. In terms of the primary endpoint, it is event-free survival, a very standard endpoint for studies such as this. We powered the study with a target hazard ratio of 0.65 at 80% power, and we built in an interim analysis at a 75% information fraction. We will be evaluating key secondary endpoint of circulating tumor DNA negativity.
We are seeing clearly strong correlations between patients who are ctDNA negative and long-term outcomes. But it is still in this formative period where it is not accepted as a surrogate endpoint by the FDA. But we want to be prepared for that if the environment changes and this could be a surrogate endpoint, it may be able to get us to a faster approval. Then of course, overall survival is the other key secondary endpoint.
What were some of the assumptions around the powering? I believe you conducted an analysis that looked at complete response rates and how that translated to event-free survival. Maybe you can chat about that a little.
Sure. Well, the powering for the study is just based upon EFS as an endpoint, and our target hazard ratio of 0.65. That also led to the number of patients that we are enrolling. Pathologic complete response rate is an earlier term endpoint, similar to ORR in the metastatic setting, that we believe and we have seen that confirmed through a regression analysis, has a strong correlation to event-free survival. We went back and we looked at 21 prior trials in the neoadjuvant setting across many solid tumors. These are both trials conducted with chemo neoadjuvant and IO neoadjuvant. And we saw that there was a very strong correlation between pathologic complete response rate and EFS hazard ratio.
That gives us confidence that when we do announce our PCR interim, which we will do in the fourth quarter of next year, that that can be a strong look-through to give investors and our team and other stakeholders confidence that that should correlate to some hazard ratio of EFS. The PCR rate we have observed in both NEST and UNICORN of roughly 30%, would translate to a roughly 0.5 hazard ratio based upon that regression analysis.
Okay.
A 0.65 hazard ratio correlates roughly to a 15% PCR rate.
Okay. So an interim pathologic response analysis that is expected in the second half of next year. What is the magnitude of the pathologic response versus the control that you would consider a clean win? What is the appropriate external benchmark here?
Yeah. I would first caution that it is observational, right? We have looked at this correlation across multiple studies to give us some benchmarks. But the data we have seen, if you actually look at the NICHE data, in MSS and in MSI, any patient who had any pathologic response, none of them relapsed. I think that the treatment effect we are going to see with BOT is probably going to be under-predicted just by looking at PCR. That said, we would love to see results that are similar to what we saw in our phase II. But even then, I think if we see something lower, we are still expecting that to translate into a significant EFS benefit.
Okay. Are there any other companies developing programs in the neoadjuvant MSS-CRC setting? Why do not you think other therapies have moved into this space despite the size of the addressable population?
Well, part of the challenge in this treatment setting is that it has been a difficult nut to crack, right? MSS has not been particularly responsive to immunotherapy. That is why the focus on immunotherapy has been in the MSI-high population. Other targeted agents, if you think back 20 years ago, Abraxane was tested in this treatment setting and the adjuvant setting, and ended up falling short, as did Erbitux. So it has been difficult to improve for these patients. In the neoadjuvant setting, immunotherapy has been very attractive in other tumor types, but those have been hot tumor types. Here in this MSS cold tumor type, you need a more active immunotherapy, which is what BOT is. To date, we are the only agent we know of that has generated this level of activity in MSS tumors. There is the data that I discussed earlier with ipilimumab.
That's the only other real example of looking at data generated in this neoadjuvant setting for MSS tumors.
Okay. I think you've sized the eligible population at around 38,000 high-risk stage II or III patients annually, a greater than $7 billion U.S. sales opportunity. Maybe you can walk us through how that market sizing was derived.
Yeah
How you're thinking about a potential pricing strategy.
Certainly. If you look at the overall size of the population in the U.S. for stage I to III colon cancer, first, colon cancer is about two-thirds of the overall colorectal population. The patients with rectal cancer are treated differently. Those patients actually currently typically will get total neoadjuvant therapy, which includes both chemo and radiotherapy. But for colon cancer, as we've discussed, these patients are typically going straight to surgery and then getting adjuvant chemo. About half of those patients are the population we're describing in the ROBBIN Study. They're high-risk stage II or stage III. That gets us to about the 38,000 eligible population here. Then in terms of thinking about the addressable market, we looked at an analog just thinking about a course of therapy for the perioperative neoadjuvant, adjuvant, looking at particularly PD-1.
An example of that is if you look at pembro in triple-negative breast cancer, that is 17 doses of pembro to treat, and it's in combination with chemo in triple-negative breast. Those 17 doses translate to about a $210,000 course of therapy for a very similar treatment effect to what we're seeing here. The treatment effect with pembro in that triple-negative setting was a hazard ratio of 0.63, similar event rates in terms of EFS. It's a nice analog for what, if you just think about what is a course of therapy that will significantly reduce EFS in this setting translate to, that's where you get to about that $200,000 price tag, if you like. Times the number of addressable patients, it's an over $7 billion addressable market.
Okay. Then I guess beyond colorectal cancer, what are other indications that you're interested in for BOT/BAL?
Well, there's a lot to go explore there.
How are you planning to prioritize-
Yeah.
all of these, I guess?
I think one of the clear near-term interests is in rectal cancer. We have ongoing studies in rectal cancer, including a study at Memorial Sloan Kettering Cancer Center being run by Andrea Cercek, who was a pioneer actually with immunotherapy in MSI-high rectal cancer. That's an area we'd love to explore. But based on the data we've seen, both in the metastatic setting across multiple solid tumors, and also data coming from other neoadjuvant studies, including NEOASIS, run by Myriam Chalabi, there are other tumor types that are looking interesting. The long-range goals for us are to be able to explore additional neoadjuvant indications here.
Okay.
Yeah. We just had a press release this morning that we'll have data presented at the International Gynecologic Cancer Society conference next month on a three-year follow-up in metastatic platinum-resistant ovarian cancer, which is a really tough disease. Not very strong outcomes from an ORR and survival perspective. We've shown some data in this setting already that significantly improved from that standard of care. There's a lot of other places we'd like to go. Right now we're focused on executing this trial, and potentially in the future, if timing and outcomes and capital markets dynamics permit, we'd love to expand beyond just MSS colon cancer.
Yeah. Sounds like there's plenty of different avenues that you could pursue, and all are very exciting opportunities with high unmet needs. We have about two minutes left, and I want to give enough time for you to review some of the upcoming catalysts that investors should be paying attention to.
Yeah. If we could pull up the timeline slide. We are projecting FPI in the ROBBIN trial in the early part of next year. The first 60 patients enrolled, as mentioned before, will be a publicly disclosed event that triggers the Series A warrant class of shares as part of our PIPE transaction we closed two months ago. Those warrants are at $4.02 a share and would bring in another $85 million of proceeds into the company if they are exercised. The next catalyst related to the trial would be an interim readout on pathologic response rate in the first 100 patients, 50 in the BOT/BAL arm. We will show the PCR rate, the major path response rate, and the path response rate. That would then trigger the Series B warrants, which are priced at $5.03 a share and would bring in another $170 million of gross proceeds.
Those two together are really where we would finance the fullness of the trial, along with our other operational expenses through the end of 2031.
Okay.
Beyond that, we are planning to present and disclose additional data at congresses. We mentioned the IGCS conference. We plan to show more data from some of the other neoadjuvant ISTs in the early part of next year. All of that will be based upon the congresses, what slots we get, and when we are able to disclose those titles and those abstracts.
Okay. Awesome. Robin, Zack, thank you so much for joining us today.
Thank you.
Thank you to everybody in the audience for attending.
Yep. Thanks everyone.
Thanks, Alexa.
Yes, thanks.