Agenus Inc. (AGEN) Earnings Call Transcript & Summary

Good morning. We'll get started with our next company, Agenus Bio, where we have with us Chairman and CEO, Garo Armen; and Chief Medical Officer, Dr. Steven O'Day. Thanks to the team for being part of the B. Riley oncology conference, and appreciate you guys in the audience joining us. This is Mayank Mamtani, one of the senior biotech analysts on the health care research team. At any point during the fireside chat, feel free to e-mail me questions at mmamtani@brileyfin.com. So with that, Garo, Dr. O'Day, congrats on having a very productive past 12 to 18 months with the ongoing Phase I bot/bal trial, generating quite impressive data at recent medical conferences, including the ASCO GI conference starting actually today.

Before we dig into some of those data sets, maybe for the interest of folks newer to the story, could you, Garo, touch on the sort of portfolio of sort of next-gen I-O antibodies that you have wholly owned and partnered and kind of touch on the development capabilities that you have underway, be it the VISION platform and CMC, as you look to deliver on the promise of cancer immunotherapy at a global scale? Garo?

Yes. So as you know, you mentioned very well, Mayank, since our first presentation at ASCO GI last June, the field has started paying a lot of attention to our botensilimab development program because of the unusual nature of all the responses that we've had. And you've always mentioned what is the difference now with botensilimab versus other CTLA-4s, just elucidate on that [indiscernible] that Dr. O'Day had the clinical experience. So one difference is the broad nature of the responses that we're getting. As you know, when ipilimumab, the first-generation CTLA-4 started, the responses were pretty much limited to melanoma. And the fact that in this very early trial, even though it's a Phase I, as you know, we have enrolled more than 300 patients. The data is [ showing ] repeatedly -- and one of the reasons, by the way, we have made a bunch of presentations ESMO GI is because of, number one, the maturing nature of data. And Dr. O'Day will speak to that. And the fact that we presented at this GI just the colorectal results. And then as you know at SITC, we presented results in 4 cohorts. And I think it's fair to say that beyond the ASCO GI presentation, which we will be on Saturday, in the first half of this year, we'll continue to present data as the numbers of patients grow and the data becomes mature in terms of the ratio of response in patients. So unfortunately, the ASCO GI abstract is not out yet. We expect that, that would be out. So we thought that we'd give you a preview today, but we won't be able to do that. And we'll have to wait until Saturday morning. But suffice it to say that there'll be more patients and there'll be longer [indiscernible], and there'll be the kind of data for the first time that we had shown this in terms of the nature of the data without necessarily specifying what it is. But Dr. O'Day, you are the world's expert on CTLA, having treated the very first patients with ipilimumab 10 years ago. And with your ASCO plenary presentation in 2010, if I were to count on someone that could make some differentiated comments, it would be you.

Yes. Well -- so thanks, Garo and Mayank. Thanks for inviting us to be here today. I think botensilimab is really a foundational asset for Agenus. It's obviously a next-generation CTLA-4. The front end of the molecule is performing like you'd expect with [ fully high ] binding CTLA-4. But really what is differentiating it is the back end of the molecule with [ FCT ] mutational enhancements that's really making the synapse between the antigen-presenting cell and natural killer cell and the T cell. It's bringing them together and producing more potent responses. And I think what's remarkable compared to ipilimumab is ipilimumab was really a groundbreaking drug for melanoma tumor that is very immunologically sensitive, so to speak. But what's differentiating this Fc-enhanced CTLA-4, botensilimab, is its ability to produce objective and durable responses across 9 different, what we call cold or PD-1 resistant tumors, meaning tumors that had already received prior I-O. We've shown this now not only in MS-stable colorectal cancer, a particularly cold tumor that I-O has failed, but 8 other tumors. And at SITC, we released some cohort data in ovarian, sarcoma and some early lung data that has been incredibly provocative in terms of signal and the KOL response. Obviously, this is receiving a lot of attention. We're moving forward, obviously, with now Phase II programs in melanoma, pancreas and MS-stable colorectal with a real plan to bring MS-stable colorectal as our first registrational opportunity with this combination.

That's helpful overview. And too bad we can't talk about the ASCO GI abstract, but we potentially can discuss what the data so far has been in colorectal MSS. So could you maybe just give us sort of the evolution of that data set, Dr. O'Day, about what we saw at ESMO GI, then SITC? And sort of, what do you expect to present at ASCO GI this weekend? And then I have a broader question, like how you think about the different indications. Now you said you've had the 9 different solid tumors show activity. Would be helpful to understand how you sort of prioritize the 3 Phase II studies that I think you touched upon, but then also what sort of things that you are thinking about as you look to, for example, work on the provocative data set in lung, for example. And I think there's also melanoma that I think you presented data in the past, but you may have more updates this year. So yes, Dr. O'Day, maybe just touch on the CRC parts of the story, but also some additional tumor types that you have in the works now.

So as Dr. O'Day alluded to earlier, one of the special attributes, even before we went into the clinic for botensilimab, was that it was designed to be active in cold tumors. Of course, you may say, how can you design all of that? We have a terrific group of people, and all they do is design molecules but also Fc engineering modifications that we have mastered the art and science of making that a number of years ago. And as you know, we have other molecules that have been designed with Fc engineering. But what's important to know is that each Fc engineering domain is not -- is a different feat. So it's not the same engineering for each one of the targets. Depending on the targets, depending on the requirements, that's what we've done. As to colorectal cancer, we knew from the beginning. Dr. O'Day and his team has significant experience in various cancers, including cold tumors. So we knew this was a challenge. We wanted to show whether or not our [ agent chemistry ] will be active. Of course, it's been active now in a very profound way. Now one of the things that I should mention before I turn it to O'Day is the fact that we believe -- and again, Dr. O'Day is an expert in the field. We believe that CTLA-4 target, in addition to the other attributes of botensilimab, CTLA-4 targeting does provide with longevity of response and potential cures. So we are going forward with the condition that right now, we're pursuing third-line patients, fourth-line patients, so patients that have no other options. They are heavily pretreated, a substantial number of the market treated with other [indiscernible], including PD-1s. And we're seeing activity. But should we go to earlier disease setting, and we intend to do that, that we will be able to show survival benefit. That is our conviction. And that is part of our strategy, which, of course, moves the needle. The requirements for success in -- profound success into either very long term is possible, even possibly cures. So Dr. O'Day?

Yes. So Mayank, just to follow up on the colorectal story. We went -- we presented 41 patients at GI ESMO and then at SITC 59. And without getting into details, we will be updating in a few days that data set further. But I think what's important for people to understand is this is a third-, fourth-, fifth-line sort of MS-stable colorectal in which the standard of care, third line, for example, long served with regorafenib has response rates literally almost 0, a couple of percent and really survival benefit of less than 2 months in large randomized trials. So that's the bar. But if you look at I-O in the same setting, ipi/nivo and regorafenib, durva, really single-digit response rates. And [ durva and trem ] has over 100 patients treated with one response. So I-O combinations with CTLA-4 PD-1 have failed in this setting. And we have -- there are 2 sets of data from ESMO GI -- I mean, yes, ESMO GI and SITC have shown north of 20% with durability, hence stable disease that's durable showing disease [ controlling ]. So this is what is really remarkable about the data set. It's certainly better than the standard here, and it's certainly responding with clinical benefit in an area where I-O combinations have not been productive. In terms of other diseases, though, obviously, ovarian, we've shown data on sarcomas and very little to -- and lung. And we're particularly interested in the PD-1 refractory lung setting. We've only reported a few patients. But again, the majority of these have responded and have the durability, the same consistent signal, and we're actively accruing to this. So we see opportunities in these areas, too, in the next year. But in terms of why we picked the 3 Phase II studies right now to focus on and we are highly focused, obviously, our MS-stable colorectal sort of speaks for itself with the combination of bal or PD-1 and botensilimab. And we have a plan there. We are also in melanoma a hot tumor where CTLA-4 clearly has a lot of activity, and we have preliminary data that we have activity in this area as we would expect. But this is a single agent, botensilimab trial that really differentiated the second line from ipilimumab. So we think it's a very important opportunity for us. And then in pancreas, this is primarily based on our preclinical data where our botensilimab in combination chemo in a highly refractory mouse model has shown curative potential that's plain remarkable. And because of that, this experiment with Phase II -- second-line pancreas is being done. So we have 3 different experiments that are moving forward quickly now in colorectal, in melanoma and in pancreas, either single-agent botensilimab, botensilimab plus PD-1 or botensilimab plus chemotherapy.

And to build on that monotherapy activity that you're looking to explore in melanoma, but also one of the goals for your next study in colorectal and maybe specifically talking about your sort of plans going forward with the Phase II study, the individual contributions of bot/bal, it seems like a big question you are looking to address in that setting and then also the -- building on the durability data set that you have already. But could you touch on how you have sort of designed this Phase II study? And what are some of the features that could allow you to meet that objective of an accelerated filing next year? It seems like a pretty big study, 200-plus subjects that you aspire to enroll within a year's time frame.

So our strategy with contribution, components and dose optimization is really to use our expanded cohort Phase I agents, which we are backfilling with dose and contribution in colorectal, for example. But also our Phase II programs are designed to continue to look at dose and contribution. So it will be a composite Phase I dose expansion -- I mean disease expansion and the Phase II data. Our primary endpoints are response, duration of response. And then because that drives survival in I-O, PFS is certainly going to be collected, but it's less important from a primary endpoint. So the Phase II data will be looking at response, duration of response and how that's impacting survival. And in colorectal, we've also announced that we will have it conform in the Phase II data set. This is very important so that it can be very [indiscernible] sort of how we're doing in terms of response, duration and preliminary survival. We think that will differentiate, obviously, botensilimab in this setting. And then, obviously, a pivotal trial will confirm that with survival.

Yes. And maybe just to hone in on the expanded cohort sort of progression. You -- I think you're getting close to wrapping that up in terms of subjects that are going into the study versus maybe continuing to follow up. So what, in your mind, is the duration of response and some of the survival metrics that you feel confident and that you reported on and you may report on the future? And maybe just put in context what we have seen with the other combination -- other CTLA-4s, prior generation combinations like the ipi/nivo but also the durva/trem combination.

Well, we can't get to specific data for the GI ASCO in a couple of days, but we will see more data regarding that. So I think more to come on that. But clearly, response and duration of response and preliminary survival, all very important in that regard.

Okay. And another question we get on that data set is the breakdown of liver versus lung met. Could you maybe touch on the importance of that? And as you know, that may also inform how you sort of do your next study and what sort of patients you enroll. Dr. O'Day, could you touch on that?

So we -- at GI ESMO, we showed that in our allcomers cohort, if you look at nonactive liver mets. So these are patients without liver mets or treated liver mets. Obviously, the response increases substantially. And so this is a known sort of predictor of response in the I-O field across tumors. So we continue to enroll patients on these trials. But in our Phase II program, we're really going to be highlighting the nonactive liver mets so that we can optimize dose contribution given the high response rate we've seen. In terms of our Phase III trial and our strategy, we haven't announced and made a final decision. We'll see what the data shows. But we think we have benefit across all patients with metastatic colorectal cancer and clearly an enriched benefit in nonactive liver mets, as you'd expect.