Agenus Inc. (AGEN) Earnings Call Transcript & Summary

Agreed.

Great. Well, Pashtoon, just going back to your -- the findings in the Nature publication and speaking a little bit more about safety. I know that we did talk a little bit about the side effect profile, but how would you characterize the side effect profile of botensilimab in relation to efficacy based on the findings from that research?

Yes. So both a little bit about the efficacy as well as safety. We -- our goal and interest was, of course as Steve pointed out, to treat pretty much all patients with colorectal cancer, whether it's MSI-high, but the unmet need is the MSS. So we wanted to focus more on those patients. But despite only two patients at the time when we wrote the publication, the reason why we wanted to get the news out is what we were seeing was very fascinating in terms of both the depth of response, the rapidity with which the response was happening. Again, remember, as I was mentioning earlier, these were patients who would get their surgery in a week or two. So all we were telling the surgeon was well, you can operate on October 18, let's just operate on 25th of October and let's -- so pretty much, we were barely giving immunotherapy. And that too in this particular trial was a single dose and only half of a single dose. So going back to your safety question, the last thing we wanted to do in a patient with colon cancer going for surgery is to have colitis, which is a common toxicity that's seen with CTLA-4 inhibitors. So we purposely wanted to make sure that the safety was the main goal of this particular study. And already all the planned patients have completed their treatment safely. So -- but what was intriguing was, as shown here in this cartoon is while we were seeing tremendous improvements in the regression, the pattern regression was also interesting where simplistically, the tumor was more so at the tip or if we had kind of did the mop up inside out, so to speak. So all the trash was just ready for pickup by the surgeon. And hopefully, that translates to more patients who are cured and potentially more patients who probably don't need the "mop up chemotherapy." That's what we do all the time, and that's what patients sometimes are confused that why am I seeing a medical oncologist, I just did surgery a few weeks ago. The surgeon got it all, but the problem is not with the enemy that we see. It's the unseen microscopic cells that may be floating around, distant to the lymph nodes, distant to the radiographic threshold of detection. So the pattern was also something that we wanted to kind of share with our broad scientific community where there are other investigators and colleagues globally as well as nationally who might be working on similar agents or settings to consider how the treatment in this case, botensilimab is leading to a response because it may not just be crudely the amount of cancer that may be left behind, but also where was it left behind? Of course, in somebody's tumor is left behind at a distant site, I would be -- it doesn't matter if it's 1% or 2%, that would be very concerning. But even if the tumor is regressed, let's say, arbitrarily by 50%. But all the 50% was just the superficial part so, as the tumor develops from the lumen and goes to the deeper layers. If the deeper layers don't have tumor anymore, this kind of response and how quickly things happen with rapidity. If things happen, the tumors that were huge in size regress to barely nothing. And repeatedly, we have our Tumor Board meeting with all the surgeons and pathologists every week, and we were hearing a lot of adjectives describing the response and the amount of immune infiltrates that were views that was too good to sit on, and that's where we did some neat analysis with just two patients, the first two, more of the story to come, but it was enough for us to get this out as soon as possible.

And Ben moving to you, what are you seeing in your own clinical research? And maybe you can also talk about how you're also managing side effect profiles in your research and also in the clinic?

Yes. I mean, this is unambiguously an impressive drug -- unambiguously an impressive result. Obviously, we need all the long-term follow-up to sort of further clarify what's happening and why. But this is a big change for cancer patients who didn't have good options. So what we're seeing is a drug that works and not like works a little. There's a line of trials where when you squint, you see the difference and this is a trial where in the right patient, and it is important to recognize that's not for every patient, but it's for many patients. That in the right patient, you don't have to squint, you can really see the benefit. And I will tell you as a clinician with years of experience, you really feel it in your clinic when you have, especially in something like Dana-Farber with a large amounts of colorectal cancer population. Patients, I mean have taken care of a high school student. Patients who were very young, who are fit, but we have no chemotherapeutic option for them, seeing these responses to be very, very impressive. The goal of every Phase I trial is to assess the safety. So strictly speaking, the Phase I trial is not does it work, it's can we do it. And what we learned pretty early on in the Phase I is yes, we can do it, but that there's risks and that's acceptable as long as we learn to manage those risks. It's not that we like risk. We just know that risk is part of the deal here. And the biggest thing that we saw was activation in the immune system, which shouldn't surprise anybody. We're giving you an immune therapy, we see activation of immune system. And we've seen in other diseases that different diseases probably activate the immune system differently, which is fascinating and cool to talk about. But in the colon cancer population, we saw a fair amount of colitis. We learned very, very quickly that potent anti-inflammatories that suppress inflammation without injuring the immune response can restore the normal immune protection of your normal tissue like your colon, but allow maintenance of the anticancer effect of the body. If the body is given a chance to chill out with anti-inflammatories, that the innate immune response that you have or [indiscernible] cellular immune response that you have can identify the inflamed microenvironment of the cancer and persistently attack that and can chill out of the normal tissue. So while many patients may develop colitis which is the most common immune-related toxicity, with early intervention and aggressive intervention with the appropriate drugs, we can see management of that, we can see resolution of that, and get maintenance of the anti-cancer immune response with tolerance of the normal tissue like the colon and resolution colitis. So I think this is a manageable problem. I think it's an understandable problem. There's nothing new. We're not inventing new problems. We're just dealing with existing problems with a new drug. And we've learned a lot about how to do it. We're getting better at it.

Yes. I think just to follow up, it's really retailing the melanoma story. The initial melanoma patients with ipilimumab, we -- they got colitis and then we withheld steroids because we thought that would interfere with the anti-tumor response. And then there were deaths associated with not treating the colitis obviously. And then we started using steroids and to our amazement, really, the colitis settled down quickly, but the antitumor response didn't seem to be impaired by the steroids. Now with longer and high-dose steroids, we do think that, that impairs. And so the field over the course of the last 10 years has taken just like Crohn's disease or IBD, long-term high-dose steroids is not the way they're treated. You use the TNF inhibitors and the biologics to spare the steroids. And what's really great is these biologics seem to not impair the immune response either and are incredibly rapid at reversing the toxicity. So the field sort of moves standard of care to address this. And obviously, our protocol and our program is addressing it with these great investigators.

Yes. And like there are certain diseases that we have where the treatment is the diagnosis, like the [indiscernible] rheumatologic diseases like PMR, you give someone prednisone and they perk back up. It's very apparent in these agents that when you treat inflammation effectively, the patient gets better really, really fast, you can avoid the injury, and then you can continue the treatment in a safe and effective way.

And you're kind of building on with Steven, Benjamin just said. In the last few months, there have been some consensus statements and the side effects of checkpoint is also flaring up overlap of taking care of diseases that oncologists weren't used to taking care of, and that's probably true for gastroenterologists to where a lot of checkpoint colitis is now managing like patients with Crohn's disease or ulcerative colitis, where they moved away from steroid kind of they keep saying steroids paying agents, but oncologists who often write these guidelines are still not probably up to speed with what's going on in the world of inflammatory bowel diseases or IBD. But it's kind of refreshing this year, last year or so where gastroenterologists, especially folks who are interested in ulcerative colitis and IBD and Crohn's where often our go to people, including hepatologists who might be involved with in the care of a patient who might have some of these side effects to act early, to be involved early in a multi-disciplinary fashion and also to use some of these biologic drugs earlier in the course of things and to lead to steroids fading. And to it -- Ben was pointing out earlier, too, like the inflammation to is we're just talking about immune activation or losing your immune stem or taking the brakes off. With some of the analysis that we published in our paper as well using this real-sized immunofluorescent platform, it sets a plethora of diverse immune cells that if you were to add the biologic because the concern was maybe it may dampen the efficacy of the drug. That may or may not be true because it's a complex network in circuitry. And we're just -- I would say, even though we've been using this for a decade, I think we're still learning about how these drugs work and work in different circumstances and what can we do to mitigate the side effects without compromising the efficacy. So there's a lot of learning that's happening in parallel.

Yes. The challenge for Phase 1 trials is about safety, right? And we spend so much time focusing on safety. But again, I think the point to emphasize here is that this is a really effective agent with side effects that were old hand out, although I think we need to improve that. And that's a discussion maybe for another day. But for patients, in particular, but those with disease outside of the liver, we're talking about a population of individuals who got relentless cancer, where we would be sitting there with more chemo or nothing. And now we have an agent with presentations that in national and international meetings that like really raise eyebrows to the point that like the first time and one of them was asking me 3 years ago, when some of these were represented, how people I talk to, like I don't believe it. And now 1.5 years in presentation after presentation, the data builds, the data builds. It is no longer a case report, right? We can show 70 people where a substantial majority of them have active disease and those are benefiting. This is a big deal.

Ben, can I follow up on that for a minute because I think this is really important. Melanoma was a 10% to 15% ipi classic RECIST drug. And yet we -- the observation in the clinic with my melanoma colleagues was about 1 in 4, 1 in 3 patients was having substantial clinical benefit. Of course, this was the stable disease or the moderate reductions that never meet RECIST. And the reason that observation was important is because response rates are so underrepresent a good I-O therapy, and that was reflected in the disproportionate survival benefit. When you look at a 10% ipi drug, it had a hazard ratio of 0.67 on survival in a randomized trial with 1 in 4 patients cured. So obviously, RECIST is not the case. Can you -- and obviously, what's encouraging me I'm watching this data come in, and I've heard it from [indiscernible] and you and Pashtoon, the RECIST responses are great, and we're getting them about 1 in 4. But there's also this additional contingent of patients that isn't having new rapid progression that's holding longer than you'd expect like a chemo. Is that your observation because from melanoma, it was seminal to really to the future. So it's encouraging if it is.

Yes. I think we need a new language to talk about these treatments and how we measure them. The same way we use toxicity tables from chemotherapy, which is relentless on recurrent toxicity, and we have toxicity tables for immunotherapy was like intermittent bursts of toxicity, which go away and yet they're presented identically. I think we have the same problem using outdated language to describe in immunotherapy benefit. So it's not obviously the clinical complete response, the destruction of the cancer by all available measures. That's great, and that's the goal for every patient, but that's currently not what we can achieve. But what we can achieve is substantial in prolonged disease control. Many times that number of individuals who have the cure, we still have the people who have the benefit, and those benefits matter and are valuable and they're common on these drugs. If you look at the post and presented data, the time on therapy is high, like 75% of people have like a 1-year disease control. And so even -- if that were a chemotherapy, it's a blockbuster drug, right? But on top of that, we have a minority of individuals who have like a waterfall plot of RECIST criteria that shows this fantastic response, but also there's that spider plot, there's that progression of survival, which is so important on these drugs, and we still need to learn how to talk about these things, medical ways and scientific ways that better reflect the modern era.

And Phuong, as a patient, all my patients used to tell me get me on the plateau because that's obviously -- and get me off treatment so that I can live a free life, not tied to a chemotherapy chair. But they also said, if you can keep me stable relatively, particularly if it's prolonged, which is not frequently seen with chemo, it can bridge me to the next new thing. And so I think there's 2 -- I'd love to get your thoughts. There's 2 things. There's one, obviously, you want to be on that cure plateau, and IO can deliver that. We're just trying to figure out how many we can build in this new revolution of cold tumors. But talk about sort of prolonged stable disease from a patient's perspective.

One of the things that I kept saying to my oncologist is keep giving me options. Don't stop, like "Okay, we've gone through Folfox, we've gone through Folfiri, what's next?" And next came, "Okay, well, there's this breaking drug that was just approved and I was like, no, I've heard of that. I actually know of people who have been on it, that's not for me." And that was important for me to say because that highlights the quality of life we were talking about. I knew that was going to kill me faster than it was going to help me in any regard. And at that point in time, I thought I would rather have a higher quality of life or a slightly shorter period than the maybe 3 to 5 extra months of feeling like actual just garbage. So I think that it's really important to have these plateaus in these stable disease periods because it allows us to feel human again. When you're getting beaten down week after week and you're getting to the point where I'm recovering just in time to be put back into the chair to pump more poison in my blood, it becomes a very difficult existence. Now if you see light at the end of the tunnel, there's a purpose to this where at the end of this, I'm going to have XYZ benefit, "Okay, we can tolerate it for that period." But when you think about immunotherapy and what it offers the opportunity of just a life that allows me to be healthy outside of the cancer. Because I used to say that to people, "How are you doing? Well, you're really helping outside of the cancer." But there it was and it was true, I really was. The cancer was the only thing that was wrong with me, so to speak. And so the idea of immunotherapy, allowing us to get to that C word or that cure word. I mean, just that hope alone is just worth its weight in gold, giving you that push to continue through to get through everything and these moments of a stable disease, these periods of being able to go off treatment, especially again when you're chemo for life and you know that, that cure word doesn't apply to you just yet, hopefully you guys keep kicking that can down the road and eventually, you guys will do your job to the extreme and find the care for us. It's amazing. And it's one of those things that really does allow you to continue forward with that hope.

I was going to say, I think Steve brings us to a good point that with newer drugs and treatment modalities, we also need new tools to assess response, to assess residual disease. The scans can horribly underestimate what's going on because they're just following size-based criteria. I think the MSI high story with immunotherapy was one of the first examples where repeated attempts of removing things just because we could see on the scan repeatedly showed that there was no cancer. So to the point that we are now confident in saying somebody who is -- has responded biochemically, tumor markers, functional imaging like PET scans, that you probably don't need a right hepatectomy. I think the stuff that we see in your liver is probably just all dead scar tissue. So stable disease, meaning that things are not moving, could also mean in the long run that maybe all of that is dead. So how do we come up with tools that can tell us, that can we just take a treatment holiday or maybe can we just call it a day. There are so many patients on some of these immunotherapy trials that they came off because of toxicity, but they haven't moved on to the next treatment.

I think we learned that very well in melanoma. Now PET scans and melanoma are much more helpful than obviously colorectal probably. But we found that small residual scars, so to speak, that we used to chase with surgery at the end of treatment, if they were PET negative, we didn't have ctDNA in melanoma like you have in colorectal, but we really came to understanding. And then we learned it in neoadjuvant in melanoma, where these nodes were getting bigger and smaller and then they go for their surgery and the CT imaging vastly underrepresented response. So I think MSI sort of is following in those footsteps. And I think with ctDNA and other imaging, I think this notion of partial responses that are as good as CRs just based on how we look at scans, is really why survival is really disproportionate to sort of any sort of system within measuring what's left, so to speak.

I was just going to ask Phuong, just given that this has the potential to fill an unmet need and a lot of patients often don't know what they should be asking for. How can patients and their families actually advocate for themselves and their loved ones? What should they be asking their oncologist about immuno-oncology options?

Yes. No, that's a really good question. I think that it's really important for patients to learn about their disease. That was the beginning of real progress for me in my advocacy. Like I said, it's really hard because you have all these acronyms, these medical terms that you don't know. But there are organizations like Fight Colorectal Cancer to help you with that, there are resources. We have a biomarker brochure that will simply tell you, here's a card, these are biomarkers that you can take in and have a discussion with your doctor, find out what are your biomarkers. Because that will help inform what clinical trials you might qualify for or what treatments you might be eligible for. And these treatments are really important because it offers not just less toxicity, but it's less invasive. We talk about earlier, surgeons, they want to get it and they want to cut that disease out and [indiscernible] as a patient, go get it. I don't want that in me. But when you have the opportunity to do essentially the same thing to kill the disease with -- and take it out of your body without that surgery where immunotherapy can't cure you, that's less invasive. It's -- you're not sitting there with the disruption in your life of having to take time off work, who's going to take care of the kids. All these different factors of life that come in and complicate treatment. That gives you just so much more life to work with in a sense. It allows you to continue with the least amount of disruptions. And I think that is really important to, like I said, learn about your disease, leverage these resources, not just not just through your doctors through online. Obviously, go through reputable resources to find out, but there's a lot of information out there. And the more you know, the more speak up for yourself and make sure you're having the conversations as well, this is important to me. Please make sure that your doctors are listening to you and that you're coming up with plans together. I think that a lot of us feel like where we have to tell you -- or we have to be told what to do by our doctors when, in fact, that dialogue really helps our doctors to craft a better plan for us.

Surani, you brought up such an important point and Phuong equated really well. Our National Comprehensive Cancer Network guidelines or NCCN, they have a line plastered on every single page of the guidelines, which I truly firmly believe in where it says that the best management of a patient with cancer is in a clinical trial. And I think it's very important to dispel the myth that trials are not necessarily options when you run out of traditional options. It could be something that could be de novo, it could be something that is a diagnosis like our trial, that was even before any therapy or even surgery happened. So I think asking your oncologists that do I have a trial and also is there a trial nearby. It's not about for a patient of mine who comes to see me at my institution. It's not about the institutions that I live or practice in, it's also about clinical trials that may be at a driving distance. Again, going back to Phuong's comment about not disrupting somebody's life, clinical trials do involve a lot of follow-ups and visits, and you want to make sure as an investigator that we will try to make trials that are as practical as possible with limited disruptions to somebody's life. So it's important to help navigate patients their options for trials that are within drivable distance.

Yes, definitely get a second opinion, it's critical.

Great. Well, we've got a few more minutes left for questions. This has been such a lively discussion. I'm really loving everyone vibing off of each other. But I do see a lot of audience questions coming in. So just to the audience, if you haven't had a chance yet. Remember, you can hit the Q&A button at the bottom of your screen. Just submit the question, and we'll go ahead and start answering some right now. So the first question is, it sounds like there may be some differences -- improvements from deploying BOT, BOL at an earlier stage. Do we think that this is also true within a stage, for example, earlier in a Stage 4 journey versus later?

So maybe I'll start. Yes, absolutely. I think the story of immunotherapy is, as we moved in melanoma from advanced refractory to first-line metastatic to adjuvant to neoadjuvant, it's extraordinary, the progress that we continue to make. And I'm encouraged in these. We've been focused a lot in the first 2 years of development of botensilimab and balstilimab in the very refractory situations, either in cold or IO resistant tumors and to see the consistent response across solid tumors. And now with Pashtoon's data and [indiscernible] has a first-line metastatic colorectal trial. It's pretty exciting to see the new data emerge. Ben, do you want to comment?

No, I was just going to say that's a natural progression. The nature of how trials are done in the early phase is that we use refractory disease, but we all believe we have to prove it, but we all believe that earlier is going to be better.

And even before even the scan shows cancer with ctDNA or as we call it like LINE-1 or adjuvant plus therapy or adjuvant. So repeatedly, if you have limited amount of cancer in the body, I think it also gives immunotherapy more time to brew, so to speak. So moving it up earlier makes sense.

Okay. Great. And the next one is, can you describe the BOT mechanism of action and how is it different from existing therapies?

Yes. That's a really important question because CTLA-4 is a potent inhibitor -- by inhibiting CTLA-4, you release these early T cells and they become activated and adolescent and they have memory. That is the effector primal response that eradicates tumors in melanoma. But historically, that has not been enough, as I said earlier, in these poorly immunogenic tumors. So at the back end of the cartoon on the left, there's 3 -- there's some green dots that are mutations in the Fc component. This is the sticky section of the back of the antibody that interacts with these key other immune cells, antigen presenting cells and natural killer cells. And this is sort of where the magic happens. It's this potency at the Synapse at the back that keeps these APCs talking to the T cells and essentially telling them this cancer, even though it's trying to hide out and it's poorly immunogenic, you need to get your act together and eradicate it. So we think this is a fundamental. And then the natural killer cells go after the T reg cells, which are the cells that fight the good T cells. So there's this back-end action that seems to be producing this really recognition of cold cancers. And that's great in the preclinical laboratory and -- but the beauty is we've now seen us across 8 different colder IO resistant tumors. And obviously, colorectal is our largest expansion and what we're racing to get on the market. So I really appreciate having these 2 and many of our other GI investigators and our patients that have supported. Because not only has the Phase I trial in colorectal when been completed a large expanded cohort, but we just finished a 230-patient Phase II trial in less than 6 months. And to do that, obviously, there has to be doctors believing and committed to the drug and patients having an unmet need and a promise. And maybe the best word is hope, as Phuong said, and it just gives me great, great satisfaction to see the data evolving. And if someone asked me would you be this -- at this stage in your career, would you be having a panel of colorectal experts talking about cure and long-term survivals and deep durable responses and is stable disease relevant and time off therapy? These are like -- this is the bible of melanoma and to see it coming into a fresh set of eyes really gives me really a lot of deep satisfaction. So we've got a lot of work to do, but I really appreciate it.

Right. Thanks, Steven. So I think that's all the time we have. We have a lot of questions. I feel like we need a part 2 to the webinar, just to answer all the questions, but you guys covered a lot in the session. I think, Steve, you have an announcement?

Yes. So just one final comment. I'm just going to give a heads up that -- I'm going to start a podcast series, and you go to my LinkedIn based on the success of this and my engagement with KOLs around the world in IO and our trials and patients, Phuong, and other stakeholders. So keep your eyes tracked to my LinkedIn and our Agenus and we're going to have some really interesting conversations with some of my colleagues in I/O and patients and others. So it will be a lot of fun.

Okay. Great. Well, that's all the time we have for today. Thanks to everyone in the audience for tuning in, and thanks to our panel for sharing their time and expertise. I really enjoyed listening as well. And also, we appreciate Agenus for sponsoring the discussion at Endpoint's webinars. Just a reminder, if you would like to rewatch the webinar or share it with colleagues, a link for on-demand viewing will be sent tomorrow. But for now I'm Surani Fernando on behalf of Endpoints News. Thank you for joining us, and we hope to see you at a future Endpoints Webinar.