All right. Hello, everyone. Thank you all for joining. My name is Matt Phipps. I'm a biotech analyst here at William Blair. I do have to first point you all to williamblair.com for a list of disclosures. I'm happy today to have both management from Agenus and Dr. David O'Malley, a Professor in the Department of Obstetrics and Gynecology at The Ohio State University, to discuss the really important results presented over the weekend at ESMO, combining the PD-1 plus CTLA-4 inhibitor bal-zal combo, monotherapy and combo in second-line cervical cancer. Today, we'll review the data, go over some questions, both specifically about the data and how this combination could fit into the cervical landscape. Also talk about a couple of the other key things being studied in this tumor type, and then finish up with more of a corporate look at what's going on.
We do have Dhan Chand here as well, head of drug discovery at Agenus, to chime in for some of that later Q&A. Dr. O'Malley, I was wondering if we could kick it off just by giving a high-level overview and maybe just your overall opinions of the data set.
Thanks, Matt. Pleasure to be here today. I really appreciate you taking the time to introduce us and the exciting results with regards to these two independent phase II trials. I think it's important to think about. Overall, we need better options for recurrent cervical cancer patients. The current landscape, as we all know, the checkpoint inhibitor pembrolizumab was approved for a 14.5% response rate in PD-L1 positive tumors. Obviously looking for more options for these patients, as they really don't have anything beyond the first-line therapy. First-line therapy is considered a platinum doublet with bevacizumab or Avastin. I'll refer to bevacizumab as bev throughout this talk, because if I say bevacizumab too much, I sound like an idiot. We'll do that, and really beyond that triplet and what we consider the GOG 240 regimen, there's really not any options for our patients.
Pembrolizumab was approved on a small subset of patients, accelerated approval for this, as I said, 14.5% response rate. This trial is really looking at that recurrent cervical cancer patient population. I'm happy to go through some of the slides if you like.
Great. I think, there's obviously going to be comparisons amongst the data sets that are initially made. You have similar drugs with overall similar results, but some slight differences. I guess one of the biggest things that jumped out was the ability of balstilimab did get some responses in PD-L1 negative patients, which wasn't seen in the cohort of KEYNOTE-158. That's why KEYTRUDA only got a label in PD-L1 positive patients. I guess, Dr. O'Malley, do you think that this is enough of an effect that was shown in PD-L1 negatives to warrant a broader label for balstilimab?
I think the option is definitely there. Obviously, the precedent for PD-L1 positive, and we know that the KEYNOTE-158, 0 responses in those, I think 17 patients that were PD-L1 negative. To see this 8%-10% response rate in patients who were PD-L1 negative, I think it offers some hope that, though it's modest, that there may be a pathway for regulatory approval moving forward. Obviously, as you know, that will ultimately be a review question. There's definitely option here since we saw a 0% response rate in the KEYNOTE-158.
Yeah. Okay. I guess the other difference being that this separate study also looked at the combination with the CTLA-4 inhibitor, zalifrelimab, and not surprisingly, I think showed an increase in overall response rate, similar to what Opdivo and Yervoy had showed. I was actually a little surprised that the response was seen to be really more driving better responses in the PD-L1 positive patients, maybe deep responses there, because they showed similar response rates in the PD-L1 negative patient population. I guess, was that surprising to you, or is that what you might thought happened based on the Opdivo plus Yervoy results?
It's interesting. I think as we're seeing these biomarker negative patients and still seeing the responses, can we make these cold tumors hot with the addition of CTLA-4? I'm not sure that's there. What we do see is the duration of responses with the combination. A marked difference in the overall response rate, I wasn't that surprised. Ultimately, the duration response and drivers in this select group of patients, or the biomarker-negative patients, I think is an opportunity again. We see this in both the single agent, where we did see a duration response reach, which is an important differentiation that we had two months longer follow-up than the KEYNOTE-158. Many people had asked me that previously. Well, they didn't see their duration response.
In those two additional months where you actually see now up to 15 months in the combination, we don't see that duration response reach in a similar follow-up. Really, when we look at the combination, I suspect we'll continue this response rate is not going to get worse, right? We know with immune therapies that we can have some late responders. Will we see that improve? I'm not sure we'll see it a marked improvement, but definitely the duration, and we see these patients potentially cured, and that's a really important differentiation. If we see the cure rate go from 2%-6%, that's the difference between cytotoxic agents and immune therapy. A complete response in cytotoxic agent is not going to be curative. A complete response in a immune therapy may be curative.
Unheard of in previous experiences in cervical cancer, that you'd have a cure in recurrent setting. Though modest at 6% in our bal-zal trial. If we have an option to cure one out of 20 patients, that's going to be pretty exciting to the practitioners who are prescribing the option for the combination.
Absolutely. On some of that talk of continuing to follow this over time, I guess just in general, do you have an idea, either you or Jen, how many patients remain on therapy at this point? Potential to get deeper responses over time and continue to increase that duration of response. Just in ballpark.
Jen, do you have those numbers on where we are on those who are still on therapy? I can't remember off the top of my head. You're muted.
Having a
All right.
Can you hear me?
Yeah, now we can hear you.
For the bal monotherapy, we have 47 patients who remain on therapy, and for the combination, 53.
Oh, wow. Okay.
Good number. Yeah.
number of patients remain on treatment for both of those. That's great.
Yeah, over a third.
Yeah.
Yeah, that's impressive. One question that's come up is, does prior Avast and prior bev, as you also refer to it, make a difference here? Have you been able to tease that out for these drugs and I guess other combinations going forward? Do you think that'll play a role?
Yeah. That's a really interesting question. One of the little aspects of the KEYNOTE-158, which was not discussed much, is that only two of the responders had had prior BEV. When you think about that, it is something that has not been looked at more closely by the regulatory agencies, but we have an opportunity to educate them with regards to we are receiving responders in BEV prior treated. I think the final manuscript will attest to that. Obviously, that's not publicly available right now, but that is something that will be further described. Now it is important to say that we also will have that broken down in BEV prior treatment. The other interesting part is this, on the KEYNOTE-158, the pembrolizumab approval was the emphasis on the squamous cell patients.
I think that's really important because those are going to be a higher chance. I think that was one of the questions, Matt. Those are going to have a higher chance to be PD-L1 positive. We're seeing those responses across, and really when you look at the squamous cell population, it's really interesting data to see the marked response rate in using squamous cell as a biomarker, which is probably a better biomarker than PD-L1 status. We know the regulatory agencies love the non-histology biomarkers.
Yeah. No, that's interesting. I was wondering that. Okay. I would like to touch on the tolerability of the combination. Not surprisingly, you do see a few increases in AEs, mainly around lab abnormalities and endocrine disorders. Overall, I would say it appears tolerable, but I appreciate your opinion on that. Also there's been this viewpoint, especially in the community setting, where PD-1 plus CTLA-4 is too toxic. I think that's been driven by the melanoma experience, which is obviously the first one and used the high dose of Ipi. To me, going forward, it's been much more manageable. Obviously, physicians we've talked to have gotten more used to it. I guess first, two questions there.
One, just talk about the combo in this study specifically, then more broadly, do you think it can be viewed in a new light as opposed to just getting bucketed under the old Ipi toxicity basket.
I didn't mean to cut you off there. Sorry. The most important differentiation here is the high dose Ipi versus the low dose. When we are looking at the design of this trial and future designs moving forward, the toxicity and the tolerance of the high dose versus, I shouldn't call it the low dose, but the more chronic dose I would call it, is an important differentiator in the tolerability. Look at the older nivolumab Ipi from the melanoma, you just see an extremely high rate of colitis as well as other immune-associated toxicities. When we're balancing which dosing to use and how to move forward, obviously the efficacy was a main characterization. Also as we look at the safety, particularly in these patients in cervix cancer, who are often challenging patients to treat from a toxicity standpoint. The majority of them have had radiation.
They've had at least one line of chemotherapy, if not more. The tolerance is really important as we look at this. Now, the combination clearly will have more toxicities, and that ultimately will need to be balanced with the patient sitting in front of the practitioner. I think with the information we have here, having both a accelerated approval for the single agent bal as well as combination of bal and zal, allowing practitioners and allowing patients to make that decision based on a slightly increased risk of side effects, right, versus an increased ability for curative intent, longer duration of response, and balancing those two things will be important ultimately in the marketplace. How many patients will get started on bal versus bal-zal?
I'm not sure I can make that prediction, clearly having both drugs in the marketplace, feeling comfortable dropping one of them, zal, if we start having toxicities. Clearly, we have to continue to educate the community about these toxicities and that they are manageable by far the majority. When I counsel patients, I usually counsel 30%-40% chance of immune-associated toxicities. Of those, 5%-10% will require hospitalization. Of those, about 1%-2% could be life-threatening or life-altering. We definitely don't see any difference in these across both of these trials.
That makes sense. Yeah, you really did touch on this right then. Okay, these agents are out there, and you have a new patient that just had recurrent disease. What are you going to look at from that patient to make a decision what to start them with, whether it's monotherapy or combo? We'll get in a second to maybe some of the other options, but first specifically bal-zal.
Well, I'm glad you're giving me the break and letting me start with bal versus bal-zal and not throwing in the competition yet. I think we're seeing extremely changing landscape in the treatment of cervical cancer, and it's going to continue to change significantly over the next three to 10 years. There will be options there. I think some of it will be obviously prior treatments. We're seeing more and more checkpoint inhibitors in the upfront setting. They previously have received a checkpoint inhibitor, then obviously single agent, then we'd go to combination, and we'll look to move forward in getting more data in that in the future. In a patient who is young, healthy, and wants a one out of 20 chance for I don't want to be too dramatic here. I want to be fair to the data.
Again, complete responses in immune-associated therapies offers an option for curative intent. When you're talking about this, about the toxicity versus the efficacy, I suspect more patients will be started with the bal-zal, and then drop the zal if the toxicity is evident. There may be people out there who say if they haven't had previous immune therapy, I'll start with the bal. I'll see how they do for the first couple of cycles, and then add zal. It's usually not the way we do it because we like to get the response earlier on, but I think both options are viable.
You brought up another part of that is there are frontline trials ongoing that are looking at, it's mainly PD-1 plus chemo radiation, I believe. Correct me if I'm wrong there, but that's mainly what's being looked at as a frontline option.
Well, as well as advanced recurrent.
Right
combine it with chemotherapy.
Yeah. I guess if a patient gets treated in one of those studies and then obviously doesn't have response or loses that response, you would be willing to say, "Okay, well, we'll try them now with PD-1 versus CTLA-4," even though they got that PD-1 plus chemo, right?
I think right now, there would be no data to hinder me from doing that. Obviously, what the approval will look like and what we can do is the question. Obviously, we'd like to see more data in the future. As we design the confirmatory trial, as we move forward, looking to see what options are available, you know that we already have RaPiDS enrolling, which is a randomized phase II looking at balstilimab versus balstilimab/zalifrelimab in a placebo-controlled trial. That is really to add to the phase II data to assure we have enough patients in these subgroups to justify moving forward an accelerated approval with the final data set. That is not the confirmatory trial. I think that's very important.
In the current time, we're moving forward with how can we bring these agents to the marketplace, both for our patients in recurrent setting. Is there an option elsewhere too?
Not surprisingly, questions coming in about data that was just presented not too long ago with the tissue factor antibody drug conjugate.
Yeah.
With tisotumab vedotin.
Yeah. Nice. I call it TV. Rob Coleman just presented that data, and I had been in my phase I clinic here. I was not a co-author on that paper, so I'm just seeing the final data as we came into this meeting here today. I think TV efficacy looks similar. Similar patient population, treated again about 100 patients. In this reporting was the phase II. What's interesting there is a similar complete response rate, I think it was 7% in what he presented. That's why I made the point at the very beginning, when we're talking about cytotox or antibody-drug conjugates, complete response rate really has not been associated with potentially curative intent. I think it's a pretty important differentiator. What's the most important differentiator?
Listen, TV is a good drug, man, and I'm moving forward and participating in those clinical trials, and I would love to see that drug also in the marketplace. As I look at ultimately what's available in the recurrent cervix cancer, there are some challenges to the toxicity profile, with particularly for neuropathy and the inflammation of the conjunctiva can always be a challenge. I think you need to look at that. Obviously, with regards to some of the bleeding issues, which I think are not that worrisome. Yet, again, if you have a patient who's already having some issues with a central tumor in the cervix, that can also come into play.
I'd love to see all three of these drugs be in the marketplace, and ultimately how we prioritize the treatment of those and where those are used will just be helpful to our patients. I think as we see more options available, we're going to see better outcomes and more opportunities for patients to get more lines of therapy. Right now, we just beat them to death. That's a terrible term. I apologize. We really are utilizing chemotherapy and just keep giving and keep giving and keep giving. I think sometimes the chemotherapy toxicity can be worse than the disease. After that, trying to get any additional therapy is really a challenge. In the future, we're going to be able to change that paradigm, and these patients will see three, four, five, six agents. Like now they only see one, maybe two.
Right. One question. I don't know if you saw this specific tidbit, but I guess there was a difference, again, in the TV data for whether or not a patient had prior Avastin.
Yeah.
Just kind of interesting here now seeing this, I guess, multiplied. Would that impact, I guess, how you sequence therapies based on whether there's somebody that had Avastin upfront, bev?
Well, I want to make sure I'm saying what's publicly available because I have some other information. I just am flipping over here and looking at what's publicly available.
I think there was a 32% response rate in Avastin naive versus 19% in Avastin extended.
Yeah.
If I'm looking at the right thing.
Thank you. I just wanted to make sure what I was stating was publicly available because, as I said, I participate in clinical trials for both of these, or all three of these agents. Clearly, there's a difference between Bev pretreated here in those patients. I'm not sure that's completely explained by the mechanism of action, the mechanism, but also how to deliver it with the antibody-drug conjugate. I think we need to continue to look at that in the immune therapy. It's probably not as marked of a difference, but yet seeing that in the pembrolizumab data, you could argue that the responses were not nearly as wide in the Bev pretreated. Another data which is maturing. As we move forward, we'll have that answer, especially in the combination and the single agent.
Yeah. Okay, Dr. O'Malley, another therapy that gets brought up a lot, and just get your opinion on that, is the tumor-infiltrating lymphocytes.
Yeah
the process of harvesting and stripping them off, having them kind of reinvigorated and grown back up and then chipped back. I mean, amazing response rates data and also kind of seems to show that durability of immunotherapy, but I'm sure a little bit laborious and burdensome to get. I guess just your thoughts on that and where that would fit in with some of the other agents that are kind of getting close.
The problem with it's a pretty limited group of patients which are going to be able to undergo that therapy. You need to have a slowing enough progressing tumor to wait for the six to eight weeks process as you go through. You have to have a tumor that's clean that you can resect and send off. A patient with a central cervix tumor can't be used. A patient that has tumor on the bowel cannot be used. You have to have the right patient that you can harvest the tumors. Again, a very exciting option for our patients, but it's going to be a much more limited population. I already talked about how our patients are really compromised from the amount of chemotherapy they receive and the prior radiation, as well as patients with a lot of comorbidities.
To undergo lymphodepletion and then the dosing the IL-2 takes a unique patient population and group of patients. The safety on that obviously is a challenge. The patient selection is obviously a challenge. I hope we have all the technologies available to us for our patients. This would be a smaller patient population.
Dr. O'Malley, you get the option to run a frontline trial with no regards for corporate incentives. We talked about there are the PD-1 chemos ongoing. To my knowledge, there's not a frontline PD-1 CTLA-4 ongoing. Obviously maybe looking at some of the TV plus the PD-1 could be interesting. What do you think you would want to try to kind of deliver the best chance of long-term duration of response to patients?
Yeah. Great question, Matt. How are we going to cure more people if we don't cure them? How are we going to improve their quality of life? You just heard me say the option of chemotherapy and continued chemotherapy. I think we need to look at can we replace chemotherapy? That's an extremely high regulatory approval to take on platinum taxane Bev versus an immunotherapy, and probably not the design of the trial that is going to ever occur because of the bar that's set by that triplet combination. Ultimately, having patients be cured with advanced recurrent, and probably most importantly, we have a lot more patients with local regional disease, which have as high as a 50% recurrence rate with treatment of chemoradiation. I'd really like to see us improve upon that.
I think the option of single-agent checkpoint inhibitor, in this case, PD-1, is already being done, as you know. Looking at the option to bring combination therapy, can we do a better job of curing more patients? On that same note, can we do a better job of curing more patients with combination immune therapy in the advanced recurrent metastatic first line? I think those are two great options that we continue to look at in our design moving forward.
Great. I think just one more question that I get is, okay, KEYTRUDA is approved, second-line for PD-L1 positive patients alone, used pretty ubiquitously across a lot of other tumor types now, so just very familiar with that. You have a new PD-1 drug that comes in. I guess on the one hand, physicians often do follow labels, especially more in the community setting. That could drive which one they reach for. Also maybe they just bucket in PD-1s as PD-1s. I guess, what do you think is going to be things that'll influence which drug on the shelf a physician reaches for, particularly if you're, I guess, looking mainly just at pembrolizumab versus bal or the bal-zal combo, I guess.
Yeah. The PD-1 inhibitors are more similar than they are different from a probably efficacy and tolerance standpoint. Can you guys still hear me?
Yep.
Okay.
Yeah.
Sorry, I'm getting. What do we really look at? When I set out in this adventure working with Agenus and the team there, I want to applaud them. We really challenged each other to say, "How are we going to do better, and do we want just a me-too drug?" That wasn't the goals here of Agenus, and it sure wasn't my goal. As we look to say, where are we from a single-agent standpoint, absolutely do I want that option, absolutely do I want to potentially expand and label to include adenocarcinomas, to include PD-L1 negative. I hope we get that. Ultimately, we'll see. The combination is really where are we going to make a difference in the treatment of these patients with recurrent cervix cancer is the combination, and that is not going to happen with pembro.
We haven't seen BMS pursuing approval, which was surprising to many of us, and I haven't heard any plans for that to move forward, nor is publicly available, at least.
Okay, great. I think with that, I would like to bring in Dhan and Jen to get some next steps and talk about where the company wants to go from here. Congrats also, by the way, of initiating that rolling submission of the BLA. That's really exciting for bal. I guess, just any high-level thoughts, Jen, on how long will that process take, do you think? If there's other things that need to be really completed, and then particularly the next steps for the combination.
Excellent. Thanks, Matt, and thank you again for joining Dr. O'Malley. Great presentation this weekend. What's next? First thing, of course, would be to fully publish these data. Dave did a fantastic job in presenting the data to date. We're in the process of preparing a manuscript of the information. The BLA submission is already being initiated. We've initiated the submission with some of the components already submitted. As you can recall, we received Fast Track designation for these agents, which makes us eligible for priority review. With our filings planned to be fully submitted this year, we would expect to have a decision by, the latest would be mid-year next year. balstilimab monotherapy will be the first submission in, and we are planning to nearly immediately, if not in parallel, get the combination in.
Great. Actually, I want to take one other question that I think will involve Dr. O'Malley, if I may.
Yeah.
I know you're part of the NCCN guidelines or committees.
Yeah.
Also while you're going through this process of that, how are you working on talking to the societies and making sure this data, I guess, gets in front of the people it needs to get in front to get into guidelines and such inclusion there?
Well, as you know, Matt, that the NCCN guidelines, unless a drug's approved in the marketplace, they're not going to include it. If it's included in another disease site, would that be an option? Potentially. I sit on the ovarian cancer guidelines. I do not sit in the cervix nor the uterine. The precedent for us is obviously, usually it has to be a large in ovary, I can't attest to cervix, but across the NCCN guidelines, it has to be a well-powered phase II to garner a compendium listing. That bar, because the number of trials being done seems to be raising a little bit more in the future. I wouldn't expect a compendium listing or NCCN guideline listing unless a drug is approved in the marketplace.
With regards to how do we get this out, well, I think that ESMO, IGCS, SGO, ASCO all being remote has been a challenge. We continue to find ways to disseminate and discuss this as we're doing a Zoom call here today. We're also working, I've put Agenus in contact with our CME groups to make sure that they're working with education with regards to recurrent cervix cancer, and we have this information out as a thought leader in the immune oncology space in GYN cancers, and as part of the GOG Partners mechanism. Much of our emphasis is placed on educating the other GYN oncologists and medical oncologists who treat cervix cancers across the U.S. and across the world involvement in these societies. We continue to look for ways to better educate during these challenging times.
Sure. I guess, Jen, on your side of things, how are you helping Dr. O'Malley here, and I guess how are you thinking about approaching the market, sizing that infrastructure appropriately to help get this out there?
Maybe just by way of just recognizing that these trials move from phase I in multiple solid tumors, generating data across a number of different tumors, including complete responses in angiosarcoma, very lengthy durable responses in ovarian, and then we expanded into the cervical cancer. All of those data are being prepared or have been presented at conferences, or published under different mechanisms. We've already started speaking through our contacts with the NCCN about the requirements and eligibility of these programs. Based on the size and scope of the trial and the conduct of the trial and the rigor of the data and the independent review, we meet the requirements for NCCN issuance. Of course, that will require a couple of things that are still pending, such as the publication in cervical cancer, which will be our first priority.
The submission and approval, Dave's right, we will need the requisite approvals for submission in cervical cancer. There are some other tumors for which we have some data, generated some data, that may be more rare than cervical, that we could be eligible for expanded NCCN inclusion, and that being tumors like angiosarcoma. We have a series of tumors that we will be planning to approach NCCN with, cervical being our highest priority, and the planning being to make sure that we line up all of the data and the publications and submissions in parallel. At the time of approval, we would hope to be included in the guidelines at that time.
Great. Jen, I guess just on a broader view and a longer view, how do you kind of balance further development of the bal-zal combo in other tumor types, or maybe other pipeline combinations, versus kind of pushing forward with 1181 and kind of replacing zal? Not to say it needs to be replaced, I think we're both pretty excited about 1181. Dr. O'Malley, I don't know if you want to get your hands on 1181 cervical as well, if you're familiar with that, the next gen CTLA-4. Just how are you thinking about that, Jen, as far as you've got to pick where to start these trials and can't necessarily do all of them, right?
Well, that's right. I think part of this is AGEN1181 is telling us where to go already. With respect to bal-zal, these are mature assets now with a significant and a robust safety database and an opportunity really to be second to market, maybe first to market in cervical possibly, and second to market in a number of indications. As we've spoken about previously, Matt, we could be second to market in some relatively large indications, even pursuing 5% or 10% of the market in tumors like lung, melanoma, RCC, for a significant upside for us. We're talking about $700 million to about $1 billion in revenue, which would be very meaningful for a company of our size, right? We're quite efficient. I would say that's an important piece.
Effectively, these agents are so far along that we have a big opportunity to take advantage of some of those markets now. The AGEN1181, we look forward to presenting some additional data at a medical conference this year. I'm really excited about how the data continue to evolve. We've presented early data, 1 mg per kg monotherapy CTLA-4, showing complete responses in microsatellite stable, so very difficult to treat tumors previously known to be unresponsive to IO agents, and we're seeing activity. We've now expanded our profile of clinical benefit in a number of different solid tumors that we're pursuing. Now, what we've looked to do, there are a few paths here. We are seeing activity in patients who are homozygous for the CD16 allele polymorphism, which is very important. These tumors are unresponsive to anything available.
While we continue to keep our trials open to all allele status patients, homozygous and heterozygous, we are expanding and enriching in tumors such as colorectal, microsatellite stable, endometrial, as well as in tumors like lung and melanoma. We will be telling you more as we share some of the data that will be coming out later at a medical conference. We'll be sharing a summary of where we'll be taking these agents with you. Stay tuned. It won't be very long, but we have a pretty exciting plan to talk to the markets about.
Matt, you're killing me, man. We're this close. You're trying to get me to switch and use AGEN1181? I mean, come on. I applaud Agenus. Their pipeline is quite impressive and actually the opportunity to partner with them moving forward with their pipeline and the options which are quite limited in other pharma partners that I work with. Having this option for our first generation PD-1 and CTLA-4 inhibitor, getting it to the marketplace, getting approval, and utilizing that as the stepping stone into further indications with the new agents is exactly where they should be. We look forward to continued exciting data from the next generation of CTLA-4 in these immune therapies.
Dave, you are absolutely right. I think that when we look at our pipeline right now, we have eight programs in the clinic, right? It's so critical that we get these over the finish line. bal, plus or minus bal, are going to be the foundation for everything else that we do. AGEN1181, AGEN1223, AGEN2373. Ideally what we'd like to do is to give all of our compounds to Dr. O'Malley. Every time a patient walks in to see him, he has something for them, right? That's the complete solution. That's what we want. We never want him to say, "What protocols do I have access to?" We want him to be able to drive that treatment decision, having all of these options at his fingertips. The base of this all will be bal bal, looking forward to getting those two to the finish line.
Well, I think that's a great transition to talking about a few of those, here in the last couple minutes, that you just mentioned. Dhan, I am going to bring you on now. I think, if you don't mind, first, there was some data over the weekend about targeting TIGIT from Merck. You guys are obviously right on the cusp here of getting your own TIGIT molecules, and you have two of them. I guess over the past six months now we've seen, not even six months, we've seen data from Roche and Merck that have generated some polarizing opinions on, is TIGIT a real target? Is it just a little bit of a step? Is it really going to be anything beyond high PD-L1 expressing non-small cell lung cancer?
Not to say that's not a important opportunity, but curious to, Dhan, what your opinions are and how you guys are thinking about the next steps with your own molecules.
Matt, thank you for that question. I take it you can hear me well? Good. Well, I would say that we remain very encouraged by the data coming from Merck and from Roche. I would say there's three things to note here. The first is that both Roche and Merck are showing that adding a TIGIT on top of PD-1 is expanding responses. In the case of Merck's PD-1 naive population, you're seeing evidence of deeper responses with TIGIT therapy. Yes, it is incremental. We've articulated many times why that would be the case. We demonstrated pre-clinically that these current generation of TIGIT molecules are not optimally designed to really target TIGIT. Now, we like TIGIT as a target. I think many people do because we recognize the importance of TIGIT.
In fact, you have to go all the way back to PD-1 and CTLA-4 to see the first IO plus IO combination. Outside of PD-1 plus CTLA-4, there's no other IO plus IO that's really starting to emerge as a validated approach other than perhaps TIGIT plus PD-1. We've stated very early on that TIGIT's an ideal combination partner for PD-1, but you need the right TIGIT molecule. We've published on the importance of FC. You'd recall from our presentation at AACR last year how our FC engineering approach gives you monotherapy activity, which is not something you see with the current generation of TIGIT molecules, both preclinically and now clinically, but also better combination activity. That's a very important point to make, that the clinical data is encouraging, but like what we've seen preclinically, we're starting to see the same thing clinically. It's not optimal. Right?
Lastly, as you're aware, at R&D Day, we mentioned that we're pursuing a TIGIT bispecific as well. We haven't disclosed what that second arm is, but we have articulated that it addresses a major or potential relapse or resistance mechanism to TIGIT therapy, and we are seeing in our pre-clinical data responses in PD-1 refractory models. That's what we've shared with you last time we spoke about this. I would say that while the data is very encouraging, it certainly bolsters our position in TIGIT therapy and we remain very encouraged by that data and of course, enthusiastic with moving our TIGIT therapies to the clinic. We believe we have a better designed molecule to address the limitations of the current generation of TIGIT antibodies.
Thanks, Dhan. I guess then just based on what you've seen, has that kind of influenced your initial clinical trial designs? Obviously that'd be dose escalation, but will you really focus on moving quickly to that combo in PD-L1 positive tumors, or you guys have thoughts on maybe other places that you can make it work?
Yeah, I think it's pretty interesting that there's a lot of focus on PD-L1 positive tumors. Not a lot of talk about TIGIT positivity or PVR positivity. Part of that could just be limitations of the tools available. As you know, when we advance our drugs to the clinic, we take a very laser-focused approach to measuring potential biomarkers, both that are predictive of response, but also indicative of activity of the drug. I think we have definitely an approach that would not only be complementary to what others are doing, but also unique to help identify the right patients for TIGIT therapy, but also identify the right combinations. I think TIGIT PD-1 is definitely a goal. There's a lot of literature showing TIGIT plus PD-1 co-expression, the clinical data supporting the combo. bal, you spoke earlier about where do you take bal next.
Well, as Jen mentioned, bal's going to be a cornerstone going forward. TIGIT is definitely going to be one of those therapies we add to bal. We also have zalifrelimab, we have 1181, right? That's another way we can differentiate as we advance our TIGIT therapy on top of having what we believe is the best-in-class molecule.
Thanks, Dhan. I appreciate that response. The other interesting thing at ESMO, from an earlier clinical standpoint, is some of the 4-1BB tumor-localized, 4-1BB targets. We saw Pieris and Roche both had updates, one HER2, one FAP. I think some interesting work. One, I do think they've shown that they can get over some of the toxicity that urelumab showed and showing signs of activation. Pieris showed a lot about serum 4-1BB, as well as increases in T cells in the tumor. I know you guys are in the clinics with 2373, which is not a tumor-specific 4-1BB activator.
I know it's partnered with Gilead, so I know there's not too much you can say, but curious just what you think about the data that was showed over the weekend and how that might influence 2373 next steps or how you're thinking about what to combine that with or anything like that.
Yeah. Matt, you correctly stated that these bispecifics are designed to be tumor-specific because they have a tumor antigen as the second arm. I would like to highlight, though, that AGEN2373 is designed to avoid peripheral activation and activation in the tumor microenvironment. One thing to point out here is that I think the idea of targeting CD137 or 4-1BB has been shown many times over, both in the cell therapy space and most recently now with these newer approaches. The goal is really to get activity in the tumor. These bispecifics, while they are designed to address safety, they're limited to just tumors that express that particular antigen.
Yeah.
Right? Whereas agent AGEN2373 does not have that problem. We designed the molecule to be active in the tumor, irrespective of whatever tumor antigen that they present. While you know that immune editing is a real concern and what do you give patients who need CD137 but no longer express HER2 or no longer express that, right? This is where AGEN2373 really shines, is because the molecule is Fc engineered to only be active or only be agonist to 4-1BB in the context of the right immune cells presence in tumor microenvironment. We're not limited in terms of indications, and we think that we still have a better molecule compared to the bispecific approach with respect to broadening the reach of 4-1BB. In terms of the soluble 4-1BB, I think the jury is still out on whether or not that could be a biomarker to predict those.
From the Pfizer study, they demonstrated 4-1BB based on immune activation. It's a well-known activation marker, but there's not really dose response to it and correlating with response. I think that the jury's still out there.
All right. Thanks, Dhan. Well, Jen, maybe I'll turn it over to you to wrap things up. I guess, just to summarize here, you hit all the marks for the data presentation this weekend. Started the rolling submission already for the mono, talked about soon to come for the combo, as well as a publication. Really getting all the pieces together to show the totality of the data here that will get you that first indication and then broadening out from there. I guess anything else you want to touch on or Dr. O'Malley as well, if you have any things worth wrapping up with. Otherwise, I think I'm out of questions.
I'll ask Dr. O'Malley if he has anything else that he wants to say, and then I'm happy to close out the call.
Yeah, I think I'm honored to talk about this exciting data. It's obviously a step in the right direction for ultimately gaining access for both these agents for our patients. We're going to continue to look for ways, and more to come on that, with regards to offering them to a greater group of patients and increasing the chances of curative intent in many of these hard-to-treat patients. Really, thank you for all of you attending. Matt, thank you for being a great moderator, and appreciate Jen and Dhan and their insight today. Thank you.
Thank you very much, Dave and Matt. Thanks very much for the call, and of course, a tremendous thanks to all of our patients who have participated in these trials. Dave mentioned this earlier, cervical cancer is a very underserved tumor. There have been very few treatment options that have come forward. The data that we presented at ESMO present a few different options, right? One, broadening the patients who can benefit from a PD-1 inhibitor. Then also potentially doubling response rates, specifically in certain histology groups like the largest histology that we see, squamous cell carcinoma. That combination with balstilimab and zalifrelimab represents some very meaningful potential best-in-class treatment benefit to patients. We're really looking forward to getting those into the market as quickly as practical.
Dhan mentioned a few options with respect to our portfolio, our pipeline, the differentiation of some of the novel therapies. I think an important piece to remember about Agenus' portfolio is we have all of these agents in our own hands. It gives us enormous flexibility to continue to deliver responses to patients over time. We can participate in their journey, ideally expanding the number of patients who can be cured. If we don't hit those cures, we continue to give them treatment options. That's what we're designed to do, and we have a pipeline and a number of programs. Eight of these assets that we've discovered are in the clinic in our own hands, and seven additional are in our partners' hands, and some of those data you also saw at ESMO. Merck presented data on MK-4830.
That's a molecule that we discovered addressing myeloid biology and ILT4 mechanism. There are a number of other discoveries like that that we've partnered with to really expand our opportunity to broaden the reach to patients. I wanted to just end on that note, Matt, and thank you again for the opportunity to speak with you today.
Thank you all so much. Thanks again. Thanks for bringing up the ILT4 antibody. I can't believe I forgot about that. Yeah, Merck showed some interesting data there, too.
Yeah.
All good things. Dr. O'Malley, thank you very much for taking the time out of your day to go over those results, and Jen and Dhan, I appreciate it again, as always, and look forward to seeing more.
Excellent. Thank you, Matt.
Thanks, everybody. Bye.