All right, thanks everyone for joining and, we'll get going with the next fireside discussion. My name is Derek Archilla. I'm one of the senior biotech analysts here at Wells Fargo. Very excited to have our next discussion here with Agenus. From the company, we have Garo Armen, the CEO. Garo, nice to see you.
Thank you very much, Derek. It's very nice to be here.
All right, well, maybe first off, it'd be good to just give a little bit of background about the company and get what you're working on, and kind of just the state of the business at the moment.
Sure. I founded the company literally 29 years ago, and the objective then was that the immune system would be the holy grail to curing cancer. And that objective hasn't changed, but what has changed in the last 29 years is that we've seen a proliferation of our tools to do that with. And of course, the field has advanced, but so have the tools in the field. Our understanding of immunology of cancer is dramatically more advanced today than it was even 10 years ago. And...
But I think, something that is extraordinary about our company is that since 2015, we have taken 15 agents into the clinic, and those 15 agents, half of them have been licensed out to companies like Bristol Myers, Merck, Incyte, Grid, Gilead, and so on, for a total consideration of in excess of $800 million that we have already received. But most importantly, the other half, the most recent half, are entirely our property. They're unencumbered. And of course, our lead program, botensilimab, is one of those latter half, which is a very exciting program.
Got it. Well, let's start there. Maybe just give a little bit of background about botensilimab and its mechanism of action, and again, kind of the development, you know, pathway that you have for that program.
Sure. So botensilimab, for the naked eye, may look like a CTLA-4 antibody, but if you look at it more closely, you will understand that CTLA-4 binding domain of botensilimab is one of about five properties that this antibody has, and that's something that is not widely understood. And those properties, beyond just binding to the CTLA-4 domain, are the ones that impart some of the key characteristics of botensilimab, which are, for example, activating T cells better, priming T cells, reducing the level of regulatory T cells, which are the bad actors, as you know, and also kicking up the involvement of memory T cells.
So these are all good things to do, and most recent data that suggests the involvement of the myeloid component of the immune system on top of all these properties, is really what makes botensilimab a very powerful immuno-oncology antibody. And of course, we can talk about the clinical activity so far.
Sure. But yeah, in terms of... Yeah, maybe we can talk about, again, how you guys have been developing that, and then we can lead into the efficacy.
Sure.
Yeah.
So what we did was, Derek, going back some years, we looked at the obvious, targets like CTLA-4-
Sure
... and PD-1, TIGIT, CD137, and we said, "Well, let's look at the existing antibodies and what their deficits are." Deficits in terms of not being optimally efficacious and/or being too toxic. For example, with CD137, liver toxicity is one of the issues-
Right
- associated with that target. And because of our molecular engineering capabilities and internal research capabilities, we were able to design things out of a molecule that are undesirable and design in other characteristics that are more desirable. And we've done this primarily by what we call FC engineering, and this is something that is proprietary to us. Other companies may make modifications to the FC, but specific modifications that we make to the FC domain of the antibody are proprietary to Agenus. And of course, botensilimab, by means of the modifications that we've imparted on this antibody through the FC domain of the molecule, is what really drives all of these wonderful characteristics that we talked about. And of course, you know, it's one thing-
Sure
To design these things into a molecule with the expectation that it will perform. It's another thing to see it perform. So what we did was design it with that expectation, went into extensive preclinical models to just test the concept, to see if it's performing the way it was designed, and then, of course, 600 patients later in the clinic, we have confirmed that what the molecules were designed to perform is indeed what we're seeing in the clinic right now.
Got it. So maybe talk about the different, you know, tumor types or cancers that you've kind of brought botensilimab into, and I guess, which are the ones that you're most excited about in terms of the efficacy and, and getting that target profile?
... Well, okay. So, if we look at the plethora of cancers, as you know, Derek, cancer drug development is a challenging and sometimes tricky business. And what we've done is looked at cancers, and because of these reasons, by the way, it's easier to get to the finish line by looking at patients or treating patients that are very advanced. So not only, of course, you know, cancer is stage 1, 2, 3, 4, but when you look at stage 4, there are different lines of therapy that patients are exposed to. And after they fail these lines of therapy, for example, with CRC patients, colon cancer patients. Colon cancer is a particularly challenging cancer because about 90% of these patients have what is called cold tumors, and cold tumors generally don't respond to immunotherapy.
So we have treated line 3 and line 4 patients and seen some remarkable results. And among the remarkable results, which have been presented, by the way, at major conferences in the last 15 months, starting with ESMO GI, which was held in Barcelona. That was the first conference where we had a debut of the data. And what we've seen here is really responses in patients that have failed everything, and some of our patients now are pushing 3 years with no sign of disease. So that's a reason to rejoice, certainly if you're a patient that responds to botensilimab. So that's where we are. And of course, we've alluded to our strategy for potential filing a BLA next year based on further data analysis.
Right now, colon cancer is our lead program, but right behind it are multiple cancers, where we've also seen some very exciting data, and we can talk about those as well.
Got it. So maybe just digging a little bit deeper on colorectal cancer, I guess, you know, can you maybe put that efficacy that you're seeing in that late line patient, you know, in the context, like, what are those patients generally getting? What are the response rates, you know, typically right now, I guess for, you know, I guess what would be probably standard of care, chemo or something like that?
Sure. So third line treatment or second or third line treatment in colon cancer. So when you have metastatic disease, typical treatment is FOLFOX and possibly adding bevacizumab to FOLFOX.
Yeah.
That's the first-line treatment. Now, when you fail that, your options are very limited. You know, you can be treated with regorafenib, you can be treated with Lonsurf, but unfortunately, these agents result in typically in the type of patients that we're treating, in about 3%-5% responses. That's the standard of care. 3%-5% responses and median survival of somewhere around 11-12 months. And what we're seeing in our trials right now is responses that are well over 20% and survival, median survival of about 22 months. And so, and what's also very important is that with immunotherapy, particularly things like botensilimab that target CTLA-4 domain, in addition to everything else, you see this tail of the curve, which denotes potential cures.
Mm-hmm.
Potential cures, because the tail suggests that a fraction of these patients go on several years with no recurrence of disease. And that's from a patient perspective-
Yeah.
That's very exciting. And in fact, you know, immuno-oncology was born with the accomplishments of ipilimumab in the early days. But unfortunately, ipilimumab only works for melanoma, mainly melanoma, and it cures about 15% of the melanoma patients. And so for the patients that are being cured with ipilimumab, that's a miracle, because otherwise they would have been dead. And so where our expectation is that botensilimab will take what ipilimumab did in melanoma to many different cancers-
Mm-hmm.
And perhaps do what ipilimumab does in melanoma better. We have some indications, some early data, that that may be the case.
Yeah, I'd like to get to that, too. So just lastly, so I know, I think in CRC, you also saw some differences in efficacy in terms of patients with liver mets and not.
Right.
Can you kind of talk to that? In terms of maybe a regulatory strategy, how does that kind of fit in there?
Sure. So, as you may know, we had a Fast Track, Fast Track designation in the specific indication that we will be pursuing approval for, and that is in non-liver met patients, or I should say-
Yeah
... no active liver mets, because-
Right. Yeah
A proportion of these patients have started with liver mets, and they have been treated for liver mets, but they don't have active liver mets at the time of treatment with botensilimab plus balstilimab. And so, that's a defined patient population, and the FDA has granted a Fast Track designation with specifics that will basically read into our label.
Mm-hmm
if we were to get approval.
... Got it.
Yeah.
So and what the efficacy look like relative to all comers? So I think you said it was like 20%. Was it higher, like, or how much higher?
I mean, so far it's 20%+, you know, because, as we add more patients, the efficacy has hovered between 20% and 25% in that patient population.
In without liver mets?
Without liver.
Gotcha.
No active liver mets. Yeah. And that's the patient population that when treated with regorafenib or Lonsurf demonstrate about 3%-5% response rate, objective response rate.
Gotcha. And so this would be the indication where you'd submit the first BLA?
That would be the first BLA, but suffice it to say that, you know, for those who are well-versed in immunological drugs, particularly things like PD-1 as well as CTLA-4, know that if a drug works in later-stage patients, and in this particular case, we're talking about third, fourth line patients, it's likely to work in earlier stages better.
Yeah.
Now, we have started an IST trial at Cornell and enrolled a handful of patients in the neoadjuvant setting. This is public information. If you go on clinicaltrials.gov, this, this trial is actively advertised there. So these are patients who are typically stage 3 B or C, which means that these are patients with locally advanced disease. Some patients have starting tumors as big as a small watermelon, believe it or not. That's upon first diagnosis.
Okay.
Upon diagnosis, which is typically done with scans as well as colonoscopy, the patients are enrolled in our BOT/BAL trial. Immediately.
Yeah.
Immediately. And typically, 4-5 weeks after they're enrolled, they're scheduled for surgery. So we've had an opportunity now to look at the pathology of the tumor at the time of treatment or right before treatment.
Yeah
upon diagnosis, and then pathology at surgery. This is a beautiful trial because you can see the progression-
Right
-or regression of the disease very nicely. So we will be publishing the results of these trial, this particular trial, or at least a handful of patients will be published very, very soon. And that trial, I think, could be a significant advance in the treatment of patients who would have potentially curative options.
Yeah.
But those curative options, Derek, are often debilitating.
Sure.
Meaning, if you're talking about surgery, you may have to live with colostomy for the rest of your life, and particularly with patients that are being now diagnosed in their thirties and forties with colorectal cancer or rectal cancer, this would be a tragedy. And so depending on the results, of course, that will be published, we may be able to eliminate the need for these debilitating treatments that are curative treatments for these patients. So that's an exciting outcome.
Got it. And in terms of like, the BLA, like, what's kind of left there, like, you know, that you need to do to kinda get that going and basically submitted? Maybe start there, and probably have a couple follow-ups.
Sure. So when you talk about BLAs under the Accelerated Approval provision, it involves a bunch of negotiations with the agency. So we're in the process of defining our strategy for those negotiations, and depending on how things go, we would be planning to file a BLA sometime next year.
Okay.
The BLA will be strictly based on overall, overall response rates-
Yeah
in a patient population that will be well over 100. And typically, for accelerated approval, 100-ish number is an important number to have as your denominator. And BLA application will also be driven by our ability to demonstrate that there is a significant unmet need in this patient population. So just to recap, what I mean by this, these are patients that have no curative options available to them. In fact, patients, as I said, with regorafenib or Lonsurf plus Bev, potentially, you have somewhere around 3%-5% responses and no curative outcomes, and progressively, toxic effects of these drugs, versus something like BOT/BAL -
Yeah
-that could potentially be curative, potentially in some fraction of the patients, and manageable transient toxicity. So that's a major delta. And we believe that if we demonstrate this differential to the regulatory agencies here and in Europe, we hope they will be amenable for accelerated approval based on the data that we have accumulated so far.
Got it. Are we gonna get any data or, like, additional data from this program in CRC, you know, between now maybe the end of the year?
Probably not.
Okay.
Probably not. Only because we have to respect the regulatory process.
Yeah.
Once we have a defined regulatory pathway, advertising data is regarded as not being very welcoming from a regulatory perspective. That's why we would define our strategy, file our BLA, and of course, based on negotiations with the FDA, and if the BLA is accepted, then we will make it public.
Got it. And then last thing, can you just kind of frame the market opportunity in that, that specific population that you're looking to get approved in? Like, how many patients and-
So we're talking about approximately 8,000 patients in North America that have no treatment options, as I said. That is the third or fourth line treatment option for patients. But it's highly likely that we will pursue a confirmatory trial-
Right
-in the first line setting, which is well in excess of 50,000 patients.
Gotcha. All right, and then maybe just shifting gears, for botensilimab, like that combo, maybe in platinum-resistant ovarian cancer. I guess, again, this is kind of all part of your, you know, different trials and looking at the different tumor types, but this seemingly had some interesting data. So maybe you can kind of just highlight that and kind of the development path there.
Sure. You know, the unique performance attributes of botensilimab are that, when we did our phase one trial, as you remarked, we did a basket trial. So we enrolled patients, primarily cold tumor patients, because cold tumors are an area where there's a significant unmet need, only because they don't respond to immunotherapy, typically. So we went after many cold tumors. We went after also some hot tumors as well, or sort of warm tumors, as we call. For example, melanoma is regarded as a hot tumor. CRC is mostly a cold tumor. A significant subset of ovarian cancers are cold tumors. Sarcomas are cold tumors. Okay? So lung cancer is regarded as a warm tumor.
And so we went after all of those and enrolled, and saw responses, objective clinical responses across all of these tumor types that we were enrolling in the trial. Now, you mentioned ovarian, of course, so we presented data on ovarian, once again, in patients that had failed everything. There are no treatment options, and we saw responses of 33% in ovarian, and we continue to enroll these patients to grow the denominator. And the purpose is that we're not a one-trick pony, if you will, in terms of our regulatory pursuance. So while colorectal is our first target because of the denominator being large enough to justify regulatory strategy, shortly, almost in parallel with colorectal, we will be pursuing lung cancer.
Lung is a huge indication, and originally we saw responses, approximately 50% responses in a small denominator of about 8 patients. We have now expanded that trial to a denominator of 40 patients. We will be disclosing results on that trial by the end of the year, and we are also expanding our denominator in the hope that there's a regulatory strategy for lung cancer, potentially with a BLA filing for lung cancer. And once again, these are lung cancer patients that have failed either PD-1 or PD-1 plus chemo. So both are enrolled in our trial, and the 50% response rate in that small denominator that I spoke about are in patients that have failed either PD-1 or PD-1 plus chemo. So once again, there's no option available to them.
If we can confirm, you know, reasonably high responses in a denominator of 100, which we hope to enroll by the end of this year, okay, that may be a parallel track regulatory strategy for lung cancer-
Mm-hmm.
the largest indication. Now, we're also pursuing a pancreatic trial. As you know, pancreatic cancer is a very, very challenging disease, very challenging disease. When patients are diagnosed with inoperable pancreatic cancer, their only option for treatment is a combination called FOLFIRINOX.
Mm-hmm.
Essentially, all patients fail FOLFIRINOX or not respond to it in the first place. We have a trial ongoing right now, where we treat FOLFIRINOX failures with gemcitabine plus Abraxane plus botensilimab. In this trial, we're not using balstilimab, it's botensilimab only. The results of that trial will also be available by the end of this year, and we will expand that trial, which will have a randomized arm, and once again, upon the results from that trial, that's a third pathway to BLA strategy. The fourth pathway would be melanoma. Again, that's going to be contingent on the results that we observe in our phase two trial.
Sure
...which is a randomized trial as well. So we've got, theoretically or practically, four different pathways... for BLA filing under the accelerated approval provision. And, but your indication of ovarian is something very interesting, of course, to pursue. The denominator is not as large, and once we get the denominator to be a respectable size, that would be another candidate for a BLA filing.
Gotcha. I guess for lung then, you know, the data that you'll present later this year, maybe can you tee that up a little bit more? And I guess, what are people—what are expectations? Obviously, the small N, 50% is very, you know, encouraging, but, you know, what do you really need to see in that population to really move the needle from a clinical relevance and clinical utility standpoint?
So you ask a very pointed question, Derek, and, I think, if you want to be less politically correct, the question would be, what on earth is wrong in the perception of investors who don't see the kind of value that we're talking about? And of course, that's a question to be asked to them. And, I don't know the answer other than the fact that they may be distracted with a whole bunch of things in a world where there are plenty of distractions. But if you ask the same question to KOLs and investigators, I think you will see the same level of enthusiasm, especially investigators that have hands-on experience with botensilimab. And these are investigators at major centers.
I'm talking about Dana-Farber, Beth Israel, Brigham, Sloan Kettering, places like MD Anderson, many of the European sites. People that have had experience with botensilimab think that this is a magical compound.
Gotcha. So do you think then that that rate will hold, or there, you know, as you include more patients, obviously the heterogeneity starts to play a role. So, like, do you think there's anything different that you'll see as you enroll more patients that could come across to, to impact the efficacy positively or negatively?
Sure. So I think, certainly, some of the additional data that we will disclose between now and year-end-
Yeah
... lung cancer being such a significant indication, pancreatic cancer, possibly, the neoadjuvant setting in colon cancer, that suggests not only end-stage patients benefit from botensilimab, but earlier-stage patients may benefit in the context of eliminating the need for surgery, debilitating surgery, and/or radiation therapy and chemotherapy, which for these patients, can also be debilitating. So as this data comes out between now and the end of the year, I think, I hope you will see a change in sentiment.
Gotcha. Okay, maybe shifting gears to, you know, 2373, your, your other program.
Sure.
Maybe just give a little bit of background about that. It's a CD137 antibody and just kind of, you know, again, maybe historical context around the target as well.
Sure. So CD137 is a very important target. It's a very important target. Among the things that it does is substantially enhance memory T cell response. I mean, when you talk about the immune system, the immune system is like an orchestra or a military system. You know, as much as we would like a magic bullet to do all the tricks, the immune system requires a host of its symphony players or many members of the military, if you will, to accomplish its task. So that's one of the reasons, many years ago, dating back to 2015, we made a deliberate decision that we needed to have all of these critical components that would comprise the immune system's ability to not just win a battle, but win the war.
And so in that context, we've developed many different agents, and CD137, which is a very important agent because it enhances memory T cell response, among other things, is one such molecule. Now, in addition to that, for example, we have an ILT2 molecule, which is also in the clinic. And beyond ILT2, we have in the hands of Bristol Myers, a TIGIT bispecific, which is progressing in the clinic very, very nicely. And, we have demonstrated that our TIGIT bispecific, which is also Fc- enhanced with a different sequence imparted into it, is also a superior molecule to some of the other TIGITs that are being worked at.
And in fact, if you look at the TIGIT landscape, there have been lots of disappointments, and, people are sort of trying to hang on to it with their fingernails. Hopefully, some good news will come about. But so far, the news has been, sort of lukewarm at best. And but we believe that our TIGIT molecule has a very, very, attractive prospect. So all of these things are going on, simultaneously. On one hand, we have BOT/BAL and BOT with chemotherapy in the case of pancreatic cancer, in multiple indications, each one of which could lead to a BLA filing. Okay, so that's on, in one basket. And on the other hand, we have multiple other molecules that, in combination with some of the other agents in our portfolio, can also be a significant driver of, success. CD137 being one of them.
... Got it. Can you talk about what you've seen so far from an efficacy standpoint in the phase 1, and I guess how you're thinking about, you know, ultimately, tumor selection and, and kind of, again, developing the development path there?
With CD137?
Yes. Yeah, yeah.
Sure. So we've done a dose escalation trial that was presented at ASCO this year, and in that dose escalation trial, we showed that with monotherapy, and dose escalation is always challenging because you're starting with a very low dose-
Yeah
going to presumably an optimal dose. With monotherapy use of our CD137, which is the AGEN2373, we've seen several responses in patients, which is very unusual.
Yeah.
And so now we're looking at not just combinations, but also combination protocols that stagger the use of these molecules, to optimize its performance. And so, very exciting program, and, much to talk about in the future as the results become available.
Got it. And I guess, is your thought to, like, combo this with, like, PD-1 or PD-1...? Again, what, what are you looking to kind of?
Yes, I mean, you know, you know, on one hand-
Yeah
We also have our MiNK subsidiary.
Sure.
We have our iNKT cells. These are-
Yeah
-native iNKT cells, unmodified, which have shown some phenomenal activity in the clinic so far, and we're expanding those trials as well, in combination with BOT-
Okay
... PD-1, in combination down the road with CD137 as well.
Got you. Okay.
And having, by the way, all of these things under one roof makes it very, very practical for us to do the kinds of combinations that are optimal for patient benefit. Whereas if you had to beg and borrow these reagents from others, it'd become difficult. So we're blessed in that regard.
That's fair. Maybe the last minute or two here, can you just walk us through kind of the rest of the year in terms of catalysts and some of your data updates for your programs? I know you have some things that you might be presenting at some medical meetings, but maybe just walk us through that so we know when it's coming.
Sure. So, as you know, at ESMO, we've been accepted for an oral presentation for our sarcoma trial. We didn't talk much about sarcoma, but that's a very cold tumor, a very challenging tumor, a very heterogeneous disease.
Yeah.
And we've seen some very, very, stark benefits, positive benefits in patients that have been treated with botensilimab balstilimab in that disease. And of course, we will be combining these treatment protocols with other things in our portfolio as well. So, sarcoma will be presented at ESMO, coming up in late October, and we're likely to present either a basket of trial outcomes that have not yet been presented, they're not public yet, between now and the end of the year-
Okay
... either in a basket form of discussing multiple indications and the outcomes or specific forms that are coming up. So.
Got it. All right, great. Well, Garo, thanks so much for joining us. I think we'll leave it there.
Thank you very much, Derek, and thank you and the audience for being here.