Good afternoon, everyone. I'm Eva Forte Verdejo, a biotech analyst here at Wells Fargo. Our next session is with the Agenus team. We have Zack Armen, Head of IR and Corporate Development, and Robin Taylor, Chief Commercial Officer. We're gonna have a hybrid between, you know, fireside chat and a few slides, so feel free to ask any questions you have. So perhaps to start, for those that aren't familiar with the story, can you provide an overview on the company, and then we can dive into questions?
Yes. Thank you, Eva, for having us. So, Agenus has been a company for thirty years, founded with really the same mission we have now, which is to leverage the power of the immune system to deliver curative outcomes in cancer. The way in which we have attacked that problem has been different over the years and has evolved, which we'll talk about today as to how our current platform and modalities are, in our minds, making a big dent in solving for that mission. However, we have been around for those thirty years and been public for the last 24 years. Our company is vertically integrated across all of the key functions of a drug discovery and development company.
We have R&D teams and labs here in the Lexington, Massachusetts area, along with in Cambridge, U.K. We have a fully integrated end-to-end CMC facility that goes from research cell bank through cGMP, drug substance and drug product production. We obviously have a very deep and experienced clinical team. Robin, who will introduce himself as part of our newly formed commercial team, ahead of what we expect to be a important and impactful launch of our lead program, BOT/BAL.
Um...
Sure, I'll just introduce myself as well. Robin Taylor, I'm the Chief Commercial Officer. I've been with Agenus for a year. A good proportion of my career I spent at Genentech and Roche, and actually twenty years ago, launched Avastin, which is apropos, as we are now developing, you know, the next breakthrough in colorectal cancer.
Great. So perhaps we can jump straight into your lead program, BOT. So can you just discuss a little bit the program, the mechanism of action, and how is it differentiated from other CTLA-4 antibodies?
Absolutely. So I'd like to start with an image. What you see up here, if you look on the left, is a colon cancer tumor, an eight-centimeter, almost completely obstructing mass. And then after one dose of BOT, three doses of BAL, and a seven-week interval from the first dose to the colonoscopy you see on the right, what we see is a complete resolution of the tumor. And this illustrates two things. One is, this is the power of the immune system. So the immune system is capable of completely eliminating an eight-centimeter tumor in the course of seven weeks, which is remarkable. What's also notable, though, is that the fact that that tumor existed in the first place means that the immune system didn't see it. It wasn't being effective.
So with the help of BOT and BAL, we've activated the immune system and actually completely eliminated the tumor, not only in this patient, but as you can see in this neoadjuvant study, five out of the nine patients achieved a pathologic complete response, which is really quite remarkable. When you think about what adjuvant or neoadjuvant FOLFOX achieves, it's about a 4%-8% response rate in this same population. And so this really does speak to the power not only of the immune system, but what we have in terms of a next-generation molecule that is able to activate the immune system in cold tumors.
So if this was an MSI-high tumor, which is where there's a very high mutation rate, the immune system recognizes these tumors quite well, and with the addition of a checkpoint inhibitor, you can achieve these same results. But in the microsatellite stable colorectal cancer space, these are not results you typically see with immunotherapy. So what is the program? BOT and BAL, we shorten the words botensilimab and balstilimab, because it's a bit easier to say. BOT is a next-generation CTLA-4. BAL is a PD-1 inhibitor, very comparable to the existing PD-1 inhibitors that are in the market right now. So the magic sauce here is really around BOT, and how is BOT different? So this is an Fc- enhanced CTLA-4.
There are point mutations that enable a stronger binding between the antibody and the Fc gamma RIIIa receptor on antigen-presenting cells. What this does is it actually allows T cells to better recognize the weak antigens that one finds in cold tumors. And so we're educating the immune system to actually recognize these tumors and then activate. That is priming, generating T cell memory. And then the PD-1 comes in, and it sustains that response. It makes sure that the immune system doesn't shut down again, that once it's primed, then we're actually able to sustain this response for the long term.
In this case, this is happening in the course of, you know, seven weeks in the neoadjuvant setting, but it's also having a significant effect in the relapsed refractory setting, that we have generated data, and I'll show you a little bit of that. This is a clinically de-risked program. We have safety and efficacy data across eleven hundred patients in both phase I and phase II studies. This broadens immunotherapy to the two-thirds of solid tumors that have not been responsive to immunotherapy, also known as cold tumors. A classical example of that is microsatellite stable colorectal cancer. Just to share the data in the relapsed refractory setting, these are third line plus patients. The current standards of care are the agents you see here, fruquintinib, regorafenib or Lonsurf, with or without bevacizumab.
In this setting, one typically sees anywhere from, you know, 2%-7% response rate in a patient population in which we're seeing the activity with BOT and BAL, which is microsatellite stable colorectal cancer, these patients without active liver metastases, and so the overall survival one sees from the current standard of care ranges from about 10 months to up to about 14 months, but what we're seeing with BOT and BAL in this setting is a 23% response rate out of our initial cohort from the phase I, and 21 months of overall survival, so a significant improvement over the currently available standards of care. Now, these are data that we've discussed with the FDA, and our plan was really to be able to take these data and do two things.
One is to show that in fact we have a dose that we can move forward into phase three, that we have our CMC components, and that we have a statistical design for the phase three that we can move forward with. Now we have agreed upon a dose for our phase three. We're close on CMC of components, and we can talk about that, and then we have an agreed upon design, and so we have everything we need to move forward with the phase three in this space. We also will come back to the FDA for a discussion around potential accelerated approval, and in the fall, we are going to the EMA for a discussion around a conditional approval in Europe, using the data we have, not only from the phase one study, but also from our phase two study.
And then finally, just the last slide I have is to show you a bit more detail around that neoadjuvant study that I started with. This is called the NEST study. There were two cohorts. The first cohort was one dose of BOT and two doses of BAL, treated for a period of about four weeks prior to surgery. Those are the red bars that you see here, and you can see that in the MSI-high, those are the tumors that have significant mutation burden, that the response rate was almost 100%, in the three patients that you see here. So this is. These patients likely do not need to go on to surgery. Many of them may not go on to adjuvant treatment.
Then when you look at the responses in the microsatellite stable, you can see that by increasing the treatment duration and increasing the number of doses of BAL to one dose of BOT, four doses of BAL, that we've significantly increased the pCR rate. These patients have a pathologic complete response, no remaining evidence of tumor in the colon. These are very exciting data. These are data that we are moving forward in terms of discussions around study designs in the neoadjuvant setting, both for colon cancer and also rectal cancer. You can well imagine in rectal cancer, if you have a pCR, that means that the patient does not need to have their rectum surgically removed. They do not need to go on an ostomy bag, and so organ sparing is very important in this setting.
Great. So lots to unpack here. So, maybe we can start, you know, in terms of the combination of CTLA-4 and PD-1. Like, kind of like, have we seen this before from other, like, competitive programs?
Mm-hmm.
And where's the synergy coming from? Can you, like, go a little bit more in depth in, like, the biology there? And also in terms of safety, what have we seen so far?
Sure. No, it's a good question. So CTLA-4 is one of the validated targets that we've seen in immunotherapy. I mean, we see this in hot tumors. The melanoma, obviously, is the classic example. Melanoma and lung cancer, where we see the activity of CTLA-4. The first generation of CTLA-4 inhibitors are more active in these warm tumors because they don't bind as strongly to the Fc gamma RIIIa receptor that we do with BOT. So the data we're seeing here in microsatellite stable colorectal, as well as other cold and IO refractory tumors, is not something one typically sees with the first generation of CTLA-4 inhibitors. There's some activity, there's just not as much activity.
And I think that's an important point because if you think about many of the drugs that are in the market now, there are many significant improvements that have come from the next generation of molecules that are improving against a validated target. You know, immunotherapy is challenging because there's a lot of exploration of new targets, and until you get to the clinic, you don't know exactly how they're going to behave. And many times I think what we're missing from those is the effect that BOT has in terms of priming the immune system. So combining BOT not only with PD-1, but with other immunotherapies, has a significant potential beyond what we've seen to date. In terms of safety, one of the features of botensilimab is that we have introduced a point mutation in a region that binds to complement.
So this has actually reduced the number of sort of harder to treat immune-mediated adverse events that are mediated by complements such as hypophysitis, which are more common with the first generation of CTLA-4 inhibitors. The main AE that we observe is related to the GI tract, which is diarrhea colitis.... And so we have worked out better ways of managing that, both with steroids and then with the use of infliximab to very quickly resolve these effects.
In terms of the phase 1b that you were referring to at the beginning of your presentation, how big was this study and what were like the key learnings that you're using to design, you know, the next, the pivotal program, basically?
Right. So the phase I overall is over 500 patients treated with either bot monotherapy or the combination with bot and bal. The biggest cohort in that group was from our colorectal cancer cohort. So we have 77 patients, so the most mature data sets, which are the 23% response rate and the 21-month overall survival we've talked about. And then our phase II study is a five-arm study that examined two different doses of bot, either a 75-milligram flat dose or 150, which are equivalent to the one mg and 2 mg in our phase I. And secondly, looked at those either as monotherapy or in combination with bal, and then there's a small standard of care arm in that phase II as well.
Together, those are the data that form, inform us really about moving forward into phase III. We have very consistent results between the phase II and the phase I. Secondly, that's the data package that we will be discussing with regulators in the future in terms of potential for accelerated or conditional approval.
Regarding the discussions with regulators, right? Like, what do you need to flesh out truly to kind of like move forward and start the regulatory path or like the pivotal studies?
Yeah. Partly it's, it's data maturity. So we plan to have another data cut later in the year, so we have longer maturity on the phase II. I think we've publicly disclosed some of the early data from that study, and that was data that we initially had discussed with the FDA. But a longer maturity will help us from a couple of aspects. One is that there's potential for additional responses to come in. What we saw in the initial phase I is that actually 20% of the responses we observed in the phase I actually occurred after six months. And so this is different than what you typically see, say, with chemotherapy, where you expect to see the responses fairly quickly.
With immunotherapy, it can take time to develop, and so the phase II is still maturing in that respect. Secondly, we'll have longer follow-up on our overall survival, and I think that's the important thing to think about here, which is the context of the currently available standards of care and what they're delivering versus what we can deliver with bot and bal, and particularly as you see those survival curves extending, and we hope flattening out. Because one of the impacts of CTLA-4, which we observe very clearly in melanoma, is there's a tail to the curve, and it takes a while for you to be able to see that. It takes a long time just to actually see that, in fact, there is this tail, but that's back again to the power of the immune system.
That's the impact of, you know, even beyond discontinuation of, you know, treating with immunotherapy. You've conditioned the immune system now to continue to recognize the tumor.
Just to clarify, Eva, Robin's comments are sort of alluding to our goal, which is to continue the conversation around an accelerator or conditional approval with both the U.S. and European agencies. With regards to your question about whether we are awaiting continued regulatory alignment to launch our pivotal study, in the U.S., we have that alignment with the FDA, and we can initiate that study based upon that alignment. We're gonna have similar discussions with Europe upcoming in the next month or two. So from the perspective of launching the pivotal, we are ready and will do that, and we will continue this conversation based upon that data maturation that Robin just described to you around a potential earlier approval.
I guess my next question is, what are the gatekeeping steps for you to launch on this pivotal program? Also, is there any reason... Like, is there a difference in standard of care between the U.S. or Europe, or something that would suggest that conversations would be different here?
Yeah, I mean, the standards of care are similar, although the actual treatment patterns between the U.S. and Europe are a little bit different in terms of the amount of access to the available therapies. So that, you know, is a little bit of a difference between the two, but the actual options are essentially the same. You know, I think the main difference between, well, any of the regulators, is each of them form their own viewpoint on the totality of the data. And, you know, we've had. I think we're coming up to an initial discussion with EMA, where we will hear their input, both on the phase III design, which we expect to be fairly similar to the input we've had from the FDA, and also the potential for conditional, a pathway to conditional approval.
So those are really where we land, which is that, you know, we have a very clear path to being able to get to an approval in the relapsed refractory setting. It's more a question of sort of what's the timing around that and what do we need to do. Either way, you know, in order to be able to get that approval, you still need to be able to run the phase III study, because it's a condition of those conditional approvals anyway.
And part of the thinking there, as we've alluded to recently in earnings calls and other forums, is the prioritization we have in finding a partner to help resource that work. As Robin mentioned, it's quite clear the work that needs to happen and the high degree of confidence we have in the full approval pathway. And we know that others whom we're in discussions with see similar path. So that becomes part of that stage gating that you asked about, Eva.
... Okay, interesting. So, in terms of the opportunity here, right? Because you're targeting the more refractory population, obviously, first, are you thinking about bringing this to earlier lines of treatment? And also, I guess my second question here would be, you mentioned organ sparing-
Mm-hmm.
-as like the ultimate goal, I guess. How are you measuring that? Is that like special endpoint, or are you just measuring the typical response rates then?
Yeah. So definitely we are looking at earlier in the treatment landscape, and that, you know, includes neoadjuvant, which would be in a setting where the, you know, the objective of treatment is cure. The specific definitions of the endpoints and the, you know, study designs are still things that we are working through, both internally and in discussions with the GI expert community. So can't comment on any details around that yet. But it's, I mean, it's clear from these data that we need to go there, right? That this is a really important development in this treatment setting. The second area I'd focus on is also within colorectal cancer, is frontline metastatic colorectal cancer. Current standard of care there really hasn't changed over the last twenty years. It's either bevacizumab with FOLFOX or FOLFIRI.
There's a smaller group of patients who can actually receive, you know, all three chemos in one regimen in FOLFOXIRI, and then there's use also of EGFR antibodies in combination with chemo in this space as well, but being able to develop in that setting, we have an ongoing IST right now that is being run by Marwan Fakih at the City of Hope, and he's examining the combination of BOT and BAL with bevacizumab and FOLFOX, and, you know, those are data that would potentially support us moving forward into that frontline metastatic colorectal cancer setting.
Yeah. You asked about opportunity, Eva.
Yeah.
And we have some numbers that are just coming from epidemiology data sources around the number of patients who are drug-treated in these settings. In the case of neoadjuvant, this hundred and thirty thousand number is actually a set of defined subpopulations that we've identified in both the neoadjuvant colon and neoadjuvant rectal arenas, that we believe offer the most high-confidence path towards a full approval. Both because certain endpoints, like organ preservation in the case of rectal cancer, are, in our minds, thoughtful design elements in certain populations, and also based upon the feedback we've gathered from KOLs.
In the late line setting, while we've heard from some groups that they believe this setting to be rather small, in reality, it's about 30,000 drug-treated patients in the seven major markets, and that is in the third, fourth, and fifth line metastatic setting in patients with non-active liver metastatic disease. So in that defined subpopulation, for which we do have a Fast Track designation from the FDA and are showing the kind of robust data above standard of care, you're talking about a roughly 30,000 drug-treated patient population in only the seven major markets. So the opportunity size in these settings, along with the frontline setting, as Robin mentioned, are really large. And in each of the different settings, we're examining a different therapeutic regimen with BOT being the backbone.
In the case of the late line, it's BOT BAL against standard of care. In the case of the frontline, it's BOT BAL in combination with standard of care, to hopefully achieve better outcomes with tolerability in combination with chemo. And in the frontline, or rather pre-surgery neoadjuvant setting, it's becoming a augmentation and potentially also a replacement for surgery, in certain cases, and hopefully a replacement or avoidance of adjuvant chemo.
Very interesting. Perhaps following up on something Robin said before, how is the regulatory path different in, like, the earlier lines? Between... Obviously, later lines are gonna-
Right.
Get faster to market, right? But is there any key differences that you're, like, aware of?
I mean, every treatment setting has its own regulatory endpoint that we've seen from precedent, and then the potential for novel endpoints. You know, that's an exploration with the different regulatory authorities around whether the traditional endpoints in the neoadjuvant/adjuvant setting are event-free survival or disease-free survival. But I think there is a lot of interest and growing sentiment among the expert community that other endpoints should be considered, such as pCR, organ preservation. You know, these are important things that, you know, being able to demonstrate the correlation between these endpoints and disease-free or event-free survival, I think there's growing evidence for that in many recent studies.
And ctDNA is another one of these, where there's-
Yeah
... growing momentum behind the correlative power of ctDNA negativity and long-term event-free survival. There was a presentation done at ASCO GI, where it was a large longitudinal study done to show that there was a highly correlative impact there between continued ctDNA negativity over a four- or six-month time course and two- or three-year event-free survival. There was a recent ODAC committee that voted in favor of using ctDNA as a primary endpoint. That was in a hematologic cancer, but it still represents what we believe to be the right kind of trend in terms of regulatory bodies being open to using these endpoints that are shorter term in nature, but are, you know, high fidelity, quantitatively measurable endpoints that are showing that they translate into longer term survival.
Okay. Moving on to pancreatic cancer, unless there's anything you haven't touched upon that you would like to discuss on this program or-
The only other thing I'll mention, Eva, is you made the point that in the earlier settings, the regulatory path would be longer. In our minds, it doesn't have to be longer in time. The burden of proof to achieve a full approval in terms of the threshold that you must reach as far as safety and efficacy will obviously be different and higher in those early settings. But in some of the early design work that our team has done, the timing of full approval across all these settings can be very similar. It obviously depends upon our alignment on the design of these studies and the endpoints as to whether that becomes the truth of our pathway.
But in each of these cases, we're planning to go engage with the regulatory bodies quickly.
What's the precedent in terms of timing for these tumor types and these type of studies?
So, you know, the recent neoadjuvant approvals, I think we've seen in melanoma, we've seen in the lung cancer setting. If you look at those, I mean, the one example that is not based purely on event-free survival was in the breast cancer setting. And the reason that ended up being established was because there was this correlation between pathologic complete response and event-free survival. And we are seeing larger bodies of evidence now that we're seeing that correlation in other tumor types. And so I think that's part of the real growing sentiment that this makes sense scientifically. And there is a lot of interest in actually being able to, you know, try to move the regulatory discussions towards adopting these as, you know, real potential endpoints.
Right. And that EFS range, it obviously depends on the powering of the study and the outcomes, but it's typically in that two- to three-year range as far as these precedent examples-
Yeah
... that have served for full approval.
Yeah.
Yeah.
I mean, and the other point, too, is that, the magnitude of the effect is important, right? And so You know, a recent example was the plenary session from ASCO, seeing, the use of ipi-nivo as a neoadjuvant treatment compared to adjuvant, nivo. And that was, Christian Blank from Netherlands Cancer Institute, you know, showing that, you know, training the immune system early when you have the intact tumor, is actually, in a sense, more powerful than once you've removed the tumor and you're trying to kind of soften up what's remaining. And so and the event-free survival on those, you know, is dramatically different when you actually see between neoadjuvant versus adjuvant treatment.
And again, hot tumor in the case of that study. In our case, botensilimab is igniting these cold tumors to effectively become hot tumors and then allow for that same dynamic to occur-
Right
... in the pre-surgery setting.
Mm-hmm. Makes sense. So moving on to pancreatic cancer, can you educate us a little bit on the rationale for BOT here? And, like, how are you thinking about the opportunity in second line versus first line, and what's the unmet need?
Yeah. It's a huge unmet need, let me start there, because pancreatic cancer has been very difficult to treat. There are very few treatment options right now in pancreatic cancer. The two most common, you know, initial treatments for metastatic disease are either Folfirinox or gemcitabine. And, you know, in the second-line setting, there are limited options available. Our initial data was a combination of BOT with gemcitabine. So no BAL in that combination, just BOT and gemcitabine. Of the first six patients treated at a 150 milligram dose of BOT with gemcitabine, we saw four out of those six patients with a response, which is pretty unusual in patients who have progressed on Folfirinox. And so, you know, that really got us interested.
We wanted to expand that, and so now we have the expanded portion of that study is ongoing, which is a phase II randomized study, very simple design, gemcitabine versus BOT plus gemcitabine. Study's on, you know, enrolling, ongoing, so we haven't seen the data yet, but we're looking forward to seeing how that turns out.
What's the bar here in terms of efficacy that would, like, convince you to move the program forward?
I mean, these patients don't respond very well to current therapies to, you know, gemcitabine in that setting. You're getting about a 10-15% response rate. They're very short in terms of PFS, and survival is very short too, so less than a year in terms of survival. So, you know, the ultimate here is actually to show that, in fact, these patients can live longer, and ideally, that we're seeing, you know, the kind of activity that we're seeing in the relapsed refractory colorectal setting, where we actually see patients who have durable responses that go on for a much longer period of time. Where do you go with that data?
I think obviously you can stay in the same setting, in the second line setting, but I think there's an argument to be made for going into earlier lines of therapy, into frontline, where the immune system is a little healthier, or even into the neoadjuvant setting. But those are all discussions we'd have once we see the data.
Have you set expectations on when are you gonna present this data? Is this like a 2025 or 2024 event?
Early 2025.
Early 2025.
H1.
Okay. Have you said anything about, you know, which platform? Like, is this gonna be a conference, or is it gonna be, like, a conference?
Not yet. We always try, we always try to present new data at a major medical congress. That's always our plan A, as we did with our phase II data in the randomized MSSCRC study. We top-line the data and are planning to show the totality of that data at a major medical congress. So that could be the route, but we always default to striving to present data at a major medical congress.
Okay. And in terms of the regulatory path here, are there any key requirements?
There's. I mean, I think the key is likely to be overall survival if it's a randomized study. Is there an accelerated approval path? Potentially. But-
Okay.
You know, we haven't explored discussions around regulatory endpoints in this setting.
Yeah, the good news with not just this pancreatic setting, but all the other settings, is we have such a robust safety package now, and with over a thousand patients having been treated across different, solid tumors and showing an overall highly tolerable and manageable, safety profile, that we think that that makes these, regulatory pathways and other treatment settings incrementally, more straightforward, that given that we've got such a robust safety package.
Yeah, and I think the other thing is that the combinability of BOT with gemcitabine demonstrates that, you know, you can actually combine with chemotherapies.
Interesting.
Becomes important in earlier metastatic lines, where many of the standards of care are chemo or chemo combos. So that also presents an opportunity, as Robin mentioned, to move up into frontline settings in combo with standard of care across various different solid tumors.
Mm-hmm. And perhaps following up on this, you also have a melanoma program. You've shown some data for this, right? Like, can you just quickly walk us through the data and kind of like, you know, what the risks, your approach here?
Yeah. So the early data we showed is from the phase one program. We have data both with BOT monotherapy as well as combination with balstilimab. That data was in either PD-1 refractory or PD-1 plus CTLA-4 refractory patients, and it led us to design a phase two study that is studying BOT monotherapy at two different doses and BOT in combination with balstilimab at two different doses, and in either PD-1 refractory or PD-1 plus CTLA-4 refractory, and obviously, the hardest to treat patient population from an immunotherapy perspective are those who've already had prior CTLA-4 and prior PD-1.
You know, those data we've not disclosed yet, but I think that will be important in terms of understanding sort of the ability of BOT and BAL to continue to generate immune responses in patients who've really exhausted all their available immunotherapies, which includes some of the, you know, the recently approved immunotherapies beyond CTLA-4 PD-1, like LAG-3.
We see this as one route in which we demonstrate very purely the power of BOT above earlier generation CTLA-4 PD-1 combos, where we've seen a patient who's failed ipi-nivo and then now responded to BOT or BOT/bal. That becomes a very pure rationale or validation that this therapeutic regimen is behaving very differently in a clinically beneficial way.
Interesting. So perhaps with the last minute, just if you guys can remind us, what are the key catalysts or data readouts that, you know, we should keep an eye on, in the next, like, you know, twelve months?
Look back, actually.
The key catalysts are first, these regulatory interactions that we have upcoming with Europe, and we-
Mm-hmm
... you know, we are looking forward to those interactions which have already started but are gonna become more robust over the next few months. So that's one catalyst. We will be presenting the totality of the phase two data that we top-lined in July. We hope that we can have a later, more mature data cutoff on that phase two data once it is presented, and we hope that that's at a major medical congress sometime soon. So that would be a catalyst as well. And then as we have further interactions with the FDA, those would obviously become catalysts because they would be quite material when it comes to the potential for an accelerated approval in this early program.
Okay. Thank you very much.
Thank you.