Agenus Inc. (AGEN) Earnings Call Transcript & Summary

Hi, everyone, and welcome to our first R&D update, which is coined Agenus Insights. There's never been a more important time in the history of cancer therapy. Technology, partnered with genomic and proteomic insights have accelerated our pace of drug discovery to speeds that have never been seen before. Agenus is at the forefront of this, with more than 15 new discoveries advancing in the clinic in just the past 4 years. A few of those first agents are in route to BLA with filings already underway. Our anti-PD-1 is delivering differentiated activity compared to commercially available PD-1 antibodies. And 1181, our Fc-engineered anti-CTLA-4, we presented a data update yesterday, and that molecule is producing very exciting results in difficult-to-treat tumors. Now TIGIT, the topic of our conversation today. It's shaping up as the next breakthrough target in I-O. And only as recently as last year, anti-CTLA-4 and anti-PD-1 were the only validated immunotherapy combinations for patients with cancer. Today, this third pathway and target, TIGIT, has emerged. TIGIT is upregulated with PD-1 therapy. With the growing number of patients treated with anti-PD-1s, addressing the biology of TIGIT and blocking these tumor escape mechanisms is critical to deliver durable antitumor benefit to patients. I believe we have the best TIGITs. And actually, when in a company's portfolio, do we have some of the best-looking compounds: 1181 is really a elegant molecule; PD-1, showing great benefit in PD-L1 negative and positive tumors; and TIGIT, which you're going to hear more about today, is demonstrating superior benefit as a monotherapy compared to competitor TIGITs in our preclinical models. So today, we're joined by Dr. Steven O'Day. This is Agenus' Chief Medical Officer and a veteran in successfully delivering immune therapies for patients with cancers for many, many years, leading to the approval of multiple compounds. Dr. Dhan Chand, a molecular biologist and Head of our Drug Discovery programs here at Agenus is also with us. I'll open with you, Dr. O'Day. Can you share your interpretation of the evolution of the clinical data emerging to date with anti-TIGIT antibodies? You're on mute.

Thank you, Jen. I'm delighted to be part of Agenus now as the Chief Medical Officer. As she said, I've had almost 30 years of experience in the clinic as a clinical oncologist and clinical researcher and was involved with the initial human studies with ipilimumab that launched the immune revolution. As you know, CTLA-4 and PD-1 have really become standard validated checkpoints in T-cell activation that has led to remarkable success in the clinic. We have been waiting for some time now after a plateau phase for new validated markers. And TIGIT appears to be an emerging marker, both on T-cells and NK cells, an important checkpoint that may further make an impact clinically. And as you know, there's different formulations of TIGIT, both the competent antibody monoclonal as well as silenced or in Fc-enhanced. So today, there was great hope that TIGITs would be able to overcome as a primary mechanism of PD-1 resistance overcome this in the clinic. To date, with the competent monoclonal TIGITs that have clinical data that is emerging, what appears to be the case is that these molecules have shown very little monotherapy signal and have been primarily targeting now combinations with PD-1, particularly in lung cancer in the first-line PD-1-naive setting in high PD-L1-expressing tumors. And obviously, this is an important discovery and will pursue clinical -- further clinical data, but there's tremendous opportunity here with TIGIT as a validated marker in randomized Phase II trial, particularly in the PD-1-resistant category. And so what I'm particularly excited about and really prompted my desire to come to Agenus was both 1181, but this TIGIT bispecific molecule that Dr. Chand is going to talk about has some features that have been engineered, both with Fc enhancement and bispecific nature that we think may fill a gap in the existing signal area of the present TIGIT antibodies. And I can't wait to have it in the clinic, which we hope to have by the end of the first half of this year and start developing this as a potential important impact in patients as an I-O therapy.

You've brought up a few very important mechanisms here, right? TIGITs alone have not delivered the kind of benefit we thought they might, based on some of the biologic insights that we've had, right? It appears to be, based on the data that's been generating to date, the combinations with PD-1s may be necessary to truly get the kind of improved performance or clinical benefits. And I'd like to -- as we think about TIGIT, and I mentioned earlier, I used the word pathways, plural, right? It's a complex biology, and our scientists have been hard at work understanding this biology in deep and insightful ways and looking at developing products that can achieve not just blocking TIGITs but also some commensurate tumor escape mechanisms that we've discovered in different ways, so blocking tumors -- blocking TIGIT perhaps in a better way with Fc engineering. And then addressing biology with bispecific approaches or alternate approaches. So maybe I'll ask you Dr. Chand to speak with us about how was your thinking about how do we build, expand and improve on what's currently available?

Thank you, Jen. As you rightly pointed out, TIGIT has emerged as perhaps the next validated immune checkpoint after PD-1 and CTLA-4. And we have made several important discoveries on the TIGIT pathway, some of which we have published and presented at major conferences. And these discoveries, we have leveraged to build our bispecific TIGIT antibody agent 1777 that allows for superior activity than the current generation of TIGIT antibodies based on all preclinical modeling we have done thus far, including the opportunity for single-agent activity and improved responses in PD-1 relapsed/refractory models. Now the first discovery we made was that Fc gamma receptor co-engagement by TIGIT antibodies, like that of CTLA-4, is absolutely critical for enhancing T-cell activation and antitumor immunity. And what I mean by that is that blocking alone is not enough. TIGIT antibodies that also engage activating Fc receptors promote better immune activation. But more importantly, Jen, I think the big discovery we made was that enhancing the binding to the activating Fc receptor through Fc engineering allows for monotherapy activity in preclinical tumor models, as shown here on the slide, where you see the superiority of AGEN's Fc enhancement compared to that of competitor-like molecules. And AGEN1777 is Fc enhanced to capture this important mechanism of action. Now you brought up bispecific. The next important discovery we made is that co-targeting another immune receptor with TIGIT, not yet disclosed, but also expressed on T and NK cells using our bispecific platform addresses a potential escape mechanism to TIGIT therapy. Now as you know, we have a platform called VISION, and I'm sure you'll hear more about VISION in future series. That validates the importance of this pathway, specifically in settings where tumors escape independent of PD-1 or PD-L1. And that is where we see the opportunity for AGEN1777 to optimally modulate the TIGIT pathway to bring single agent -- to make single-agent activity possible but also improve responses in PD-1 relapsed/refractory models. In fact, if you look at -- if I can get the previous slide, you will notice in a model here where it's poorly responsive to PD-1, you see almost complete responses in all of the treated mice that was given AGEN1777. This is a remarkable finding. TIGIT therapy alone, particularly the conventional approaches, do not have such compelling activity. But through Fc engineering and through co-blockade of potential escape mechanisms to TIGIT therapy, we were able to see monotherapy potential and activity in PD-1 relapsed/refractory models.

And Dhan, maybe I'll stop you there for just a moment. You've brought up the VISION platform. And just for those of you who may not be familiar, this is a platform that our scientists have designed that allows us to recapitulate the human tumor microenvironment, essentially the interaction and fitness of immune cells or cancer-fighting cells. What this system allows us to do is to actually monitor as our immune cells are fighting tumors. There are points at which they may upregulate certain markers that illustrate that they may be exhausted. They start to lose their cancer-fighting potential. We can identify at what point in that cycle we could actually intervene, modulate and change the fate, increasing the tumor fighting capability of the immune cells and decreasing the chance of cancer survival. And this has helped us not only to accelerate our drug discovery. But also, it has allowed us to determine at what point in the development should we be including monospecific agents, the combination or the sequence of certain monospecific agents or do we better address the biology with the bispecific? And maybe what I'll ask you to do, Dhan, is talk a little bit about how you came up with the bispecific approach here to optimally target TIGIT.

Absolutely. When we discovered this pathway has been critical for enhancing both T and NK cell biology, we looked at whether or not co-blockade of TIGIT and this other receptor was possible with the combination of monospecific antibodies. And what we determined was that the added benefit was not as impactful as we would have predicted. But when we took those targets, the antibodies to those targets, and we reformatted them using our bispecific platform, we start to unlock biology that you could not get from the monospecific antibodies. And that's a critical piece of our drug development here at Agenus. We are, as you know, platform agnostic. We want to pursue the best biology. But also, format matters. Fc format matters as well as the format of which you are going to co-block these receptors or co-target these receptors.

Thanks, Dhan. And maybe just one more point. You mentioned Fc engineering. Now we have seen at Agenus, we have a first-generation CTLA-4, zalifrelimab, very active, performing like a first-generation CTLA-4 and IgG1. We've applied this Fc engineering technology to optimally target CTLA-4 biology, and we're seeing that we're achieving that now in the clinic. Improving the tumor-fighting capability, improving immunogenicity, expanding the population of patients who benefit from the agent. And that includes patients, over 40% of whom have a polymorphism in their CD16 allele. But maybe for those listeners on the line, Dhan, who don't really know what -- we're looking at TIGIT landscape. There are a number of TIGITs that are emerging. What does this Fc engineering mean or do? And what is the landscape, the variation of this engineering that's available today?

Absolutely. So apart from the finding that Fc gamma receptor co-engagement is important, we also identified the specific receptor that was needed. And that was the Fc gamma receptor IIIa or CD16. Now we have seen from not only our experience with CTLA-4 but others as well, that molecules that depend on this binding show activity in patients that express a high-affinity variant of this receptor. Now patients, as you mentioned, up to 40%, can express the low-affinity variant. The reality today is that the conventional approaches to TIGITs, such as IgG1 approaches, or much less so Fc-silent approaches, do not adequately engage this receptor. We have done head-to-head comparisons of our Fc-enhanced approach to those of the IgG1 or Fc silence. And what we see is improved binding to all polymorphic variants. So we would expect better activity in patients that express the low-affinity variant of this Fc receptor as well as the high-affinity Fc receptor. And Jen, this is playing out clinically, as you see with 1181.

That's right. And maybe importantly, Dr. O'Day, with 1181, you've made specific comments about the Fc-engineered CTLA-4 was designed to avoid complement-mediated toxicities. If you could perhaps explain what that is, what those toxicities are and what the experience has been with an Fc-engineered CTLA-4. And then I'd like your prediction as to how this may play out with an Fc-engineered TIGIT with related to toxicity.

Well, as you know, Jen, with CTLA-4 as one of the pioneers in the clinic with this, there are a spectrum of toxicities with these activated relatively early adolescent T-cells that are migratory and that includes skin, GI, liver and neuroendocrine as well as other endocrine abnormalities. So complement-mediated toxicities, particularly around neuro, endocrine and hypophysitis, is a -- the pituitary gland is a central gland that controls endocrine function. It's a very important gland. And we know with ipilimumab and first-generation CTLA-4s, this is in 10% to 15% of patients, they may develop this toxicity, which are manageable but can be -- are essentially lifelong replacements of drugs. So the preclinical models of 1181 suggested that these complement-mediated neuroendocrine toxicities would be aggregated. And so far, with over 40 patients treated clinically have not seen this toxicity, which we would have likely expected to see with the traditional CTLA-4 drug. So that's very, very encouraging. Obviously, as we move this technology over to TIGIT, this will be an important issue. Also with 1181, we've seen little to no liver toxicity, another major toxicity for CTLA-4 and to a lesser extent, PD-1 drugs. So again, the profile of this Fc engineering, in addition to improving efficacy, potentially priming and depleting regulatory T-cells, the toxicity piece may be very important for patients and clinician management. So we're excited about all these things.

Excellent. Thank you very much. And I think just for the listeners, we have in the clinic now, there are Fc-silent molecules, and I'll ask Dhan for his opinion on Fc-silent molecules and where the complications or challenges may be, Fc-competent and then the Fc-engineered TIGITS that you're seeing here.

Yes, absolutely. So maybe I'll start with the Fc-silent variant. So these are molecules that are designed primarily to block the TIGIT pathway. They do not capture that important Fc mechanism, which includes binding to Fc gamma R-receptor IIIa; improved immune synapse formation, which we're seeing with our molecule; or perhaps, myeloid activation, which others have reported. And the premise there is that by just blocking TIGIT alone, you may spare depletion of effector cells, the tumor-fighting cells, T-cells. We, of course, have validated this extensively internally and others have as well. And that is a piece of biology that we believe is critical to the activity is that Fc co-engagement for added T-cell function. Blocking TIGIT alone is not enough. In fact, we've been down this road before with CTLA-4 molecules, where we know that it's not all equal. You need to leverage additional mechanisms. The famous example I'd like to use is ipilimumab versus tremelimumab, both good blockers of CTLA-4 but very different activity when you consider the Fc piece. TIGIT in preclinical models has played out the same as well. Now with the Fc-competent TIGITs, that, of course, captures some of the biology but not all of it. As you've seen in our preclinical models, the Fc-competent TIGITs still do not show good activity in a single agent in -- or tumor models or in T-cell activation assays. That is because while they still engage the Fc receptor, they're not binding optimally. They're not creating that strong immune synapse that you'd expect if you had an Fc-enhanced approach like what we have advanced here. And that Fc-enhanced approach opens up biology for us that are -- that is not captured by the Fc competent and much less so by the Fc silent, biology that is leading to single-agent responses and biology that's leading to responses in PD-1 relapsed/refractory models.

Thank you very much, Dhan. And consistent with our intent with these miniseries, we're doing a deep dive but not too deep, right? We want to keep this to about 15 minutes, 15 to 20 minutes on content and then open it up for questions, which we'll do now. So using your chat function, you can ask questions. For our panelists here, we're happy to answer them. I think importantly, just for -- before we're going, you're going to see topics here on new mechanisms, new insights, new molecules in our portfolio and beyond, some of the most sought after information in immuno-oncology. And we'll be bringing to the table a series of experts who can speak with you in more detail. In addition to this format, we also very actively publish every 2 weeks a newsletter. And that newsletter is a more detailed summary of some of the activity, clinical data, some of our talent, our science, and upcoming activities in our -- on our portfolio. So that newsletter will continue. It's issued biweekly, and it's also available on the Agenus website. And while our panelists -- while our listeners add questions into the chat room then, perhaps Dr. O'Day, what I'd like to know from your thinking is what are you going to do with this molecule that's actually heading into IND-enabling studies actively? And our IND is just a matter of weeks, not months away. And so we're really enthusiastic about that. What's next? Where are you going to test it?

Well, it's pretty clear that the data we have in the field with the competent Fc monoclonal is that they're actively targeting high PD-L1-expressing advanced lung cancer in the first-line PD-1-naive setting. So that's a niche that obviously is moving forward quickly to larger trials. Because of what Dhan has talked about in the Fc-silent monoclonal data, we hope to see sometime in this year from our -- from others. What we're really focused on is both the Fc enhancement component and the bispecific nature of this molecule. But what I can tell you is we're very excited to have it in the clinic, and we will obviously look at initially in the Phase I to trial in solid tumors, obviously, enrich for tumors that are more immunogenic as is our platform. And then as we clear doses of the single agent, obviously, be very interested in combining it with PD-1. But we will be looking for signals both for monotherapy and combination, and this is really important because I think we shouldn't rush to any conclusions yet about monotherapy with TIGITs for the reasons Dhan discussed. So both the monotherapy and the PD-1 resistance and even low PD-1-expressing cohorts of solid tumors, which is a huge population, is what we're going to be focusing on in addition to any niche drivers of high PD-L1 expression, which is certainly potentially low-hanging fruit in addition.