Good afternoon, ladies and gentlemen, and welcome to the Next Generation Immuno Oncology Therapeutics Conference Call. At this time, all participants have been placed on a listen only mode. It is now my pleasure to turn the floor over to your host, Mayank Mamtani. Sir, the floor is yours.
Thank you, John. Look, good evening, everyone. This is Mayank Mamtani. I'm a Senior Analyst covering biotechnology company at B. Riley FBR.
I hope everyone is keeping well, thanks for joining. I'm pleased to welcome you to our expert panel call today to recap an exciting data rates ASCO weekend, and in particular focusing on next generation CTLA four agents where we saw Janice present encouraging early data as monotherapy and in combination with p d one. We have with us on the call doctor Steven O'Day who were the leading clinical investigator who presented that data and also doctor Charles Drake who have and both of these guys are obviously don't don't need interaction, but but they've obviously pioneered the checkpoint inhibitor biology space over the past several years, including in translational research and clinical development. Before we get started, I need to quickly walk through my disclosures. In the normal course of its business, B.
Riley FBR Capital Markets seeks to perform investment banking and other services for companies under coverage and to receive compensation in connection with such services. As such, investors should assume that B. Riley intends to seek investment banking or other business relationships with any and all of the companies mentioned today. Agenus currently is, within the past twelve months, was a client of B. Riley FBR.
The services provided were investment banking services, and we intend to seek additional compensation over the next three months. B. Riley FBR has managed the public offering of securities for Agenus and acts as a market maker for Agenus securities. Doctor Steven O'Dea is the executive director of the John Wayne Cancer Institute and Cancer Clinic, and director of Providence Los Angeles Regional Research. Doctor Ode has been at the forefront of new drug development over the last two decades, including playing a leadership role in the development of the breakthrough anti CDLF for ipilimumab or commonly known as Yervoy, as well as anti p d one antibodies including mux, pembrolizumab, and and BMS, nivolumab or Opdivo.
Doctor Charles Drake is the codirector of the cancer immunotherapy program and coleader of the tumor biology and microenvironment program at the Columbia University, Herbert I Irving Comprehensive Cancer Center. Prior to joining Columbia, doctor Drake served as a co director of cancer immunology program at John Hopkins Kimmel Cancer Center and has been a lead investigator on several pivotal clinical trials and immune checkpoint inhibitors. We appreciate doctor Oday and doctor Drake spending time with us today on the call. Also facilitating the dialogue with me is Jennifer Bill, our president and COO of Agenus. We appreciate our panelists spending time with us today.
Their opinions are their own and do not necessarily reflect those of B. Riley FBR. We ask them to avoid any disclosure of confidential nonpublic information. We obviously have a lot to go through in the call. We'll be happy to take questions if if you want to email them to me directly at mmamtani@brileyatbr.com.
So with that said, Jen, why don't you just kick kick us off and and just talk about a little bit about what we saw from what we learned from you at Agenus, and then, obviously, we we wanna hear from the two doctors that we have here.
Wonderful. Thank you very much, Mayank. And Doctor. O'Dea and Doctor. Drake, thank you very much for taking the time to be with us.
It's always wonderful to be with you and particularly exciting to do so on the heels of ASCO. As Mayank mentioned, you're pioneers in the field of immuno oncology and collectively your work has paved the way to a much deeper understanding of the most validated cancer checkpoint targets CTLA-four and PD-one and also has driven the work that we've been doing here both in how we're dosing the molecules and combining them to optimize the benefit for patients. The durable and curative benefits that we're seeing in some patients are direct results of your contributions. That includes how to administer these agents and you're also in the forefront of identifying gaps in these first generation combinations or therapeutic. Doctor.
O'Dea, you were the first patient the first person to dose patients with Yervoy, a first generation CTLA-four more than twenty years ago. And you're now the first to dose patients with our next generation CTLA-four, AGEN1181, which is a multifunctional T cell engager that also binds to CTLA-four. And we designed the molecule to approve upon what we believe to be important efficacy and safety parameters and also to expand the patient population of patients who benefit from the first generation CTLA-four. And as Mayank mentioned on Friday at ASCO, you presented exciting data from our Phase one trial on this molecule. So I'd like to start the conversation by asking you, what have you learned from your experience with CTLA-four and PD-one?
And how has your thinking about this combination evolved? And what do you both believe that we need to expand in order to expand the effective and durable responses for patients with cancer?
Well, thank you.
This is Steve O'Dea. I'm delighted to be on the call today. And and, Jen, thank you for that lead in. You know, it really has been an extraordinary twenty years. I was in the field of melanoma where we had very few therapeutics.
About twenty years ago, was fortunate enough to work with a small group of investigators that put ipilimumab into human melanoma patients with very advanced disease. To make a long story short, we've discovered an extraordinary result. One in four patients who received four doses of a CTLA-four inhibitor resulted in long term survival. And these were patients with very advanced melanoma, including brain metastasis. It was an extraordinary finding and it then resulted in almost ten years of clinical trial research, Phase onetwo, and then culminating in a Phase III trial that was presented at ASCO, I was able to give the plenary session then in 2010 showing for the first time in a randomized controlled trial that CTLA-four, any drug in melanoma, improved overall survival with remarkable cure in one in four patients.
So clearly this was an important checkpoint that then launched the revolution of immuno oncology. Very shortly after that, obviously the intensity of our clinical researchers and immunologists and oncologists, Doctor. Drake being a primary focus in that whole field, discovered that there were other checkpoints. You all know the story. PD-one then became front and center.
I think what I'd like to say just at the outset is that I really felt that there was a misunderstanding of mechanism very early on. Obviously, CTLA-four helped a very small subset of patients with melanoma, but it was so dramatic and it produced durable responses suggesting memory after very few exposure doses. But very soon after that, the thought was that the T cell life cycle had other checkpoints and that PD-one obviously seemed to have a lot more activity. And then CTLA-four sort of got looked at as the poor stepchild, an inferior version of PD-one. I think that was unfortunate because in my mind, they're two very separate targets.
They do share in common a T cell. But as we know now, T cell life cycle is very different in how antigens are processed in the periphery of the immune system. The army is built, sent to battle, Then they encounter the tumor microenvironment and the battle even begins there. And then they get exhausted. And then they upregulate exhaustion markers like PD-one.
And so PD-one responses were remarkably more common than CTLA-four responses. And so it deserved its front and center. But with time, the durability has been less and we neglected CTLA-four for a while. What I'd like to reiterate though is I think that in the last two years, it's extraordinary how CTLA-four has been brought back, a better understanding of the distinction of the two targets. And now across many solid tumors now, six indications, CTLA-four has been shown in combination at lower doses and even more less frequent doses has been an important background, not only in melanoma, but renal cell, non small cell lung cancer, hepatocellular, colorectal.
So I think it's here to stay. I think so the combination, we obviously need better, and then I'll let Chuck and and and others, we can talk some more about why we need better versions. But the existing CTLA four that we have, ipilimumab, is a very front and center platform now in combinations. Having said all that, I think let's go back to what we learned initially as monotherapy with ipilimumab. And remember, well, you may not know, but it really did have a dose escalation, dose dose response at higher doses in melanoma in the metastatic study and up to ten milligrams.
It was superior in a randomized study than three milligrams, but toxicity also increased with dose. And because at the time, the toxicity seemed overwhelming, if you really put it in perspective now, the gain that we get with the toxicities with CTLA-four blockade are much more reasonable. It's just that it was a huge toxicity paradigm shift for oncologists back in 02/2010. Now we're very fast at managing these toxicities, and it's changed things and allowed us to do combinations. But having said all that, we still want to reduce immune related toxicity, not necessarily completely get rid of it because there is a correlation between mechanism of toxicity and response.
But we certainly wanna mitigate severe toxicities. And obviously there is a limiting factor to first generation CTLA-four regarding that. What I'm excited about in the next generation, which we'll talk about, is that we need to re explore the dose if we have a less toxic drug, and that's the hope with eleven eighty one because single agent activity may be still dose related. And secondly, we never really got to study very many tumors with CTLA-four. We got a little signal in prostate cancer, a little signal in renal cell, and then it sort of left us as PD-one was launched.
And so we really don't have a good idea of CTLA -four cross solid tumors, particularly with more potent drugs that I think we have in second generation and less toxicity. So for those reasons, I think both CTLA-four monotherapy and combination is coming back. And I think it's it's very clear that this is a critically important target and and the most important target at present in combination with the the p d one background. I've probably spoken more, but I wanted to give that background, and we can move into biology.
That was outstanding. And I'll just say that I'm glad that you mentioned the new approvals where ipi and nivo now have been able to be dosed tolerably and effectively and now over six different tumors. Have a label and approval in over six different indications. I'm hoping and looking forward to a Genesis contribution for that and that we have a first generation CTLA-four as you know as well as a PD-one advancing in two BLA path trials, monotherapy PD-one in patients with refractory cervical cancer and a combination in refractory cervical cancer as well. And we presented some data demonstrating that patients with PD-one monotherapy have response rates of about fourteen point three percent and that's quite comparable to the fourteen point three percent that pembrolizumab was approved on via accelerated approval in this indication.
The combination, however, is what we're thrilled by. We're seeing twenty six percent, maybe a little over that response rates. And that's showing you're doubling of responses in patients with refractory cervical cancer, which shows a potential best in class benefits for these patients. And these responses, what we're seeing now, are durable. So we have a number of four complete responses, 10 partial responses, and these responses are very long lasting.
Maybe I'll turn it to you Doctor. Drake now to speak about some of the learnings about CTLA-four and PD-one, the mechanisms in terms of T cell modulation, effector memory cells and some of the underlying immune activity that is helping to drive these durable responses?
Sure, I'm happy to. First of
all, would like to just
start out by agreeing with Steven actually on the basic point that he made at the very end saying that the immunological pathways mediated by PD-one and CTLA-four are very different at the molecular and cellular levels. I actually had a similar experience. I was lucky enough to treat the first kidney cancer patient in the world with anti PD-one in 02/2008, And they had a complete response. So we were all excited. This was going to be the next generation.
It looked like PD-one was, more effective and then maybe less toxic than anti C24. But I think that as time has emerged, there are actually and also the field is accelerated greatly by a series of animal models, which show that if you add PD-one to something in mice, it always works. I think the field got a little bit overexuberant about the idea of using anti PD-one in combinations. But really the clinical data hasn't so far borne that out to the degree it has, at least with CTLA-four, in that CTLA-four blockade is approved with PD-one in six different indications. And it's actually the only immune checkpoint that reliably combines with anti PD-one.
So I think that's kind of what the field has taught us. I would take slight exception to one thing that Doctor. O'Dea said. In prostate cancer, I was actually fortunate to be one of the international PIs on our potentially pivotal Phase III trial. And what he's right about is that we had to use a higher dose, right?
So definitely with C. Twenty four, there's a dose response relationship. But we almost won. In prostate cancer, had a hazard ratio of 0.8, and our p value was just on the edge. It was 0.53.
We really came pretty close with a high dose of ipi in prostate cancer, and that's not what you see with PD-one monotherapy in prostate cancer. Think the other thing to keep in mind is from an immunological basis, studies from Rafi Ahmed's group and then several other groups, really Steve Reiner and actually we've repeated some of these studies in our lab so now we really, really believe them. And the idea is that actually PD-one blockade, is important in T cell biology in that it basically really, exploits the effector phase. So basically, T cells have two jobs. One is to go ahead and kill, and the other one is to, turn into memory cells.
So PD-one definitely augments the effector phase, and that's why you see a nice response rate. But that does come at the expense of forming memory, and that memory phase is actually more strongly supported by CTLA-four blockade. And I think that's really kind of an easy way to think of why the combinations are usually additive, and sometimes they even appear synergistic, actually. So I think that all those things together do suggest that Doctor. O'Dea and I totally agree that CTLA-four has been sort of, marginalized to some degree for a while, I think the emerging data really have pointed out why C2A4 is an important checkpoint and then why new approaches to, versus standard ipilimumab might advantageous.
Thank you very much. Doctor. O'Dea, do you have anything to add to that?
No. I'm so yes. I sorry. I may have slighted the prostate group, but I I remember that that was very close. And in fact, I was so disappointed because, you know, essentially, there was a ninety four percent chance that that was a positive study, so to speak.
So and and cold relatively cold tumors like like prostate cancer with very few infiltrating T cells normally, it it just makes the the strong point that c t l a four may work better in some diseases than p d one. And it makes a strong point, And it's based on biology, and the two together always seem to be a little better. But there are diseases where c t l a four by itself may be may be the best drug of the two. I don't think that's fully appreciated by the wider community. But I'm just delighted to see it now back, front, and center and to be involved with the sort of full circle for my career to to put the first, you know, c t l a ipilimumab, be be involved with that group in two in around February, and then this year or last year to put really the first eleven eighty two second generation from in in a person.
So that was that was exciting.
Well, that that's a perfect segue and an opportunity to start talking about some of the next generation approaches for CTLA four. And I also wanna ensure that we cover in this in this category the opportunity to potentially really build on the learnings that we have to date and how there may be some monotherapy opportunities for anti CTLA-four given our enriched understanding of the biology now, as well as other non PD-one combinations that we can contemplate as well. So transitioning to the next generation CTLA-four where there has been quite a bit of activity and notably also at ASCO. Our eleven eighty one is Fc engineered and we've designed this to increase the dwell time or the time between the antigen presenting cell and the T cell interaction to increase immunogenicity, of course to activate T cells, but also to improve priming. We also with the Fc engineering, we believe that we can now dose and benefit patients who have polymorphism in their CD16 allele.
And those patients appear to have had no response or suboptimal responses to first generation CTLA-four. The molecule is now in the clinic and perhaps I can ask you Doctor. O'Day just to highlight a few key features a number of your patients have been treated with the therapeutic and give your perspective about this molecule and perhaps then we can turn it over to Doctor. Drake to talk about how this approach may differ from some of the other approaches that are in the clinic.
Yeah. So I've been fortunate enough to be involved and sort of to lead the initial phase one trial. And what I like about it is sort adaptive design. We're we're doing sort of parallel phase one monotherapy eleven eighty one. And then as we clear doses, we are then starting that low that lower clear dose into the the combo.
So I think we've treated a little over 20 patients with these and what we've seen, obviously, it's early days for efficacy and all that. What you really wanna look at, obviously, early on is toxicity signals both with the monotherapy and the combination. We've seen what we might expect with the c two l four blocker with skin and some GI toxicity that's been manageable. What we're particularly interested in based on the FC engineering and the complement aspect of this is the neuroendocrinopathies, particularly hypophasitis, which is a is one of the more significant endocrine toxicities that you don't typically see with PD-one inhibitors. You tend to see more thyroid and other, but with CTLA-four, with ipilimumab, anywhere from ten to fifteen percent of patients can knock out their pituitary glands.
Where it's not life threatening, it does produce lifelong need for hormonal adrenaline and thyroid and testosterone and men replacement. So it's not a trivial issue since these tend to be the long term survivors. So anyway, on preclinical models and the FC engineering, was this hope that they really didn't see these neuroendocrinopathies. And so far, again, in twenty plus patients, we have not seen any of these neuroendocrinopathies. So that's encouraging.
Otherwise, it's been a fairly reasonable toxicity profile without any new signals. And then, of course, we have seen some some responses. One, in monotherapy at a very low dose and in a disease endometrial that it doesn't have a track record in in CTLA four and had the haplotype, the low affinity haplotype that you would expect to have a very low response based on melanoma data with ipilimumab or the first generation. So for all those reasons, low dose disease that had not previously been a c t l a four disease, so to speak, and a low affinity haplotype, that's really exciting. And it was a complete remission, and it happened within twelve weeks of starting.
So very dramatic, and it's been durable. So that's, again, one patient, but exciting. We had another patient at the very lowest dose of the monotherapy that's had ovarian cancer and had now almost a year and a half now of prolonged stable disease. And so that's been she's tolerated it beautifully. And then we've we've seen a combination patient.
Again, low dose of c t l a four of eleven eighty two point three milligrams with full dose PD one, and and we've seen a very nice response rate, multifocal ovarian disease that was progressing through chemotherapy after multiple regimens, and now having almost an 80% shrinkage with most recent scans. Again, very dramatic, very early. So so we are what is nice to see, and again, all of these early studies are let's get to an optimal dose with monotherapy, let's get to an optimal dose of combination, and then obviously expand these cohorts, which we plan to really focus and use our energy knowing the field, where would be the biggest impact to get both a monotherapy on the market or a combination in diseases that that traditionally might not be cold or or tumors, so to speak. So so we have a very well developed advisory board that is well versed in IO that is is is is really doing its job to think of where we're gonna put these optimal combination doses and schedules and monotherapy in the coming months. We're also looking at both a three week and a six week monotherapy regimen.
So we're looking at a couple different dosing regimens.
Thank you very much. And doctor Drake, you've been an an expert in the area of tumor microenvironment conditioning agent Treg depletion is a mechanism of tumor progression, tumor escape mechanisms as well as T effector activity. One of the features of AGEN1181 based on its design is we're anticipating And perhaps we could ask you to speak a bit about what you believe these next generation CTLA-4s may be able to do, and also what your thoughts are on where to bring these forward, both as monotherapy as well as in combination with PD-one.
Yes, that's a great point, actually. In the lab, we've been fortunate to have an analog of a CTLA-four depleting antibody. It's a mouse IgG2a, and it depletes brilliantly. With that drug, we can see activity in tumor types in mice where anti PD-one has no activity. And so I'm really very enthusiastic about the ability to optimally engage Fc receptors and potentially deplete Tregs.
And so mutation that's in November, the DLE mutation, is unique. It's actually not in any other antibody that's in the clinic now. If anybody wants to delve into the deep science, we should point them towards the beautiful cancer cell paper actually that shows this molecule compared to native type C2A4s and actually several other mutations. That's why I'm excited about the mechanism. But the other reason I'm excited, I got to tell you, is that when you push a tumor, what you get is an expansion of both number and function of regulatory T cells.
By that, I mean if you radiate a tumor, you think that you're increasing the TME inflammatory status. And you do, but that's very well balanced by an increase in the number and function of Tregs. And those Tregs express C. Like highly, actually. We published this in Clinical Cancer Research.
We recently published the same thing in prostate cancer. Hormonal therapy is immunotherapy. You get CD8 T cells come in. You're very proud of yourself. And then shortly after, you see a nearly perfect adaptive increase in Tregs.
We call this adaptive Treg resistance. And I have to tell you, it probably happens to everything. It probably happens to PD-one, probably happens to chemo. And so I have to say that I think that there's a very, very broad spectrum of tumors and combination modalities that an optimized CTLA-four has a place in. I think what Steven said, which I agree with, is one place to start is just to reexamine the tumors in which we either didn't carefully explore or which we saw a whiff of CTLA-four activity.
Prostate's a very good example. But then I think going forward, frankly, there's multiple, multiple applications. Think that in kidney cancer, there's certainly a good chance that a drug like this is more active than traditional C2A4 drugs. Do agree with Steven. I think the place to start, though, would be to look at an optimized antibody in tumors that we think have a chance of being immunologically sensitive.
But then I think going forward, I think that frankly, combination approaches with really most things that are pro inflammatory in our hands, actually benefit from CTLA-four, not blockade by using a CTLA-four optimized bleeding antibody. We have another paper that we haven't published yet in progress where we combine it with the cancer vaccine, have lost sort of interest. But I can tell you that it's the same thing. You push the tumor microenvironment with the vaccine, you get more Tregs. If you get rid of the Tregs, then the vaccine works beautifully, actually.
So I think that there are really many, many applications for an agent like this, frankly.
Very helpful. Now, maybe I'll just ask for a perspective from your experience. Both of you were at the front edge of using CTLA-four in tumors, and you've seen, you know, the benefit as well as some of the challenges. To see responses this early, and at the low doses that Doctor. O'Dea just highlighted, how common, in your opinion, common or unusual is it at this stage to see the kinds of activity that we're seeing?
Know, I think go ahead. Why don't you start with that?
You've seen more because you do more melanoma. What I'll say actually is the fact that you're seeing responses at low dose are very clear evidence that biologically this is a different molecule than it's been talking about. I think that nobody could argue that, right? I I think that the fact that you see responses at 0.3 and that maybe even spacing it out to every six weeks is possible. I think that this is biologically a different molecule than if you look at map.
So I think that's very important. I think that in terms of the true measure of the clonal activity, I once again will agree with my friend Doctor. O'Day in that I think that the key to really understanding that certainly seeing responses early is encouraging, right? But I think that the fact that we're getting close to what looks like a recommended phase two dose, both as a monotherapy and combination, really means that within a relatively short time, we'll be able to get a better readout for exactly what the activity is. So I think, again, that the low dose shows very clear this is biologically different.
I think that seeing responses early is encouraging, and we really very much look forward to what happens in the expansion cohorts.
Yeah. I would agree. And I think the fact that we again, it's still some confidence in the rules around this statement, but I mean, not seen any neuroendocrinopathies so far in a drug, ipilimumab, that we saw, you know, a fair amount, ten to fifteen percent certainly gives me hope that this might be different from a toxicity point of view. But, obviously, that's gonna be really critical too.
Thank you. And perhaps Doctor. Drake, given your experience with some of the other next generation approaches, how do you see the profile, the observations of safety, the absence of neuroendocrinopathies in your opinion?
I think it's very exciting. I mean, in terms of full disclosure, I'm actually the local PI on a competing molecule, frankly. It's the BMS version of Ichthi. It's the nonfukoxylated antibody. And the idea there is similar.
There have been no data presented publicly. We treated the first patient, at Columbia actually in 2017. Someday those data will be released. So we can't comment publicly. But I think that Dfucocylation and the DLE mutation are again biologically different, actually.
And this is shown in the white paper, which I encourage people to take a look at. The, other, approaches out there include, a molecule called the pro body. This is a very clever joke, right? So you have an antibody and then a pro body, right? So the pro body has the antigen binding region masked by cleavable peptide, and the idea of this drug is that the anti CTLA-four activity only becomes effective within the tumor microenvironment where that peptide is cleaved by the appropriate protease.
Hopefully it's there. That's been going along. The Probody's been going along. They increased the dose to a fairly high level and then saw, some toxicity, some C. Pylori toxicity.
I think that's a very interesting molecule. I think the challenge is that, there will always be some tick over for a molecule like that. Whether that molecule can achieve its promise, that is either decreased toxicity with the same activity or the same toxicity with more activity still remains to be determined, actually. Think it's an interesting molecule, but so far still in development. There's also a couple of other ideas.
There's some bispecifics. Think Xencor is in the lead with this. They have an antibody that binds both PD-one and C. Pla4. And there's several other companies that have a similar construct.
The idea there is that you really only work on cells that have both PD-one and CTLA-four. Yes, that's a blessing and of course that might increase specificity and decrease toxicity. In the tumor microenvironment, the Dregs do have a little bit of PD-one, and so this might, help, increase some specificity. And some of the CD8s also have a little C24, and so I think it's a reasonable concept. It's still early on, for that molecule.
There's a couple other ones too, but I think that, again, I just keep saying this over and over, but I think really my take home point is the DLE mutation that alters the Fc gamma R3 binding is different than any other molecules. And I think that this is the lead compound that has that. And I think that's why this one is particularly exciting. Have to say I'm a little bit jealous of Doctor. O'Dea being able to present the data a little bit at this point.
We'll make sure that we share in some of the novel innovations that We're you have in your hand as in
the same sandbox.
Well, maybe this is a nice transition then as we you've referenced the cancer cell patient and the cancer cell paper where we actually highlighted the Fc engineering that we modeled into our November molecule for CTLA-four. That same publication, we also had shared some data on our next generation, our TIGIT molecule. We have a family of TIGITs, a monospecific approach that's actually engineered, as well as a bispecific approach that we're really both of which we're really quite excited about and they're on the moving into the clinic end of this year, beginning of next year. Do you think that this Fc engineering, based in your opinion, with a TIGIT molecule may have a similarly beneficial impact on this type of target? We'll start with I you, Doctor.
Think that's best for Chuck to address.
So definitely, actually. I think that in terms of addressing, but in terms of the differential, actually. So I think that basically the presence of Fc receptors in the tumor microenvironment, to be fair, has not been very well studied. It probably actually is a dynamic parameter that changes as the tumor evolves or undergoes treatment. But the fact that this, DLE mutation allows stronger binding to the Fc receptors and also equalizes binding between the low and high affinity variant, which are both present in fairly reasonable proportions of the population, really means that molecules that incorporate this could be different, actually.
And so I have to say that TIGIT is a very reasonable target going forward. We published a paper in the Journal of Clinical Investigation where we looked at sorted regulatory T cells from multiple tumor types and did very careful analysis of RNA sequencing. TIGIT is certainly one of those molecules, actually. Approach is to try to use a blocking antibody that maybe reprograms those TIGIT expressing cells. But another approach actually is to consider, that there might be mostly regulatory T cells and once again, attempt to try to get rid of them with depletion.
So I think that, just like just this is the case where the DOE version of IPI is different than IPI C5a4, I think that Fc modified TIGIT is certainly going be different than the other TIGITs that are out there, actually. And some of them are particularly engineered to not have any Fc receptor binding. So those are primarily designed to be blockers, right? And so I think that you'll see what will happen is, much like the CTLA-four antibody, you'll see very stark differences in both activity and toxicity. Honestly, this is obviously speculative, but I would be really surprised if the Fc modified TIGIT doesn't look different than the other TIGITs.
That's very helpful. We've actually been able to share publicly some data preclinically, both with our TIGIT monospecific as well as the combination demonstrating superior tumor control in preclinical models compared to competitive molecules in our hands. So I from our perspective, it certainly does play a differentiating role with this particular target. Was curious to hear your take on that. Thank you.
Mayank, let me go ahead and open it up. There were a few questions I think that you had specifically on the ASCO landscape related to TIGIT targeting.
Yeah. And and maybe, since we have both doctor O'Dea and doctor Drake, maybe if you could comment on the Roche's first line lung cancer study data that we saw from the cityscape study and and just your general comments on on the path forward. And then, obviously, I I know we are still very early with the mono specific and the bispecific approach for for Agenus. This kind of high level thinking on on where this could go. And then you also obviously know there's a the ARCIS molecule and there's also a couple of other molecules in the TIGIT landscape.
Maybe doctor Drake, if you wanna take that.
Yeah. So well, obviously, this is not an error that I have been that involved with, but I so I don't wanna I've I've seen the lung cancer data, and, obviously, I'm aware of the target. But I think it's reasonably encouraging data with response rates that were approximately doubled. Think response rate in when we've done PD-one plus we've been through a lot already. Not to get back to CTLA-four, but obviously, it is the one player that has held its own, not based on response, but obviously durability and long term survival.
But so I'm a you know, we went through the IDO experience with Incyte. And anyway, this is encouraging. It's a randomized Phase II trial, reasonably good, seventy, eighty patients per arm. The response rates were better. I am much more interested in plateau of PFS curves at twelve to eighteen months to really see if the next immunologic manipulation will both recruit, either change ratios like what Chuck said in the in the tumor microenvironment of of of of pro antitumor effects as well as suppressive effects.
So or or bring in additional molecules that are that that can affect outcomes. So, obviously, macrophages and repolarizing them and and myeloid derived stem cells that are all immunosuppressive. So I think the phenotype of the of the microenvironment is is critical to making a big change, and we will see. But it's certainly an early signal that that looks promising. I I know they're launching a large phase three trial.
Whether it's premature or not, in my mind it may be based on waiting for more durable data, such as it is. Chuck, do you have some thoughts?
Yeah. Think that the story is not too dissimilar from, I think, what we're learning from CTLA-four. That is, careful studies of the TME show that CTLA-four is mostly expressed on the regulatory T cells, although there's a fair amount on CD8s, be fair. Could you just similar there's more on the regulatory T cells in CD8s? Anderson and Vijay Kukuru have a very beautiful paper in the Journal of Clinical Investigation, kind of really, in animal models at least, suggesting it's almost only on the Treg that matters.
That gives you sort of an immunological rationale for this combination, a rationale that's not dissimilar from the PD-one and C24 rationale, actually. The response rate difference is encouraging. I guess the thing that that bothers me a tiny bit is that there were several other anti TIGIT molecules, in the clinic. BMS had one, and I think, you know, three or four other ones, Arcus. So, like, did they just miss this?
Yeah. Merck had one. So to be fair, Roche did a fair number of patients. This was about 60 or 70 patients, if I recall correctly, in each arm. And it looked like it was placebo controlled.
So maybe this is a little bit more compelling than some of the IDO data. But I think what Steven says is true. Obviously, we would prefer to see initial response rate can sometimes be a little misleading in these studies. Seeing a longer PFS or potentially an OS signal, I think, would we need to see. But to be honest, when we go back to the thing that you guys just said in the beginning, right?
So if a TIGIT works, right, that's great. Would it would an Fc optimized TIGIT work better? And the answer is probably. Right? So so, I mean, yes, it's not a bad thing.
I mean, this is if this is correct and this is TIGIT activity, I think that, you know, exploring the pathway with next generation molecules more quickly than we did with c 24 might be a good move forward. Right.
Okay. And and, another question I got, in terms of, just thinking about the the path forward and and specific tumor types that, and keeping in mind the CD16 allele high activity there. I'm just curious if one of you can take this question on where this can kind of go forward, what could be a path. And I know the advisory board, all that work, we still have to see. And and there maybe also would be helpful is if you could comment, like, can CDLA four in some some tumor types can actually start becoming backbone and and we can start thinking about it as PD one and and maybe there are other agents that would need to combine.
And I'm obviously thinking I think there's some data with d reg, for example, other alternative approaches where where CDL4 actually works really well, that combination.
Yeah. Well, let me take a crack. I mean, I think, you know, everyone has historically wanted to combine something with PD-one that isn't CTLA-four because they're worried about its toxicity profile and this notion that it doesn't really have much tumor coverage, so to speak. It was sort of a melanoma drug that didn't work elsewhere. So we you know, I think, like, coming back to the beginning, I I think of them as very different drugs and mechanisms, and they only share a T cell but a very different life cycle.
So there may be as we understand the biology better of how CTLA-four works, there may be drugs combining with CTLA-four that are optimal to PD-one. Mean, TVAC and drugs like that that have activity as a priming agent. The obvious, there's data with CTLA-four with ipilimumab that actually looked in my mind better than their combination with PD-one, and yet they went to a large Phase III with PD-one. So we need to be smarter, I guess, in terms of the combination. The other thing I would just add is I think one of the most exciting areas I think is in the microenvironment is with TKIs and VEGF based therapies.
And as people know, levatinib is getting more and more interest across solid tumors as a combination with PD-one. And Chuck can comment, the renal cell data looks tremendous and melanoma data is probably forthcoming. But with the bar that the the resistant PD one patients overcoming that secondary resistance, which is a high bar. But my sense is if if a new drug can can do that, then its benefit in naive IO naive patients is highly likely to be equally, if not better. So so some of these drugs, I think the obvious place to look for benefit is if they can reverse a resistant phenotype after PD one exposure.
And anyway, so these are areas that we're looking at. Obviously, in melanoma with with eleven eighty one, obviously CTLA-four can be used in sequence after PD-one or even in resistant patients. And that would be a great area to look at in a single arm to see if you could overcome resistance.
Yes, I agree. I would say that in addition to the phenomenon of adaptive Treg resistance, which again occurs probably to many, if not most, prior therapies, rationalizing C5-four, there's another phenomenon. Think, Steven, you kind of hit on it. It's adaptive myeloid resistance. So basically, same thing happens with radiation.
You see initially a beautiful influx of activated CD8 T cells, killer. You're, again, proud of yourself, but then it's balanced by both Tregs and then later on by myeloid cells, right? And these myeloid cells fall into several categories, M2 macrophages, granulocytic MDSCs, monocytic MDSCs. The reason I think lenvatinib is a nice partner because lenvatinib blocks multiple tyrosine kinases, And some of those are critical for the function of these myeloid components. So I think in terms of combinations, another way to think about going forward is to consider that other suppressive component of the TME, in addition to the evil Tregs, for which eleven eighty one should be a very good drug, to consider some of the myeloid targets that might be involved in mediating that resistance.
Certainly, as you mentioned, I mean, certainly the TKIs not only lenvatinib cabozantinib probably does similar things as well. We have a paper in view where we looked at the immunological effects of cabo and find reasonably similar effects on the myeloid compartment. And there's other drugs that fall into that too. But I think that thinking about it a little differently, thinking about pushing the tumor and then worrying about the Tregs, eleven eighty one, good idea. And thinking about what are you going do about the myeloid component another way to think about combinations perhaps.
Yeah. I can't wait to get CTLA-four, PD-one and TKIs in combination because I do think it's very delicate ratios of effectors and suppressors that can just turn it into a full you know, particularly if they can keep the regs away and keep the mileage away and then drive the CD eights. I think the dynamics of that's gonna be really exciting. But CTLA-four both drives fresh T cells, The primed expanded T cells as well as PD one's really focusing more inhibition on these exhausted cells that have gotten out there but are losing the battle. So there's tremendous mechanistic opportunities to hit this at multiple sites, and I just hope I'm I'm here in the coming years to really witness this because I think there's gonna be some dramatic forward.
I mean, it's it's gonna be exciting this next ten years.
We we we absolutely need you. We absolutely need you to to to to to
to stay healthy. I'll try to stay healthy. Or or Chuck will take over for me.
I think the reason that most of
you it won't be that long, man. It's gonna be fast.
No. We'll we'll all be fine. In the next six months, we're not even remember what this this time frame look like, and we ever had a voice last year. It looks
like That sounds so
but but quickly, maybe doctor Blake, if if you think about this next level of innovation, and I'm thinking more orthogonally, like, you start with melanoma. I mean, that's kind of the typical line of thinking, which is obviously easier to explore and then for the for the mechanistic reasons that we just discussed. Like, is there a new paradigm that with what maybe we learned the stages in terms of more high risk approach. But, like, how do you how do you think about these agents that that are obviously coming along in in large volumes? Like, how do you how do you develop them differently going forward then?
And what was our understanding maybe ten years ago? Could you just comment on that?
So I guess I I had a little trouble. My phone was I had trouble. What what was could you repeat the question?
Yeah. Sorry. So a little odd orthogonal question, which is basically asking you as we thought about clinical development, like, ten years ago, we obviously start out with melanoma, and then we think about other tumor Depending on the immunogenicity. And but but what we know about all these DME suppressors, it's already tumor specific, and the targets obviously are guiding us in different ways.
So how do you think about drug development maybe in 2020 as as you think about a newer target coming along?
Yeah. I mean, I think, you know, I think, obviously, melanoma has been a prototype as a very you know, it's it's it's UV signature, it's mutational burden, and kidney cancer also to a certain But melanoma has just been such a prototype of a tumor that's visible to the immune system. We now know that it does recognize it as foreign and it also battles. And then but, you know, so each tumor type, though, really depending on its source and its mutational and neoantigen signature is is really gonna be different. But there are common mechanisms like like Chuck was talking about.
I mean, I think we're understanding the players, the orchestra that the tumor is involved with. And that milieu is really, really interesting. And there's both common elements and then then very unique elements. So I still think disease specific biology and and clinical experts are gonna be critical to figuring the targets out because there will be differences. But I'm also encouraged by when we find targets that are effective like PD-one and CTLA-four, how broadly they can be applied.
I think the bigger issue will be once the immunologic sort of understanding of the tumor and its microenvironment are understood, we may need direct cytotoxics, whether it's radiation, chemotherapy, targeted drugs for brief bursts to disrupt and allow that platform to take over. And colder tumors may need more work than warm tumors. But warm and hot tumors still kill people because of these ratios. And so I we're just getting a lot more sophisticated. It's it's gonna be a really exciting time to I I think we need our disease specialists, but our our immunologists and biologists too.
It okay?
Doctor, may doctor? No
problem. I'll just say one comment and thank you and thank you very much for your vision and your leadership in this space both of you. I'll make a point that optimizing combinations is so critical and the underpinnings as to how we've designed our portfolio. And we will have some very exciting data that we'll be reporting out on in just a couple of weeks at AACR that may help us to elucidate the best ways of approaching some of these combinations, and we're looking forward to doing them together with you. Mayank, please go ahead.
Yeah. My my I guess my final question actually, you set that up nicely, Jen. Maybe if, Jen, you wanna start the first end of this question, and I wanna ask doctor Drake also. Essentially, for the upcoming for the remainder of 2020, what are the some of some datasets that we should be looking out for specifically in the checkpoint inhibitor space and, obviously, mostly now combinations because a lot of monotherapy act activity is kind of at least for PD one is out of our out of the way, but but, obviously, CDLA for monotherapy, I think, we'll learn more. So maybe, Jen, can you just just set the stage as for for 01/01/1981?
What what sort of we should expect to the remainder of 2020? And then maybe doctor Drake, for the broadly for the space, it would be helpful what what should investors focus on.
I'll just take a moment. I wanna make sure we turn it over to doctor Drake. We have for November, we have some interesting data, as I just mentioned, coming up at AACR, looking at best ways to optimize combinations for patients with cancer, looking for those long, durable, curative responses and broadening the patient population to do so. We'll have some data at AACR. We're also going to have some additional clinical data as the trial matures.
And as you know, we've been very aggressive at getting these data out so you could look for data at upcoming major medical conferences. Beyond that, our BLA filings are are actively underway, and we're planning on filing those this year. So we're ideally, once we've, secured the filings, we'd be looking to release an update on the data to date. So I'll turn it over to you now, Doctor. Drake, to address the remainder of the question.
Sure. I mean, think that some of the other combinations are going to have some more mature data towards the end of the year. LAG-three, which I have a vested interest in, went into the clinic a long time ago, hopefully we'll see some data from BMS from relatinib. And there's a couple other anti LAG-3s in the clinic. There'll be some TIM-three data as well.
In terms of the TIGIT pathway, I think many people forget that that TIGIT pathway is a parallel pathway. So it's TIGIT binds to PVR, but there's another pathway, PVRIG, binds to molecule called PVRL2. And there's an antibody against PVRIG in the clinic from a small company called Compugen that gave a little bit of data, I think, at ASCO, and they're going forward at the triple combination. But the other thing I think that investors, if I was an investor, the other thing to keep an eye out for to combine and I think Steven said this very well, actually. So this idea is you probably need something to treat the tumor and radiation chemotherapy, those are good things.
I think that in addition to for something to combine with IO, the drugs that are really seeming to really be rising quickly in interest is the antibody drug conjugates. So we saw data from anti V7 H3 from ADC from MacroGenics. In prostate cancer, were some nice responses. There's a similar drug from the D. T.
Sankyo in the clinic. In bladder cancer, this is going to lead, actually. So we're going to have enfortumab as the backbone and first line, and then we're going to add checkpoints to that, actually. Think that unfortunately not CTLA-four, which is what we should be adding at this point. But still, I think that what Steven said is the basis for many combinations will include something to get rid of the tumor, probably in many cases PD-one blockade still, but c two a four blockade as well.
So I think that's what we'll see over the next, next couple of months, I hope.
Great. Lots to lots to come. It it looks like we're just starting out 2020. And and from doctor Ode's vision, we are, like, just scratching the surface here on the immuno oncology innovation that's ahead of us. I think with that, we are at time, Jen.
Are there any questions at your end or any closing remarks? Otherwise, we can close the call.
Thank you very much. No closing thoughts from me. Just great appreciation for your time and participation in the call. Thank you.
Thanks. Thank you. Thank you, doctor Ode. Thank you.
Thank you.
We really appreciate it. And thanks for everyone for joining us, and please everyone stay well and healthy. And back to you, John. Thank you.
Thank you. Thank you, ladies and gentlemen. This does conclude today's conference call. You may disconnect your phone lines at this time and have a wonderful day. Thank you for your participation.