Agenus Inc. (AGEN) Earnings Call Transcript & Summary

So Dr. O'Malley, now to your -- you get the option to run a frontline trial with no regards for corporate incentives. Yes, we talked about there are the PD-1 chemos ongoing. To my knowledge, there's not a frontline PD-1/CTLA-4 ongoing. And then obviously, maybe looking at some of the TV plus 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?

Yes. 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? And you just heard me say the option of chemotherapy and continued chemotherapy. So 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 immune therapy, 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 but ultimately having patients be cured with advanced recurrent. And probably most importantly, we have a lot more patients with local regional disease which are -- have as high as a 50% recurrence rate with treatment of chemoradiation. So I 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. But looking at the option to bring combination therapy, can we do a better job of curing more patients? And then 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 2 great options that we continue to look at in our design of our -- and moving forward.

Great. I think just one more question that I get is, okay, KEYTRUDA is approved second line for PD-1-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, yes, especially more in the commune setting, and so that could kind of drive which one they reach for. But also, maybe they just kind of bucket in PD-1s as PD-1s. And so I guess what do you think is going to be kind of things that will influence which drug on the shelf a physician reaches for particularly if you're, I guess, looking mainly just at pembro versus bal or the bal/zal combo, I guess?

Yes. So the PD-1 inhibitors are more similar than they are different from an efficacy and tolerance standpoint. But what do we -- can you guys still hear me?

Yes.

Okay. Sorry, I'm getting -- so 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? And that wasn't the goals here of Agenus, and it sure wasn't my goal. So 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 the label to include adenocarcinomas, to include PD-L1 negative? I hope we get that. We ultimately will see. But 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 there's been -- I haven't heard any plans for that to move forward, nor is publicly available at least.

Okay. Great. So I think with that, I would like to bring in Dhan and Jen to kind of get some steps -- next steps and talk about where the company wants to go from here. So congrats also, by the way, of initiating that rolling submission of the BLA. That's really exciting for bal. And I guess just any high-level thoughts, Jen, on how long will that process take, do you think, and kind of 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. So what's next? First thing, of course, would be to fully publish these data. So Dave did a fantastic job in presenting the data to date where we've already prepared -- 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. So with our filings planned to be fully submitted this year, we would expect to be -- have a decision by -- the latest would be midyear next year. So balstilimab monotherapy will be the first submission in. And we are planning to nearly immediately, if not in parallel, get the combination in.

Great. And actually, I want to take one other question that I think will involve Dr. O'Malley, if I may. I know you're kind of part of the NCCN Guidelines or committees.

Yes.

And so 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, to get into guidelines and such inclusion there?

Well, as you know, Matt, that the NCCN Guidelines, unless the drug is approved in the marketplace, they're not going to include it. So 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. So 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 of the number of trials being done, seems to be raising a little bit more in the future. But 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 the 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. Yes, 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 immuno-oncology space in GYN cancers and as part of the GOG Partners mechanism. We -- that's -- 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. So we continue to look for ways to better educate during these challenging times.

Sure. And so 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 in sizing that infrastructure appropriately to help get this out there?

So Matt, 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. So 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. And based on the size and scope of the trial and the conduct of the trial, 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 dates right, we will need the required -- 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. So 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, so 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 and other tumor types or maybe other pipeline combination versus kind of pushing forward with 1181 and kind of replacing bal. Not to say it needs to be replaced, but 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 in cervical as well, if you're familiar with that, the next-gen CTLA-4. But just how are you thinking about that, Jen, as far as you got to pick where to start with these trials and can't necessarily do all of them, right?

Well, that's right. I think part of this is 1181 is telling us where to go already, so with respect 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. And 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. And we're talking about $700 million to about $1 billion in revenue, which would be very meaningful for company our size, right? We're quite efficient. So I would say that's an important piece. These trials are -- effectively, these agents are so far along that we have a big opportunity to take advantage of some of those markets now. The 1181, it is -- 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 and microsatellite stable, so very difficult to treat tumors previously known to be unresponsive to I-O 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 opening -- keep our trials open to all allele-status patients, right, homozygous and heterozygous, we are expanding and enriching in tumors such as colorectal, microsatellite stable, endometrial as well as in tumors like lung 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. So stay tuned. It won't be very long, but we have a pretty exciting plan to talk to the markets about.

You're killing me, man. Let's stay -- we're this close. You're trying to get me the switch to use 1181? I mean come on. So I think what we need to -- 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. So 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. And we look forward to continue exciting data for the next generation of CTLA-4 in these immune therapies.

You are absolutely right. And that -- I think that we -- when we look at our pipeline right now, we have 8 programs in the clinic, right? So these are -- it's so critical that we get these over the finish line. Bali plus/minus zali are going to be at the foundation for everything else that we do. 1181, 1223, 2373, I mean it is just -- but ideally, what we'd like to do is to give all of our compounds to Dr. O'Malley. Every time a patient likes 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, and we want him to be able to drive that treatment decision, having all of these options at his fingertips. But the base of this all will be bali/zali, so looking forward to getting those through to the finish line.

Well, I mean I think it's a great transition to talking about a few of those here in the last couple of minutes that you just mentioned. So Dhan, 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, you're getting your own TIGIT molecules, and you have 2 of them. And so I guess over the past 6 months, we've seen -- not even 6 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 like IPO on expressing non-small cell lung cancer. I'll say that's not an important opportunity. But curious, 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 that 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 3 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-naïve population, you're seeing evidence of deeper responses with TIGIT therapy. Yes, it is incremental, and we've articulated many times why that would be the case. We've demonstrated preclinically that this current generation of TIGIT molecules are not ultimately designed to really target TIGIT. Now we like TIGIT as a target. I think many people do because you 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 I-O plus I-O combination. And outside of PD-1 plus CTLA-4, there's no other I-O plus I-O that's really starting to emerge as a validated approach other than perhaps TIGIT plus PD-1. We've said -- we've stated very early on that TIGIT is an ideal combination partner for PD-1, but you need the right TIGIT molecule. And we published on the importance of Fc. You'd recall from our presentation at AACR last year, how our Fc engineering approach gives monotherapy activity, which is not something you see with the current generation of TIGIT molecules, both preclinically and now clinically, but also then our combination activity. So that's a very important point to make, that the clinical data is encouraging, but like what we've seen preclinically, we were starting to see the same thing clinically, it's not optimal, right? And then lastly, we -- as you're aware, at R&D Day, we mentioned that we're pursuing a TIGIT bispecific as well. And 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 preclinical data responses in PD-1 refractory models. That's what we've shared with you last time we spoke about this. But I would say that 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 therapy to the clinic. We believe we have a better-designed molecule to address the limitations of the first -- or current generation of TIGIT antibodies.

Dhan, I guess then just based on what you've seen, does that kind of influence your initial clinical trial designs? I mean obviously, not going to be dose escalation, but were you really focused 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?

Yes. 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 can 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. So I think we have definitely an approach that would not only be complementary to what others are doing, but it's also unique to help identify the right patients for TIGIT therapy but also identify the right combination. I think PD-1 is definitely a goal. There's a lot of literature showing TIGIT plus PD-1 co-expression. The clinical data support the combo. Bali, you spoke earlier about where do you take bali next. Well, as Jen mentioned, bali is going to be a cornerstone going forward. TIGIT is definitely one of those therapies we add to bali. But 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 as a best-in-class molecule.

Dhan, I appreciate that response. And then the other interesting thing at ESMO kind of from an earlier clinical standpoint is some of the 4-1BB -- tumor-localized 4-1BB targets. So we saw Pieris and Roche both had updates, one on HER2, one FAP. I think it's 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. And 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. And 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 shown over the weekend and how that might influence kind of 2373 next steps or how you're thinking about what to combine that with or anything like that.

Yes. So 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 2373 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 ready to get activity in the tumor. And these bispecifics, while they are designed to address safety, they're limited to just tumors that express that particular antigen, right, whereas agent 2373 does not have that problem. We designed the molecule to be active in the tumor irrespective of whatever tumor antigen that they present. So while you know that, I mean, anything is a real concern, what will you give patients who need CD137 but no longer express HER2 and no longer express FAP, right? This is where 2373 really shines. It's because the molecules Fc engineered can only be active or only be agonist to 4-1BB in the context of the right immune cells present in tumor microenvironment. So we're not limited in terms of indications. And we think that we still have the 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 that's not -- 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 already dose response to it and correlating with response. So I think that the jury is still out there.

All right. Thanks, Dhan. Well, Jen, maybe I'll turn it over to you to kind of wrap things up, I guess, just to summarize here. You kind of hit all the marks for the data presentation this weekend, started the rolling submission already for the mono. You talked about soon to come for the combo as well as the publication, so really kind of getting all the pieces together to show the totality of the data here that get you that first indication and then broadening out from there. But 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 just -- 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.

Yes, 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 these -- both these agents in -- 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 these hard-to-treat patients. So 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, tremendous thanks to all of our patients who have participated in these trials. Dave mentioned this earlier, cervical cancer has been, is a very underserved tumor, and there have been very few treatment options that have come forward. And 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; and 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. So 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. And I think an important piece to remember about Agenus' portfolio is we have all of these agents in our own hands, so it gives us enormous flexibility to continue to deliver responses to patients over time. So 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. So 8 of these assets that we've discovered are in the clinic in our own hands. And 7 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. And there are a number of discoveries like that, that we've partnered with to really expand our opportunity to broaden the reach to patients. So 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 for bringing up the ILT4 antibody. I can't believe I forgot about that. We have Merck share some interesting data there, too.

Yes.

So 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 well, and look forward to seeing more.

Excellent. Thank you, Matt.

Thanks, everybody. Bye.

Bye.

Bye.