It's two minutes past the hour, so we will start as promptly as possible. Firstly, thank you very much for being here today. We appreciate your time. I know for investors, this is a precious time, as the market will be opening soon. We particularly appreciate your efforts to be here. Let me start by, I guess I'm controlling things here.
With our disclosure of forward-looking statements, all I'll say is that there's a lot more detail on our website on this and in our SEC filings, so we invite you to do that. We have over the years, as you know, we have been in the cancer immunotherapy business for, it'll be 26 years in April. The company was formed 26 years ago.
It's been a long haul, and it's been a long haul with no regrets because the field of cancer immunotherapy has advanced to the point where now it is the most promising treatment modality for cancer patients going forward. Of course, I'm not suggesting that nothing else will be used, but cancer immunotherapy is front and center.
Stating the obvious, so to speak. We've, over the years, had ambitions to cure cancer and, of course, that's a dicey word, to cure cancer. This is the best that we've come up with, inspired by some recent developments that came to my attention.
We strive to or aim to have cancer patients living longer and better. That's the objective. Better is also very important because living longer alone, which has been the regulatory standard for a long time, is not sufficient.
For example, if a patient lives longer by a month or two months, in their case reporting forms they show that as a benefit, but the patient is not functional and not happy. That, of course, doesn't really accomplish much. This is our new tagline. Today we invited you here, to tell you about the latest developments with the company.
Over the years, we have strived to have a very broad portfolio of cancer therapies, and we have also strived to be fully integrated as a company. Fully integrated is a very important component because without being fully integrated, we couldn't have made the advances that we have. Treating cancer requires more than one or two agents. It is like a military force battling the enemy, and having just one component of a military force doesn't really work well.
That's one of the reasons we have strived to have many of the components that are necessary and can be called upon when they are necessary to battle this disease. Today we have a fantastic lineup actually. To start from the left, Dr. Charles Drake is the co-director of the cancer immunology at Columbia, but more importantly, he has had a very long pedigree in cancer immunotherapy.
He's one of the experts, among other things, in the field of CTLA-4, which is something that we will be talking about today. Next is one of the top experts in cervical cancer. Why cervical cancer? Because that is a target for our first set of product approvals, and we will be filing our BLAs this year for two compounds for cervical cancer to be presumably followed with other cancers as well.
Dr. Brad Monk is one of the world's top people in cervical cancer, and we had the pleasure of meeting him a couple of years ago, and he has been a fantastic inspiration in directing our programs in this field. Next is Dr. Tyler Curiel from UT Health San Antonio. Dr. Curiel, I believe was the first one to publish on PD-1. Sorry, PD-L1.
He is a phase I experimentalist physician and a scientist, and he will be telling us about the how of some of what we're doing. We've got the lineup from Agenus. Mostly homegrown, mostly individuals that have risen to the top in their fields over the years at our company. Dr. Jen Buell is now president and COO, has risen to the ranks over the last 15 years entirely internally. Julie DeSander also a professional.
She's the head of our business development. She'll make some few comments about how we're going about our business model. Julie has risen to the ranks as well through the Agenus tenure. We have Dr. Dhan Chand has been with us for seven years now. He's the head of discovery.
He and his team have been responsible for making the innovations and filing as many INDs as they have in the last few years. He'll be talking about our pipeline. We have Dr. Mark Exley, who is one of the world's top experts in the field of iNKT cells. We believe iNKT cells are going to be a key driver of our cell therapy strategy, and he'll be talking to you about that.
Dr. Anna Wijatyk, who I cannot claim to be homegrown, but she is a consummate professional, a drug developer in the field, and she's the head of our clinical department. We will be having a very succinct presentation to you covering all areas and with the exception of commercial development, which I promise you we will do at our next meeting because we're furiously working on our commercial development strategy, commercial launch strategy, building the department, and that will be ready for discussion next time we convene.
Last time I was here, I made a statement that we will have six clinical readouts in 2020. Six clinical readouts. Two of those are readouts from our first generation CTLA-4 and our PD-1 molecule, which is now being readied for filing for cervical cancer with two BLAs.
Now, people may say, "Why does the world need another PD-1?" Because there are so many of them. Here I draw your attention to the fact that it isn't another PD-1 that matters, it is what we do with it and the prospects for our PD-1 in combination with many other agents that will make that PD-1 potentially a very, very competitive agent.
We don't claim to have a differentiated PD-1, but we do claim that what we can do with our PD-1, which is a very important building block for cancer immunotherapy, will be highly differentiated. Highly differentiated.
For example, if we look at our PD-1 in combination with our CTLA-4 molecule, the first generation CTLA-4 molecule, there are certain advantages, as you'll see from Dr. Monk's presentation, that are going to be unique to us in getting to the market with a differentiated strategy first.
Also very importantly, if you look at our PD-1 in combination with our highly innovative agents in the pipeline, including our second-generation CTLA-4, that could offer an advantage that no other PD-1 has today. That will drive the market potential of our PD-1 in combination with the other agents in our portfolio.
Next, we will discuss our clinical data from our AGEN1181 molecule, which is not just the next-generation CTLA-4, but much more than that. We'll provide you with some of the details of that, including a very important development in terms of a very exciting early response in one of our dose escalation patients.
The other three molecules here, AGEN1223, AGEN2373, and the Gilead GS-1423, which is a compound that we licensed to Gilead last year. That was a preclinical compound, now it's in the clinic.
When we licensed it to Gilead as a preclinical compound, that was a subject of $150 million upfront payment from Gilead to us. Gilead is progressing that molecule in the clinic very rapidly now. There's a possibility that they will be disclosing data on that this year as well. In addition to that, as I mentioned, we expect additional IND filings.
More specifically, we expect at least 2 IND filings this year, and you'll hear about some of them in stealth mode. We're not going to disclose the targets for competitive reasons, but we will discuss the mechanisms of what they do. Then of course, the 2 BLA filings. With that, it is my pleasure to introduce Dr. Monk. Thank you.
Thank you, Garo, and good morning. I appreciate you being with me today. My patients appreciate you being with me today. I've been working on cervical cancer for 30 years. As a medical student, I worked in the lab where Gardasil, the HPV preventative vaccine was developed, and we still have a lot of work to do, and I get it that vaccination is the cure, but it will not happen in our lifetimes.
We have to continue to develop effective and tolerable medicines for the patients who have not had that opportunity. I chair the GOG. I also run The US Oncology GYN committee, and I'm the international chair for the group of groups called the Gynecologic Cancer InterGroup. I'm very passionate about this. You'll feel my enthusiasm. I come from Arizona, where we have a high cervical burden, cervical cancer burden.
In this country, there are about 3,000 deaths, about 12,000 cases. I get it's a global disease, but there's certainly more, too many deaths here, and we have our work to do. I want you to see, I don't know if I have a pointer here. I want you to see. You can see this lesion here. My residents call it a cauliflower lesion.
You'll probably never look at cauliflower the same. Right? You look at that, and it's staring at you, HPV related. That tumor has been resected. You don't need to be a radiologist. I wish I had a pointer.
If someone had a pointer, I'd appreciate it. You can see this lesion here on the left, where it's too big to resect, and she was treated with chemotherapy and radiation. That's what we're here to fight, and I want you to understand it.
The average age for these patients is 49. These are young women. Okay? Within our group, the Gynecologic Oncology Group, we did seven studies over three decades and really didn't get much accomplished. We showed that platinum works. Duh. We showed that paclitaxel, which you know as Taxol, in combination with platinum works, and we didn't get really anything accomplished over 30 years. Okay?
It was this cisplatin, it was paclitaxel, and patients were still only living about a year after the diagnosis of metastatic disease. Then we kind of broke through. We broke through in The New England Journal, also published in Lancet.
Krish Tewari was my medical student, resident, and fellow. I'm the last author here on both of these publications. And we really sort of had a breakthrough with the addition of bevacizumab or Avastin to this paclitaxel, cisplatin combination, a triplet.
It helped patients live 4 months longer, to Garo's point. Okay. It's not enough. We've continued to push, but this was transformational. Genentech really never needed to sell it, because once the doctors heard it, they immediately pivoted to this becoming the standard of care.
This is a great example where the need was really unmet, and even though it was an expensive medicine, it still was transformational. We really didn't have much happen between 2014 and 2018 until we got pembrolizumab approved in second line. Approved for after failing platinum/taxane, bevacizumab.
You're like, "Well, that's great." Really? It's great with a response rate of 14%? Okay. The need was so unmet that generally, as you know, accelerated approval, you need about 100 patients. Okay. This was 77 patients, and this was in a biomarker-restricted population. Okay.
Biomarker is positive, PD-L1 expression in about 80% of patients. I get it that this was sort of interesting. Again, Merck never really had to sell this because doctors, in a day, once they heard about it, began to use it because there's really no other option. That's been now in June of 2018, and we've continued to labor, and I think all of you recognize that the way to make anti-PD-1 molecules work better is three things.
Adding it to chemotherapy or radiation. You see that in lung cancer and breast cancer and all sorts of things. Adding an anti-VEGF, you see that in kidney cancer, all sorts of cancers, lung cancer. Third, adding an anti-CTLA-4. Those are the three ways, and that's where we're at. We're working on all of them.
I'm here to talk to you about adding anti-CTLA-4 to anti-PD-1 because 14% response rate isn't enough. All right. There's this company, it's called Bristol Myers Squibb. You've probably heard of it. BMS, right.
They make these medications called nivolumab and ipilimumab. Why don't they do a cervical cancer study? Well, they did. It was an investigator-initiated trial, okay. BMS really had no intention of expanding their brand.
With my friends, Anna presented this at ESMO. She's in Barcelona, Spain. It was a study really of all sorts of different patients and doses. They really didn't have a strategy because Garo doesn't run BMS, at least not yet. These are patients with metastatic cervical cancer, and they studied two different doses.
This nivolumab, three milligrams per kilogram, then sort of a slow, consistent ipilimumab dose, or the higher ipilimumab dose of three milligrams per kilogram, okay, every three weeks. It was lots of different types of patients. It was patients that had PD-L1 or didn't, it was patients that had had bevacizumab or hadn't, it was patients that were either newly diagnosed or in the more traditional setting of second-line.
It was a group of patients and really had no regulatory intent, sort of an investigator-initiated trial. Again, there are lots of different groups of patients, biomarker positive, first-line or second-line, all presented at ESMO and in the public domain. They showed that even in the lower dose ipilimumab, that there was an improvement in response rate, sort of back of the napkin, inappropriate cross-trial comparison, which we do anyways.
That 23% in this patients for prior systemic therapy for recurrent or metastatic disease, that 23% was a step in the right direction. Maybe it was even a little better if you used a higher ipilimumab dose, but the higher ipilimumab dose, as you know, is more toxic.
We love this because we were already working with our commercial sponsor, Agenus, to do this exact same thing. We were encouraged that there was indeed a proof of principle, a concept, and quite frankly, we were ahead of this even if they decided to develop this commercially.
This is my good friend, Wendel Naumann, who works at the Levine Cancer Institute in Charlotte, North Carolina. This is his patient, and you can see, and you don't need to be a radiologist. This is the heart. This is a CAT scan.
You can see all this white, which is cancer. Just after two months, basically it's gone with combination ipilimumab and nivolumab. He biopsied this patient after seven weeks, and you could see that there was an infiltration, these little dark brown spots, of immune cells that are trying to fight the cancer.
The addition of the CTLA-4 caused this dramatic improvement in clinical, I think, clinical response and was very innovative, and we're excited. By the way, I'll go back a slide. This patient had failed radiation cisplatin in sort of the typical New England Journal FDA-approved 2014 regimen that we developed.
I get it. It's all about tolerability. The treatment-related adverse events in this nivolumab, ipilimumab proof of concept, relatively high. Grade 3/4, 28.9%. However, those leading to discontinuation or the serious ones is relatively low, particularly with the low dose ipilimumab.
You guys know this. You're familiar with nivolumab and ipilimumab in combinations in many different tumor types. We were concerned because many of these patients had had radiation, that we'd see higher intestinal toxicity because, as you know, we radiate the colon that's in the pelvis, and we didn't really seem to see higher intestinal toxicities than what we had seen in other tumors, although they generally are between 5% and 10%, and you see that.
We strive as a group, you as an investment community, me as a clinician and investigator, and as a company, to be best in class and really to bring this to the clinic. That's why I got on an airplane yesterday and flew all the way to New York, and that's why I have a 1:00 A.M. flight back, okay. Because I need PD-1, anti-PD-1, anti-CTLA-4 in the clinic.
Again, if and when this becomes available, it will just be transformation. Doctors will use it. What else are they going to use? Single agent anti-PD-1? Of course not. Right. There's nothing else approved. Okay? That's why single-agent pembrolizumab got FDA approved at 77 patients in a 14.3% response rate 'cause duh, right.
It's what patients need. We're here today, and why am I presenting this here today? I was asked by my friend, Dhan. He says, "Why aren't you showing this at the AACR San Diego or ASCO?" It's an excellent question.
This is so impactful for the company and for my patients, I can't wait. It's a little unusual, but we have to move forward quickly. We really don't have time to present it at a meeting because the BLA filing is soon, and we'll just present the entire data set.
We didn't really think that it was worth it to send half of the data to the meeting, but we thought it was important to disclose to you and also, I think, to the scientific community, sort of in a more informal setting, that this is a big deal. It's a big deal not only for patients, but it's a big deal because it shows that these agents are effective and tolerable.
That's why we're here today, and I think that's why the room is full. Again, trying to, here in green, to improve upon the, in the lighter color, the anti-PD-1 or PD-1 signal and anti-CTLA-4 can make that deeper responses and more impactful across many tumor types, and we're here to talk about that cervical cancer opportunity. These are our data sets. This is as of October.
You know, it takes three months or so to clean it. I want to thank Anna and her team. She's supposed to be on vacation. Thank you for being here. That's how excited we are about this. There's 42 patients. I told you pembro has a 14%. This is 12%. I think that the duration of these responses and these patients are still on treatment.
That one, for example, I think is encouraging. It's not enough, but it shows that this class of molecule, as manufactured by Agenus, works. I get it. It's five out of 42 patients. There was some CR, and that's interesting.
It's really not at least my goal to make a replacement for pembrolizumab, right? Because we already have it. My goal is to bring the combination to the clinic because this isn't nearly enough, right?
In a smaller subset, now we're seeing more CRs. Now we're seeing about a doubling of the response rate, very similar to the nivolumab, ipilimumab sort of investigator-initiated trial that I showed you. This data set is a little. The cut was in July, not October. These are valuable patients.
There are other patients on study, and I'll let Jen and the team talk to you about what the anticipation is for the timing of the filing. I can pretty much assure you, in my opinion, that. If the application is accepted, and it should be, it will be a priority review.
As you know, a priority review is generally six months or less. I'm really excited about this, and you can see these responses are still ongoing. Okay. Some patients have long-term stable disease, so I think this is sort of an impactful opportunity.
That's why I'm here, and that's why I'm excited. Because now we're getting into durations of responses and the number of responses I think that me and my colleagues can get behind and will be exciting for our patients. Again, this is at the lower dose, the same dose that was studied by BMS in nivolumab and ipilimumab, really for the tolerability opportunity.
I hate to do cross-trial comparisons, so I'm going to do them. It's just kind of what we do. You can go ahead and you can compare either the combination that I showed you from BMS presented at ESMO or this that I just presented today, and these numbers are in the same range. Again, our goal is to be better, and we have our scientists and our business development to talk about the next generation CTLA-4.
Yes, this is better than single-agent anti-PD-1, but we really want to be even better still than what the anti-CTLA-4 opportunities are. Here's the single agent, same sort of thing, 11.9% versus 14.3%. Again, this is encouraging for the CMC and the manufacturing capability. It's encouraging if you're interested in investments.
I'm not. What's most important, it's encouraging for patients and that help is on the way. Okay. This is the adverse event profile for this combination. Again, these on-treatment AEs are what they are.
Importantly, leading to discontinuation is relatively low, which what we're interested in. Cervical cancer is still here even though we have a vaccine, and it's not going away in any of our lifetimes. Hopefully, someday it will be like polio and smallpox, but it's not today.
Accelerated approval from small single-arm clinical trials is an established way to the clinic. We did it in cervical cancer with 77 patients last year. We did it in ovarian cancer with niraparib, in endometrial with pembrolizumab and lenvatinib.
We do this over and over again. It's established paradigm. Anti-PD-L1 activity is in this 10%-15% range, now we have balstilimab, which is an opportunity. There's no question that the combination of CTLA-4 to PD-1 is an opportunity. Accelerated approval alone, maybe in the combination, in my opinion, is likely. Thank you for having me. Thank you.
Good morning. My name is Anna Wijatyk, and I'm the head of clinical development at Agenus. Before I start, I wanted to thank Dr. Monk and the GOG partners for their support to Agenus, not only in the execution of our clinical trials with cervical cancer, but also strategic support for the BLA path and their continued commitment to cervical cancer patients, very much in line with what our mission is to help patients live longer and better.
I joined Agenus 18 months ago after more than 20 years in various organizations, including Shire, BMS, and Baxter, freshly off the successful BLA filing for ALL indication with Shire. At the time I joined Agenus, there were only handful of people in the clinical organization.
In the last year and a half, clinical development has grown exponentially and added number of functions essential to not only deliver 2 BLAs in the 2020 year, but also, at the same time, to execute clinical studies in an accelerated manner. True to our commitment to help patients live longer and better lives.
Data from our cervical cancer trials that Brad just shared shows that we are on track to deliver data sets that will be needed for the BLA filing. This, coupled with the fact that we enrolled required number of patients with exceptional speed, confirmed that we are on target for the 2 BLA filings in 2020, both as a monotherapy with balstilimab and combination balstilimab and zalifrelimab. Next slide. How do I move those? Okay. Move on next one.
Please.
Oh, sorry. Sorry.
You might want to go back.
All right. No. Not going back.
Can you go back one slide?
Okay. Now. When we met last time, I shared with you cases of patients that were complete responders in our cervical cancer studies. I wanted to just briefly review those cases again with you, just to remind you what we presented last time.
First case is a 60-year-old patient from our monotherapy trial. She presented with recurrent metastatic squamous cell cancer of the cervix after being treated in 2016 with a platinum doublet.
That patient presented with the target lesion in mediastinal lymph nodes. As you can see from the data on the right side, this patient was a complete responder already on week six and maintained that response, as you can see from the pictures on the left side, from screening versus the cycle 36. The patient remained a complete responder for a very long period of time. Another case comes from our combination study with balstilimab and zalifrelimab.
That patient is also a complete responder. She presented with the recurrent metastatic cancer, and her target lesion was in vaginal stump. You can see the picture from the screening at the top, comparing it to the week 27 on treatment. That patient started to respond already on week 6 and continued to be a responder at week 27.
Durable, complete response. As a clinical organization, we are set to deliver unprecedented outcomes. This slide shows you a glimpse how we executed in 2019 and how we are set to deliver even more in 2020. In 2019, we have been operating in 25 countries with 120 sites.
We have enrolled more than 300 patients and carried out 8 clinical studies in different stage of development and different indication. We delivered data for two interim analysis, and we continue to analyze our data in an ongoing manner.
As Garo said, we are set to deliver unprecedented number of readouts in 2020. Our organization now counts 54 people, and I mean clinical organization. Remarkable growth from just a year and half ago, when we only had few people. We have and are continuing to deliver data on number of programs with different molecules, different indications, including novel molecules which would potentially address significant unmet medical need.
We broke industry record for the time from the IND clearance to the first patient dose. It is 65 days versus industry standard of 168 days. Our operation team has performed exceptionally. We enrolled patients with unprecedented speed in a very complex setting.
As you know, there is a big competition for patient, and notably in cervical cancer space, when there are already some treatments registered. There are also many clinical trials that are competing for the same patient population.
It's very challenging to enroll patients in this type of indication, and we did it. In 2019, we enrolled the required number of patients to deliver 2 BLAs in 2020. We are off to a very good 2020 with 2 filings on target and multiple studies either continuing or starting to deliver the readouts for patients to live longer and better lives. Thank you.
Thank you very much, Ana. That is very exciting to be able to share with you. Maybe just to take a moment to let you digest some of the key points that both Dr. Monk and Dr. Wijatyk presented to you. Ana did share some metrics, and I will just highlight another very important one. We're on track to file our BLAs within about three years from our IND for second-line cervical cancer.
That's another record-breaking timeline. It's exceptional. I am so honored and proud to be a part of an organization who did spend the time that was required to actually interrogate tumor biology and understand the underlying mechanisms of tumor escape mechanisms, of how to actually prime and educate the immune system, and then to really learn how the tumors were fighting back to protect themselves from the immune system.
From those learnings, we had the knowledge, the intelligence, and the foresight to develop not just one CTLA-4, because we knew the value of it, but a next generation, an enhanced molecule that you're going to hear more about today.
Before we go into that, though, I'm standing in the precipice behind our speedy and very productive, exceptional clinical development team led by Ana, our expert clinician, Brad, who's been guiding us along the way in identification of patients who need these types of therapies.
Patients with cervical cancer, these are predominantly virally induced tumors. They exhibit some features that are phenotypically akin to those tumors that respond very well to PD-1, but respond much better to CTLA-4 and PD-1. These are tumors with high mutational burden. These are tumors with already some semblance of baseline immunogenicity. Some immune recognition is already existing de novo.
When we add a CTLA-4 to patients who present with that phenotype, you see this doubling and sometimes tripling of response rates, and that's where we very much want to see our products advancing, where we could make meaningful differences to patients. This is why we've been focusing on the durability and the response rates, and I think you can see a semblance of both.
We have presented the data to you here today, not only because we want your undivided attention, we want to give you ours as well. We also certainly didn't want to wait any longer, mid-year, to present at ASCO or a little sooner at AACR. We had these data in our hands last year, and we had wanted to share them with you.
In our discussions with the FDA, they asked us to partner with them and to hold the data and not share them until we were closer to our filing, our BLA filing. There were a few reasons for this. Number one, they did not want us to dilute or compromise the integrity of the patient population that we were accruing.
They didn't want the data to be in the public domain that might influence our ability to complete our accrual with patients that were homogeneous. Which, by the way, our patient population is different than some of the populations that Brad has presented to you earlier.
The patients from Merck, as well as from Bristol, some of whom were treatment naive. Our patients are a homogeneous patient population that ideally represent how patients with refractory cervical cancer are treated today.
These are patients who have failed the platinum doublet and in some cases have also been treated with bevacizumab based on the data that Dr. Monk and his team at the GOG has presented. This allows us to actually understand where and how our products are working.
We've decided to present these data to you now because we've not only completed accrual, but we've surpassed what our accrual obligations were. We have an even more robust data set to draw from.
There's no problem with us potentially compromising accrual. Our patients are in. They're on treatment. They're being followed. The FDA was also concerned that if our interim analysis did not represent our final analysis, there would be a conflict.
However, we have enough data now, having completed accrual and gone beyond our requirements for our analyses, to feel very confident in the data that we're presenting in this interim analysis.
We're quite excited, and now we're just watching and monitoring the durability, which we anticipate, much like other tumors that present similarly to cervical cancer, CTLA-4 in combination with PD-1 will not only enhance response rates like we're seeing, but will also enhance the durability of response, which is so important.
Now, these patients who have had complete responses or partial responses, when you take a look at the Swarm plots that Brad presented to you see some durability peeking through. You see some complete responses who have the patients with complete responses and with partial responses have durable responses.
Those are continuing, which is very exciting and of course, akin to our mission to enable patients to live longer and better lives. This is a semblance of our ability to do that. Now I'm going to talk to you about what's next.
We've brought some experts to speak with you today. We have been interrogating the immune system for many, many years. We've designed CTLA-4 and PD-1 for all of the reasons that I've told you, and they're playing out in the ways that we want them to play out.
We know that PD-1 and CTLA-4 represent a multi-billion dollar opportunity. As a matter of fact, the PD-1 market today is about $20 billion. Ipi and Nivo themselves are approaching $8 billion-$10 billion in revenue. We have the most clinically advanced CTLA-4.
Bristol has an approval with YERVOY, ours is the most clinically advanced CTLA-4, which we believe, if we remain on track, will be second to market, which is incredibly exciting. We didn't stop there because we've been interrogating why do only 20% of patients respond to YERVOY as a monotherapy?
How can we actually expand the response rates, the durability of response, and broaden the population of patients who respond to a CTLA-4 inhibitor? Dhan and his team, as he presented to you at our last meeting, went to work to figure out what's going on with these patients, these non-responders.
There are a few things, and one that's very important. CTLA-4 in and of itself, it activates T cells. Our first generation CTLA-4 does the same. Our next generation CTLA-4 is designed to do the same, there are some pieces that are missing.
We need to prime the immune system, and to optimize priming, we need to better educate our immune cells. We've designed our next generation molecule, AGEN1181, to actually increase the time that the antigen presenting cell and the T cell are together. That education time improves the way that the immune system can recognize that antigen.
The molecule is designed to, and preclinical data have demonstrated that it is doing so. I'm going to hold my urge to tell you a little bit about the clinical data for just another moment. The other component that CTLA-4 antagonists were designed to do were intratumoral Treg depletions, and we don't see that with a first generation molecule, and as much as I'm aware, and many of the experts have shared with us.
The way that we've designed our next generation CTLA-4, we have demonstrated pre-clinically that we may be able to achieve this. The only way we're going to know that today clinically, as the translational data are being analyzed, are clinical responses.
We've designed a molecule that can go beyond the activation of T cells, what a first-generation CTLA-4 can do, and we've designed something that can also prime, and it can also deplete these suppressive Tregs.
That's why we're calling it something beyond CTLA-4 antagonist. It's a multifunctional T cell engager because of the features that it presents. The most important feature that I see in this molecule is its ability to increase the exposure from the 20% of patients who respond to Yervoy to over 60% of patients, and maybe even more.
These are patients who we've seen, and others have reported on as well, who exhibit a genetic polymorphism that renders them unable to respond to a first generation CTLA-4. These are patients with a mutation in their CD16 allele status. We're measuring that. We've brought in today Dr. Chuck Drake, who's world-renowned in this space.
I asked him if for as long as I have been in this field, I asked him how long he has been in immuno-oncology, and he said, "Since, I think 1990." Maybe you might have said 1989. You were six. I said, it's so exciting to be able to share the stage with him. What Chuck will tell you about today, of course, are how important T cells are. The effectors are important. What about some of these other cells? What about the T regulatory cells?
How about the myeloid cells, the macrophages? Tyler's going to speak with you a little bit about that as well. Today, we are going to present to you data on AGEN1181, a case example. What we have seen in the clinic right now with over 20 patients treated, we've seen disease stabilization in the majority of patients who are responsive evaluable.
We have a patient with a solid tumor, a patient with endometrial cancer, a patient who has had the poorest prognostic factors genomically, phenotypically, who has had a complete response on AGEN1181. In only the first few patients, the first 20 patients, we've seen this complete response, which is incredibly exciting for us. I'll tell you why it's so exciting. Beyond metastatic melanoma, there have only been four solid tumor complete responses to YERVOY, to first generation CTLA-4.
Those were all in prostate cancer, and Chuck Drake knows those cases quite well. We are in a position where we are seeing something, and those four patients were observed in more than 1,000 patients treated. As you can imagine, this is outside of melanoma. We're seeing something quite exciting with just a limited sample size right now.
Now, AGEN1181 is in the clinic. We launched it. We're dosing as a monotherapy as well as in combination with our own PD-1 and the molecules moving forward. It's one of the components that we'll be looking very forward to sharing additional data with you, ideally at major medical conferences and specifically this year, certainly beginning of next year as well. These data are very dynamic, and they're continuing to present.
Tyler Curiel is here. He's going to share with you a deeper look at what might be happening with this patient with the cell types. He's going to introduce Dhan Chand. Dhan, our head of drug discovery, is going to share with you how we're now going beyond just effector T cells. We have the most robust and productive research engine that exists in the industry today, I believe.
We have outpaced Big Pharma in our ability to deliver novel agents to patients, and these molecules are moving forward in our own hands as well as, importantly, in the hands of our partners. With a company of just about 320 employees, we've outpaced Bristol, Merck, and AstraZeneca, and Novartis and many others in delivering new discoveries in IO to patients with cancer.
As Brad just mentioned to you, it was palpable how urgently he is seeking new therapies that will work for his patients. We know right now it's a volume game, right? You need more discoveries. We need to continue to test them and interrogate them.
We need to combine them optimally, and we need to be able to deliver them to patients in a way that is feasible. We've designed a portfolio and a pipeline to do that with our monoclonal antibodies, our bispecific programs, with our allogeneic cell therapy approach that Mark is going to speak to you about, and many more.
In our hands, we have experts who not only have been able to discover and develop the molecules targeting CTLA-4 and PD-1, optimizing what is working to something that may be working much better, and continue to discover to manipulate other components of the tumor microenvironment. These are going beyond effector T cells, as I've mentioned earlier.
We developed the ILT4/anti-ILT4 molecule for Merck. We're experts in this space. We've discovered and licensed to Gilead, as Garo mentioned, GS-1423. This is a first of its kind CD73 TGF-beta trap molecule. Dhan's going to highlight a couple of features of that.
We have some undisclosed targets as well that we will be looking forward to speaking to you more about. Of course, our programs with Incyte are also advancing in phase II in multiple combination studies.
We have our discoveries advancing in our own hands, in the hands of partners, and generating a series of key catalysts throughout the course of the year, including cash milestones that we are quite excited to be reporting to you as these data continue to mature and these milestones come out. Without further ado, I am going to turn it over to the esteemed Dr. Chuck Drake, who's going to walk you through some important features of CTLA-4 and AGEN1181.
Thanks. Well, thank you all for coming, and thanks for that introduction. I'm not so sure about all the esteemed parts, but one part that is true is I've been working on cancer immunology a long time. I treated the first kidney cancer patient with anti-PD-1 with nivolumab in 2007. That person was lucky.
They had a complete response, actually, and today they're still alive in a complete response with no evidence of recurrence. That's some of the things that we can see immunotherapy do when it works. Today, I'm going to talk to you about regulatory T cells and CTLA-4. What I'm going to first show you is some clinical and then a little bit of preclinical data to tell you why Tregs are so important.
I'm going to talk to you about a new approach to address the problem of Tregs in patients, that'll talk about the generation of the molecule that you've heard about, 1181, how it works. I've been privileged to share some of the early clinical data from the phase I trial. Actually, there's a little bit of confusion in the field. In the tumor microenvironment, there's many cells.
There are suppressive cells like macrophages and myeloid suppressor cells. Frankly, anti-PD-1 works mostly on the CD8 cells. It blocks the interaction between PD-1 and PD-L1 or PD-L2. If it works, CD8 T cells are activated, they proliferate, most importantly, they make interferon gamma. Interferon gamma reprograms, when it works, the entire tumor microenvironment, it actually cures some of the many other problems.
Within many tumors, there's a population of T cells called regulatory T cells. They express a canonical transcription factor called Foxp3, and they are designed to be bad. They are like our enemy in cancer immunotherapy.
They secrete factors that make CD8 T cells not work. Not only that, they make natural killer cells not work. They basically make a tumor effectively cold even when it's infiltrated. Tackling this problem has been a goal for cancer immunologists for a long time. We knew this from mouse models.
This is old mouse model data which we wanted to replicate in humans forever. These are mice. This is B16. This is your cold tumor. It grows in mice, has no T cells. It grows. Anti-PD-1 doesn't work. Anti-CTLA-4 doesn't work. It doesn't work, actually. I've done this mouse model hundreds, perhaps thousands of times.
What happened was a group engineered a mouse model where you could deplete all the Tregs. These had Foxp3 with a diphtheria toxin receptor. Basically, when you give the mice the diphtheria toxin, all their Tregs disappear. Even in this cold tumor, getting rid of all the Tregs is amazing. It basically cures the mice.
This is 2010, right? We wanted to have a drug like this in humans for a long time, and I could tell you that we've been looking for such a drug, actually. Frankly, we don't really have that yet. What I'm going to show you next is three pieces of data that tell you even more why we need something to address regulatory T cells. The first one is from a cold tumor, which is prostate cancer.
Before anti-PD-1 and anti-CTLA-4 and checkpoints were cool, what we did was vaccines. This is a trial to try to make a cold tumor hot with a vaccine. This is an old vaccine. Some of you may be invested and lost money in a company called Cell Genesys. This was the Cell Genesys GVAX vaccine. We had data from animal models that if you give hormonal therapy, which is the most common treatment for prostate cancer, you get a T cell influx.
The idea here was we were going to convert that to hot with a vaccine and see what happens. These data showed us something very, very interesting. On the top line, we have the primary outcome of the trial. That's how many T cells are in the tumor. That's 96 cells per millimeter squared. That's low. Melanoma is typically 400, 500.
That's baseline. That's the control. If you give hormonal therapy, it works. Hormonal therapy is a kind of immunotherapy. You double the T cells in the prostate gland. The vaccine kind of worked a little bit. You went from 200 to about 250. This was, in fact, not statistically significant. We actually did see a small signal in terms of progression-free survival. What's most important is the next line.
At the baseline, there's plenty of Tregs in the prostate gland. Most of the CD4s in the gland are, in fact, evil Tregs. When you double the CD8s, you exactly, this is not something you can make up. You exactly double the Tregs. Double. If you get a little bit more CD8s from the vaccine, guess what? The Tregs go up another notch, actually.
This is a phenomena that probably occurs in multiple tumor types when you have an immune response, and we call it, and other people have called it the same thing, adaptive Treg resistance. This suggests that we should really do something about these regulatory T cells, and I'll show you in a little bit exactly how.
This actually happens in mice, too. We have a mouse model of prostate cancer. These mice develop cancer. It responds to hormonal therapy for a while, just like patients, and then it grows out.
If you look at those mice, the green bar up there is CD8 cells. Guess what? In the mice, the same exact thing happens. You castrate them, and you double the CD8s in the tumor, but you also double the Tregs. What can you do about it? What is a good target for regulatory T cells?
It turns out that the drug you've been hearing about many times this morning, YERVOY, ipilimumab, and the new Agenus molecule, are really probably mostly focused on regulatory T cells. These are RNA sequencing data from sorted Tregs from prostate cancer. We've done the same experiment from GBM, from bladder cancer, and from several other tumor types. These are multiple patients.
This is about 12 patients. This is RNA sequencing profiling. Where is CTLA-4 in the tumor microenvironment? The answer is crystal clear. It's almost entirely on the regulatory T cells. That's the TIL Tregs.
There's some mythology, and some people present this in a confusing way, and I can tell you it's not true. There's very little CTLA-4 on the CD8 cells in the tumor. It's mostly a Treg marker. Anti-CTLA-4, like ipilimumab and the next generations, probably target mostly regulatory T cells.
That's good, right? That's why you can have the effects we saw before, which are potentially even synergistic. Anti-PD-1 on the CD8s, anti-CTLA-4 on the Tregs. It's actually not rocket science immunology. It's fairly straightforward, actually. It turns out, though, that the antibody that's in the clinic, ipilimumab, anti-CTLA-4, is not a good drug for depleting regulatory T cells. It blocks them, but it doesn't deplete them.
These are experiments in these mice trying to treat them. This is a really challenging model. Just like patients, it doesn't respond to anti-PD-1. On the bottom, you see androgen deprivation therapy, a drug called degarelix plus anti-PD-1. None of the mice are cured, and it doesn't even slow down the cancer. Importantly, on the top right is a version of anti-CTLA-4, the mouse version that's like YERVOY. It's like ipilimumab. It's a non-depleting.
It doesn't deplete Tregs, and it doesn't work. If you use an antibody, this is a mouse IgG2a that binds to mouse Fc gamma RIV. If you do this, actually, you can reliably cure between 15%-25% of the mice forever.
They're cured, actually. The idea is that if you really could deplete Tregs in humans, you might have a different effect than just blocking CTLA-4, like the top panel. This is not only with hormonal therapy. It probably happens with any time you push the immune system within a tumor, the tumor probably adapts with adaptive Treg resistance, okay?
Radiation therapy, there are many trials that show that radiation therapy increases the CD8s in the tumor. This is looking at the Tregs in the tumor. These are three different kinds of tumors, a melanoma, a kidney cancer, and a colorectal cancer.
You can see on the top is control, on the bottom is after radiation. When you increase the CD8 cells, you increase the regulatory T cells. Reliably, actually. Radiation therapy also increases the regulatory T cells in the tumor. We performed similar experiments in these models. On the top is untreated mice treated with radiation.
Radiation doesn't cure advanced tumors in mice if you let the tumors become more advanced. Our group with Michael Lim, we were one of the first to publish that anti-PD-1 combines with radiation therapy. You can see in the middle row on your far right, it does, actually.
With anti-PD-1 plus radiation, you can cure some of the mice, actually. Anti-CTLA-4 has some activity in this model. This is the colorectal model. The depleting anti-CTLA-4 is amazing, actually. Basically, that plus radiation cures the majority of the mice.
The question you should always ask me, you see mouse data like, okay, how reliable is this? How relevant is this? Are they really cured? These experiments were done by a radiation oncology resident who was in the lab. Somehow he left. Okay. He went down to the NIH to do a rotation, he was there for like three months, then he came back.
He came back, he said, "You know, I still have a lot of these cured mice. What should I do with them?" I said, "First of all, you wasted a lot of money. Second of all, we should try to see if they really are cured." This was a surprising finding, which was repeatable. That is, if we challenge the mice that were cured with radiation plus anti-PD-1, they weren't all cured.
They were not all cured. 50% would still take a tumor. The mice that were cured with the depleting CTLA-4, the enhanced CTLA-4, they were all permanently protected, actually. The idea, and Jim Allison says this all the time, and I didn't believe him, quite frankly, that anti-CTLA-4, given in the proper context, promotes T cell memory, and that's a good example of this.
These mice had sat for about 60 to 80 days, I think this is enough time to show that we really do have memory. That's what we want. We want this kind of drug, actually. What do we have? This kind of got a little space. We have ipilimumab. It's an IgG1. It almost certainly does not deplete Tregs in humans. In fact, in some experiments after ipilimumab, you see what I just showed you, adaptive Treg resistance.
In fact, there's sometimes more Tregs, actually. There is about 25% Grade 3/4-related adverse events. tremelimumab is an IgG2. This is a non-depleting antibody. tremelimumab doesn't deplete Tregs. You just heard about the first-generation molecule from Agenus. BMS has a version in the clinic that's an afucosylated. It is an enhanced CTLA-4. It hasn't been reported yet.
Merck has a trial, a drug that's actually reported nothing. Their CTLA-4, they affectionately call this Merck Ipi or Mipi, actually. We know nothing about this, actually. There is some enthusiasm in the clinic for anti-CTLA-4. There's other molecules. These are just a couple of selected ones.
The reason I'm here is because I'm excited about this molecule. If you could have an ideal anti-CTLA-4, what would you want? First of all, you want a high affinity for anti-CTLA-4. That goes without saying.
That comes with most modern antibody selection techniques. What you'd really want, though, is it be Fc optimized to enhance depletion of regulatory cells. You really want to get rid of them. If that occurs, then you would see enhanced T cell activation, and as I showed you, what you would really hope for in the long run is those long-term responses with T cell memory, and also reasonable tolerability, but we know that drugs like this are likely to cause some immune-related adverse events. How can you do this?
This is a lovely paper, and if you really want to read into the heart, I think actually, of Agenus, you should read this paper. It's in "Cancer Cell." Okay? It's a great paper. You got to read it slowly. It has a lot of abbreviations and things, so it took me a long time.
I read it once and I read it again yesterday just to be sure I had it right. What they did was they enhanced CTLA-4 molecule so that it would bind more strongly to the Fc receptor, particularly in humans, the version is FcγRIIIa. Here, I'll go over here and show you. Here's an antibody.
It's an IgG, so it has two arms. This is the standard IgG1. It blocks the interaction of CTLA-4 with CD80 and 86 on antigen-presenting cells. That's the blocking function. What you'd really want though is not just that. You'd want it to bind more strongly to FcγRIIIa. How can you do that? It turns out that there have been mutations in the Fc portion of antibodies described that would more strongly bind to FcγRIIIa. One of these is called DLE, actually.
It's a scaffold of IgG1 that binds more strongly. That's what 1181 is. It's an Fc engineered enhanced CTLA-4 antibody that's intended to bind very strongly to FcγRIIIa so that the mutations or the variants don't make any difference, and that should lead to enhanced depletion and to enhanced T cell activation.
That's the molecule that we're going to talk about a little bit next. I'll show you three pieces of preclinical data. You might say to yourself, "Why aren't you showing any mouse data?" The reason actually is this is enhanced to bind to human FcγRIIIa. Mice do not have human FcγRIIIa. It's hard to show those kind of things. What, they don't look okay?
It fell.
Sorry about it. Thank you. This happens all the time. I'm being rearranged. This is, I think, the job one of an enhanced CTLA-4 molecule would be to deplete Tregs. This shows a parental IgG1, again, similar to ipilimumab, showing perhaps in vitro some depletion, but the enhanced molecule showing a gorgeous depletion of regulatory T cells. These are important in vitro data. More importantly, I like this figure the best. This is from the paper, which I encourage you to read once again.
This is a wild-type IgG1, and this is T cell activation measured by IL-2. Here's the wild type. This is what you'd expect from ipilimumab or potentially other IgG1 antibodies. It's pretty good. It basically leads to T cell activation. These molecules really do have to bind to the Fc receptor for this to work.
This is a mutant antibody that doesn't bind to the Fc receptor, and it quite simply doesn't work. Actually, only moderately leads to T cell activation. This is the one that's in the clinic. This is AGEN1181, the DLE engineered, and it really increases T cell activation through that enhanced binding. We heard from Dr. Monk that anti-CTLA-4 by itself as a monotherapy is FDA approved in melanoma, and we don't do it that way.
Nobody does that anymore. It's always used in combination with anti-PD-1. If there's really going to be a good clinical candidate, then it should work with anti-PD-1. These data are practically even more impressive.
Here's the parental antibody plus anti-PD-1 down here, these black bars, and here's the next generation with anti-PD-1. You can see this doesn't look like additive. It looks like it might even potentially be synergistic.
Again, the idea is this is an enhanced molecule, potentially with more activity. We have a little bit of data, and I've been tasked with presenting some of the early clinical data. This is a first look. Take it for what it's worth. I think it's interesting. I'm actually involved in phase I. This afternoon at 4:30 P.M., I'll go to our phase I meeting and we'll review phase I.
Phase I is not what it used to be. Phase I patients have a lot of options, and to see activity in phase I has become much less common than it used to be. We're actually very, very happy when we see stable disease in our phase I trials because there's so many other treatments that patients could have, including off-label anti-PD-1 by compassionate use or other molecules.
This is a dose escal-- I've got to go back. I don't know if I can go back. Okay, good. There it is. This trial was initiated, the combination was initiated in 2019. So far, 20 patients have been treated either alone or in combination with balstilimab, the anti-PD-1 that you just heard about.
What's, I think, amazing or surprising is there's been a complete response in this small group of patients, actually. This is a patient with endometrial cancer. They had, as is typical, a long treatment course, initially with surgery, adjuvant radiation, anti-PD-1 pembrolizumab.
Almost every patient in our phase I group has had prior anti-PD-1, so this is not atypical. They progressed. They were treated with a PI3 kinase inhibitor, palliative radiation, and then went on to trial. This is a monotherapy response to the enhanced molecule.
This is one of the target lesions, a large lymph node lesion. This patient is a woman who had severe abdominal symptoms. After two doses, she had her symptoms resolved, and after four doses, she had a complete response. We heard recently that this has been confirmed yet another time.
This is unusual. It's unusual to have a complete response to a monotherapy in phase I in a patient like this with multiple prior treatments, including, again, pointing out anti-PD-1. To compare to the literature, as Dr. Buell talked about, in the entire literature of anti-CTLA-4 in clinical trials, this is all with ipilimumab, there are really not a lot of complete responses as a monotherapy. We ran two large phase III randomized trials. I was the global PI on one.
In prostate cancer, there were a handful of complete responses. Again, that's well over 1,000 patients and very, very few complete responses. Seeing a complete response at this stage is actually quite rare and, to be honest with you, surprising. I said surprising. There are also multiple patients on this trial who have long-term stable disease.
I think this is important because this shows an early signal for this drug as a monotherapy. It's now in a combination with the anti-PD-1. I think that's where we're going to see an enhanced activity.
We're excited for this to move forward, actually, not only into phase I but in multiple tumor types. This is my summary. Actually, even though I'm not an investor guy, I made this say forward-looking. Forward-looking. This is an interesting molecule.
This is a really, really unique Fc-enhanced CTLA-4. If you look at the paper, you'll see there's beautiful data of in vitro activity in multiple models with multiple controls, and it's a Cancer Cell paper.
It's a very strong paper. We already have some data for monotherapy activity, but the real future of a molecule like this lies in combination with anti-PD-1 or, as I showed you, potentially with radiation therapy or potentially with any anti-cancer therapy that induces this adaptive Treg resistance because I personally believe that our data and other data really point to this as a mechanism by which multiple tumor immunotherapies or other therapies fail.
In bladder cancer, we actually showed that the response to chemotherapy depends on Tregs. If you look at initial response to chemotherapy, patients who have a lot of Tregs, it doesn't work.
The patients who have fewer Tregs, it works. I think Tregs hold back the response to multiple cancer therapies, making this an attractive candidate going forward. That's it. I'd like to thank you for your attention, for coming out. Thanks.
Thank you very much. Thank you very much, Dr. Drake. That is thrilling for us to hear and to see how the molecule preclinically was designed, is now playing out in the clinic, and I'm going to have Dr. Curiel walk you through what might be happening just at the cellular level as well based on our findings in the clinic. Tyler.
Thanks. Can I get miced up or do I have to stand in front of this?
Sure.
All right. I like to move around. Well, good morning, everyone, and thanks for giving us a few minutes of your time. I just want to clarify on your program, my credentials. I actually am also a medical doctor, board-certified medical oncologist, and I specialize in, thank you, cancer immunotherapy phase I trials, and I used to run the phase I program for immunotherapy and all phase I cancer drugs at UT Health.
I initially trained in infectious disease and actually switched to cancer immunotherapy back in 1995. I've been doing this a very long time as well. Our group was involved, thank you, with work that led to the drug that's now durvalumab, and I was the local investigator for the registration trial for that.
We were also the group that showed the relevance of Tregs to cancer immunotherapy in humans for the first time. What I want to do now is just I want to go back to that patient that Dr. Drake just presented that had the remarkable response to 1181 and try moving this. How do I advance?
Okay. Take a look at that patient's response and just talk a little bit about what might be going on there, what it might mean, then where the future holds going from there. If this patient had come to see me in the phase I clinic, I would have looked at her and I would have thought, "Okay, her tumor's BRCA wild type.
She's MSI stable, meaning not likely to have a lot of mutations that are actionable for immunotherapy. Tumor is PD-L1 negative." You heard a little bit about the Fc isotypes. Her FcγRIIIa, which is also CD16, she's the FF phenotype.
That's the low prevalence, low affinity phenotype that's associated with poor outcomes with many types of immunotherapy, particularly with first generation anti-CTLA-4. Now that I heard the presentation, I'll also add that she failed another immune checkpoint agent, anti-PD-1.
These are all terrible risk factors for response to immunotherapy, I would not have predicted that she would respond to another immune checkpoint agent or for immunotherapy in general. Yet she didn't just respond, she had a complete response that's confirmed and durable. I think that's really remarkable in this one single patient.
When I'm thinking about immunotherapy for cancer, what's going to happen next? First, I think about these things here as poor risk factors, yet she had a response. There's two big areas that I think about.
Garo led off by talking about cancer as being a battle. You think about in the battle, you have the troops, which are the killer cells, then you have the battlefield itself, which is the tumor microenvironment.
If you're going to have effective immunotherapy, you either have to improve the numbers or function of your troops, or you have to soften up the battlefield. What I'm going to show you is AGEN1181 can potentially do both of those things. We'll also talk about how that plays into thinking about other treatments as we go forward.
What's becoming pretty clear is you've heard a lot about the fact that in cancer immunotherapy, the prime driver is CD8 positive T cells. They're really important, but we're now understanding that there are many other immune cells participating in that immune response that are also very important, and we're just starting to pay more attention to those cells.
How do you do the laser pointer? Is it the red thing? Let's try it. Does that? Oops, no. Okay. I'm mic'd up, so okay. This is an analysis of blood cells, and this is an in vitro analysis of the AGEN1181. This is the second generation anti-CTLA-4 you've heard about. Oh. Oh, okay. AGEN1884 analog, this is essentially first generation anti-CTLA-4.
You can do an in vitro analysis, take peripheral blood cells from humans, treat them with a control with first generation, which is AGEN1884, or second generation, which is 1181. You do an analysis called RNA-Seq, where you look at the gene expression of the cells, and then you do bioinformatics, and you say, "Put the cells into different groups and let me see what's going on."
You get maps that look like this, that'll show you different populations of immune cells. I want to call your attention to this population of memory cells here in these patients that are treated with 1181, which is here.
Here's your isotype control, and you see this population of memory cells looks like this in the control. The first generation anti-CTLA-4 can increase that population a little bit, but 1181 increases it a lot more.
Now what you can do is go back and say, "Well, who are these cells?" They're these cells here. This is a specific population of memory cells. Dr. Drake just got done telling you about the importance of immune memory and how first-generation anti-CTLA-4 can induce memory, and memory is critical to immunotherapy.
Without memory, your responses are not likely to be durable. Here's an important memory population that is largely improved by the second-generation anti-CTLA-4, 1181, and that's a pretty good candidate mechanism for why this patient could have responded as well as she did, despite all those negative factors. The next thing is in looking at other kinds of killer cells. Next, this is data that's mined from a publicly available source, oops, which is in the reference. It's up there somewhere.
I don't see it highlighted. This is publicly available data. These are patients in a trial of metastatic melanoma receiving ipilimumab plus nivolumab, anti-PD-1 plus anti-CTLA-4. You do the same kind of analysis that I just showed you.
If you re-mine the data with bioinformatics, you can see that in the patients, there's a population of gamma delta T cells, and these gamma delta T cells are different than conventional CD8 positive T cells. Conventional T cells that everybody's talking about are antigen specific.
They're tumor specific. These gamma delta T cells are prevalent. They're in most tumors that have been looked at. They're not as antigen specific as conventional cells, but they're clearly important to anti-tumor immunity, and now we're starting to see they're relevant to immune therapy outcomes.
If you take this publicly available data and you mine it and do the same type of analysis that I just showed you from our in vitro data, you can see that these gamma delta T cells are highly activated by this combination therapy, whereas other cell clusters, looking at these same genes, were not so activated.
This is fairly gamma delta T cell specific. If you look at patients that were defined as responders versus non-responders. In the non-responder patients, their gamma delta T cells did not go up on therapy, whereas the responders, the gamma delta T cells went up quite a bit. This is correlative data. It doesn't prove anything, but it says that maybe gamma delta T cells are important in this treatment outcome, as they've been seen in other kinds of outcomes.
We go back to our in vitro analysis. Now we're back to Agenus data again, looking in vitro, taking peripheral blood T cells, activating them with the agents as I showed you before. Now we're going to take that data that we generated with 1181, the second gen anti-CTLA-4, and compare it to that data we mined from the public data set in that clinical trial. Here's what you see.
This is the data in the publicly available data set from the clinical trial, and this is the data from our in vitro experiments using 1181. What we can see is this is a heat map of activation of gamma delta T cells, and 1181 is also activating the gamma delta T cells, also activating the same genes, but also looking like it's doing a better job, and you're not seeing so much in other kinds of T cells.
Further, consistent with the data that's in the public data set, you can see that the second-gen 1181 anti-CTLA-4 is increasing the number of gamma delta T cells much more so than the first generation anti-CTLA-4 analog that we're comparing it to here in vitro.
When we look at specific genes that everybody cares about, this is the interferon gamma gene. That's also strongly activated by the second generation anti-CTLA-4, but not the first. This suggests that activation of gamma delta T cells can be contributing to the immune response, and it requires more work to understand that better, but the preliminary data suggests that could be a player.
I'm not showing you the data here because Dr. Drake already presented it. In vitro, you've got the ability of AGEN1181 to activate T cells that have that low affinity, poorly responsive FF allele of their Fc gamma receptors.
You now see that because of that ability of AGEN1181, that's another reason why it can activate the soldiers. That's improving the killers in the army here, activating gamma delta T cells, bringing in a new kind of soldier. Inducing the memory is improving the soldiers that are already there, the conventional T cells.
Lots of reasons to think why AGEN1181 could be better than anti-CTLA-4, first generation. I'll say a little bit more about that again. To summarize this, we've seen that AGEN1181, the second generation anti-CTLA-4, could be a superior approach over first generation because it's improving immune cell memory.
It's activating another killer cell, the gamma delta T cell. It's effective in a patient that has the FF low affinity, low responsive allele. I'll say more about, there's other experiments ongoing to improve on these observations, which can be summarized here. The next steps are, we want to make better killers. We want to make better battleground softening agents. When you look at most biotech companies, look at big pharma companies, they tend to have one approach.
They're either going to have drugs that are going to improve the killers, or they're going to have drugs that soften the battlefield. It's unusual to see a company that has agents that can do both.
Agenus has products that Dhan's going to talk about in a minute, and you're going to hear from Mark also, that are in these other categories of agents that can either improve the killers, improve the battle softening, all in one company, and these agents are rationally designed to work with each other, so that within the company, you have the improved killers and the improved battleground softeners as well. In that regard, boy, don't ask me to operate the microwave.
Okay. Let me see if I can finally do this. AGEN1181, in terms of making better killers, I've talked about that. CAR iNKT cells you hear are better killers. In silico algorithms that can predict immunogenic epitopes for which you can direct immune therapy and other approaches that you may hear about today. On the softening the battlefield area, AGEN1181 reduces regulatory T cells.
Regulatory T cells are keeping the killers from doing their job even though they're there. There are other agents, bispecific agents you hear about, that are reducing soluble immune suppressive factors. TGF-beta you heard about. CD73 you heard about, can improve myeloid cell function, which is a major reason that the killer cells don't work. All of this is in the pipeline moving into the clinic, and I'll let Dhan give you the details.
Thank you very much, Tyler. Maybe I'll just give you a well-deserved pause, a thinking pause, and I'll have you take off your science hat for a moment and just walk with me on the business side of things and think about, you're the one company who has a CTLA-4 and a PD-1, that's Bristol, and they knew that they needed something more besides the first generation.
They launched the two molecules that Dr. Drake told you about, which are moving, not at the pace of ours. To the best of our knowledge, we have exceeded the pace to getting our 1181 into combination with PD-1. To our knowledge, they have not yet.
What's more important, imagine yourself now, all of the other companies with a PD-1 who need to compete in this space and need to differentiate themselves to actually take advantage of the opportunity that is out there, the business opportunity, the opportunity for patients.
That comes to the likes of Merck and Pfizer and AstraZeneca, and these companies who have a PD-1 or a PD-L1 and need a molecule to differentiate. AGEN1181 really jumps ahead in years to accelerate the opportunity for some of these PD-1 molecules as our own, to be differentiated and to start to actually take advantage of a very significant revenue opportunity out there.
You've seen the science, you've seen the data on our first generation CTLA-4, on our next generation CTLA-4, and I just want you to spend a minute thinking about what this molecule, 1181, could mean for our PD-1.
I'll ask you to think about what it could mean now in combination, given the features with some of our other therapies that only we can do, such as our allogeneic cell therapy combinations as well. I'm going to turn it now over to Dhan, who is going to share with you how we're thinking about the rest of the tumor microenvironment, and some novel and exciting targets. We'll close with Mark Exley and Julie DeSander. Thank you.
Thank you, Jen. Thank you to the experts for providing their insight into how Agenus innovations are already creating better outcomes for patients today. To all of you on this journey, welcome. Thank you for being with us. My name is Dhan Chand, and I'm the head of drug discovery at Agenus. When we last met almost three months ago, we spoke about the innovations that went into the design of our next generation anti-CTLA-4 agent.
You heard from the experts today the promise that this molecule holds for patients, including a case report of a complete responder who, by all means, would not have been eligible for therapy with a first-gen CTLA-4 or anti-PD-1. This represents a fraction of the innovation that's occurring at Agenus.
Today, I will provide you with an overview on our next wave of innovation, molecules that are designed to go beyond the T cell, address mechanisms of resistance, and relapse to current therapies, and condition the tumor microenvironment for a better response.
In fact, two of these molecules are already in the clinic, and two more are expected to see INDs filed later this year. This speed to innovation, this ability to go from an idea to an IND in less than two years is inherent to us.
It is reflective of our capabilities to identify relevant targets and mechanisms and design optimal solutions in real time to address the biology. I'll provide you with four mature examples today. The first is addressing two very potent immune suppressive factors in the tumor microenvironment.
You heard from Dr. Curiel the need to soften the battlefield. Here is a case where in the tumor microenvironment, you see high expression of adenosine and TGF-beta. In the presence of adenosine and TGF-beta, you cause broad immune suppression, as well as contributing to relapse and resistance to current therapies.
Adenosine is generated by an ectoenzyme known as CD73, that is expressed on tumor cells and tumor stroma, as well as certain immune-suppressing cells. This target is well known to you.
TGF-beta, on the other hand, is a pleiotropic factor that enhances tumor progression, promotes angiogenesis and fibrosis, but also drives myeloid-derived immune suppression. What we observed in our studies is that TGF-beta also drives the expression of CD73, and in fact, in PD-L1 low patients, you see a high expression of CD73.
Our solution to this problem was to design a bifunctional molecule that potently blocks CD73 and prevents the degeneration of adenosine in the tumor microenvironment and neutralize all forms of TGF-beta.
This design of the molecule demonstrated superior activity compared to either therapy on its own or the combination of either therapy on its own. This molecule, GS-1423, binds to CD73, blocks the adenosine production, and neutralizes TGF-beta, essentially conditioning the tumor microenvironment for a better immune response.
As you heard from Garo earlier today, this molecule was one of the features of the Gilead transaction and is currently advancing in the clinic. Just to give you an example of the activity of this molecule, here we used a system that mimics the suppressive nature of the tumor microenvironment, a system that you heard three months ago.
Here is it in action. You see GS-1423 or a CD73 TGF-beta trap molecule enhancing the ability of antigen-specific T cells to kill tumor cells. More importantly, it enhances that in combination with anti-PD-1. This molecule is currently advancing in the clinic, and we look forward to further updates.
The second barrier, as Dr. Drake so eloquently described, are regulatory T cells. These are cells that by nature protect you and I from overactivation of our immune system and autoimmune-like symptoms or diseases.
Cancer co-opts these regulatory T cells to protect themselves. The challenge here is addressing that Treg barrier. That barrier that Dr. Drake mentioned was promoting resistance to current therapies, relapse to current therapies, through multiple mechanisms suppressed the tumor microenvironment, even including secreting TGF-beta, sopping up IL-2, and directly inhibiting effector T cells.
The problem with therapies that are directed to deplete or get rid of regulatory T cells is that they're not specific to intratumoral Tregs. That is why you see autoimmune or systemic toxicities with some of these therapies that are designed to just go after Tregs. Our solution to this was based on an observation that we made that on intratumoral Tregs, they co-express two targets, and that the engagement of these two targets can lead to selective binding to intratumoral Tregs.
We designed a bispecific molecule, AGEN1223, that binds to these two targets. We're not disclosing the targets there, so we'll just refer to them as X and Y, that are only expressed in the intratumoral Tregs. They're not expressed on peripheral Tregs. More importantly, we engineered this bispecific molecule to engage activating Fc receptors by introducing mutations into the Fc portion of this bispecific molecule.
Not only are you getting selective targeting of intratumoral Tregs, but you're also enhancing its ability to deplete these Tregs. This is reflective of the innovation and discoveries that we have at Agenus. This molecule is already in the clinic as of December 2019, and we look forward to providing you with updates.
To give you an example of the power of this molecule, its ability to deplete regulatory T cells, here is an example of AGEN1223 compared to that of monospecific approaches to the same targets.
The targets are well known. In fact, there are drugs in the clinic already going after either one of the targets, but none of them are designed to deplete regulatory T cells. In this particular example, we co-cultured regulatory T cells that are reflective of intratumoral Tregs with depleting cells such as NK cells, and we demonstrated that when you treat these cells with AGEN1223, you significantly deplete or enhance the depletion through selective binding and through enhanced Fc gamma R interaction.
When you compare that to monotherapy approaches to either one of those targets using competitor antibodies, you do not see that depletion because they're not designed to do that. The only way you can get this selective depletion is using Agenus' bispecific platform in combination with Fc engineering to extract this unique activity.
This highlights why you'd need to design it this way. Designing the bispecific is important to us because it gives us activity that you otherwise cannot extract from the monospecific antibodies. More importantly, if you use the monospecific antibodies in combination, you still do not see that same level of activity.
This is unique to AGEN1223. The third example, as you heard from Tyler and Jen, is addressing myeloid cells, tumor-promoting or immune-suppressing myeloid cells. When you think of the activity of PD-1 and CTLA-4, they're generally driving T cells or cytotoxic T cell activity or addressing the Treg bar in the case of 1181 and 1223. Macrophages or myeloid cells, by nature, protect you and I from infection.
They clean up cellular debris. They act on our behalf. When they infiltrate the tumor microenvironment, they get converted into immune-suppressing macrophages. Unlike the previous example where we wanted to deplete regulatory T cells, here, we want to turn those macrophages back into tumor-fighting macrophages.
We don't want to deplete them. Not only are they important for phagocytosis of target cells, but they're also antigen-presenting cells. We need those cells to further the immune response and deepen the immune response. It's similar to what we did for Merck. We built Merck's ILT-4 antibody, a very difficult target where only Agenus was able to deliver an antibody. That molecule is also advancing in the clinic.
Here, we discovered another receptor expressed on tumor-associated macrophages that binds to a ligand expressed on tumor cells, and that engagement results in the suppression of macrophages, converting them from tumor-fighting macrophages to tumor-promoting or immune-suppressing macrophages.
Moreover, the engagement of this receptor suppressed Fc gamma R signaling when done in combination with targeted therapies like cetuximab or other targeted therapies that depend on Fc gamma R interactions. Our solution to this problem was to design an antibody that potently blocks the interaction between this target and the engagement of its ligand on tumor cells.
Unlike the first two, it's just a monospecific antibody. That's because that was the best solution to this target. We're not designing bispecific just because it's fashionable, we design it because it's necessary. In this case, a monospecific antibody is absolutely necessary to block this interaction.
We observed that blockade of this interaction turned those tumor-promoting and immune-suppressing macrophages, otherwise known as M2 macrophages, back into tumor-fighting macrophages. Now they work on your behalf, they can, in addition to that, work in combination with other therapies that depend on antigen presentation. This molecule is projected to have their IND filed by the end of this year.
Just to give you an example of the activity of this molecule, AGEN1531, you will see on the left a co-culture assay of macrophages, in this case, M2 macrophages treated with AGEN1531. The tumor-promoting, immune-suppressing macrophages treated with 1531.
You will see that when you block this interaction with its ligand, you convert those macrophages into tumor-fighting macrophages, as shown by the pink graph. This conversion was analogous to just adding the M1 or tumor-fighting macrophages to your culture.
Rather than taking a cell therapy approach to give you these macrophages, this molecule can convert those macrophages for you. The next example was the ability to enhance Fc gamma R signaling when done in combination with targeted therapy. As I mentioned earlier, one of the other features of this target, when it engages ligand, it suppresses Fc gamma R signaling.
When we block the molecule at AGEN1531, we are able to enhance Fc gamma R signaling in combination with a targeted therapy. The last molecule I'd like to speak to you about, which is in line with our goal of bringing therapies to patients that do not respond or relapse to current therapies like anti-PD-1, is based on patient progression due to the upregulation of secondary immune checkpoints upon treatment with anti-PD-1. There are multiple immune checkpoints out there, several of them.
Identifying the right ones is important. We used several different approaches to identify and guide us to what are the right mechanisms and the right targets to go after. You heard about the Treg depletion, addressing adenosine. Those are all relevant mechanisms that can enhance an immune response. In this particular example, we observed that patients treated with anti-PD-1 upregulate a network of interactions that contributes to relapse.
In addition to that, non-responding patients showed high expression of this particular network. When we investigated this network that was promoting immune evasion outside of anti-PD-1, we discovered that blocking these targets not only promoted responsiveness in settings where PD-1 no longer matters, but also enhanced both innate and adaptive immune arms of the immune system, enhancing both T cells and NK cells. The ligand for this target is overexpressed on tumor cells.
It's driven by interferon gamma, the same signal that drives PD-L1 expression, and if you take away the PD-L1, the system becomes heavily dependent on this ligand. Blocking these targets became critically important. When we approached them, we observed that the best way to block these targets was in a bispecific format.
A bispecific format that co-blocks the two inhibitory targets, moves the ligand over to a costimulatory target on T and NK cells. Not only are you reducing the inhibition, but you're also promoting the activation at the same time of both T and NK cells.
We also used our bispecific platform in this case and engineered the Fc to further promote and further enhance the activity using a unique combination of mutations that were specific for this particular drug. This molecule is also expected to have an IND filed later this year.
Just to give you an example of the activity of this molecule, here we used a PD-1 refractory or a model that responds very poorly to anti-PD-1. This is a mouse model using CT26 colon carcinoma cells. PD-1 in this model does not work very well.
When you treat this model with AGEN1777, our bispecific molecule that co-blocks these two targets, what you observe is near complete response at almost all of the mice treated with this unique bispecific molecule. 13 out of 15 mice showed a complete response.
When you rechallenge those mice with tumors, you see no growth. Consistent with the mechanism of action of enhancing both the innate and adaptive immune arms of the immune system. We look forward to having the IND filed later this year.
Not only will novel therapies allow us to expand the therapeutic reach of IO, but novel combinations. No one is better equipped than Agenus to advance and explore these novel combinations.
We are the only ones with a next generation CTLA-4 like AGEN1181 cell therapy approach, as well as tumor microenvironment conditioning agents that we can use to broaden the therapeutic reach of immunotherapy and promote durable responses and enable curative combinations.
I'm pleased to announce that later this year at AACR, we will be presenting data on these combinations, particularly around our next gen CTLA-4 AGEN1181 with other novel agents in our pipeline, including cell therapy. I look forward to presenting that at AACR. What I'd like to end with, and I hope you've seen this exemplified throughout our journey together is that Agenus is biology-focused. We're not a one-trick pony.
We're not married to one specific platform. We're committed to the biology. We're committed to what patients need next, and we're going to build the therapies that best address the biology. Our bifunctional CD73 TGF-beta trap that we licensed to Gilead is representative of this. These are capabilities that prior to discovering these targets, we did not have, but we saw the need to build a molecule that does that, so we did it.
Treg depleting agents that target a novel pair or a novel finding that Tregs only co-express two targets required us to build a bispecific molecule that was Fc optimized to selectively deplete Tregs. We did that. We're not trying to force one particular platform onto the whole biology. We're looking at the biology and building solutions for patients.
This is a type of innovation that allows us to go from an idea to an IND in less than two years, and why, as Garo and Jen mentioned, we've been able to outpace Big Pharma with bringing new solutions and new therapies to patients. Thank you.
Well, it's a privilege to be here presenting AgenTus for my colleagues. AgenTus is a cell therapy subsidiary of Agenus, and it's also a privilege to be presenting it with this audience and the world's top immune oncologists here, and Dr. Hidalgo and others who are working with Agenus on our clinical trials.
My background is that I was working in academia for many years. For the last five years, I've been with Agenus and then AgenTus. Before that, I was in Boston in Harvard Medical School as a professor with a lab, working on a population of cells called invariant NKT cells, and I'll briefly just summarize them and their capabilities. Really that work was to understand them, but also to exploit them and to develop reagents and tools to manipulate them in people and in the clinic. That's where we are now with AgenTus.
During that process, we founded as an academic MiNK Therapeutics, which developed some reagents which we are now using and as we acquired them into AgenTus Therapeutics. What is AgenTus Therapeutics? What do we have? We have several attributes which are unique in the cell therapy industry and which are obviously synergistic with everything you've heard about so far with the checkpoint antibodies.
Those are, we have novel targets as well as validated targets that we've worked with Agenus and our colleagues on to identify for tumor targeting. We have a mammalian display platform for developing CARs and TCRs, which we have shown is very effective at producing highly specific TCRs in particular. This has actually benefited and was derived from the mammalian display platform that was used for developing all the antibodies you've just been hearing about.
A very powerful tool and platform for developing and weaponizing the cell platform. Finally, we have the cell platform itself, and this is a thing that I've been working on for many, many years and taking now into the clinic in the AgenTus context. What are NKT cells?
They're a type of T cell which has some of the benefits of NK cells, but none of the disadvantages of either T cells or NK cells. It ticks the box for many attributes for a desirable cell therapy which are not so present or only partially present in the other types of immune cells that other types of approaches are exploiting.
They are able to kill tumor cells directly, as shown here, and this is important for their activity, certainly, clearly, and they are very potent killers of tumor cells with the right targets, expressing the right targets. They can also either modify and affect, repolarize the myeloid cells, the antigen-presenting cells that Dhan was just talking about in the tumor microenvironment or if necessary, if you like, kill them.
This gives them a second way in which they can have an anti-tumor activity. The third way is indirectly, they are able to activate NK cells, other T cells in the immune system. They have an adjuvant-like activity in the tumor microenvironment. They can repolarize the antigen-presenting cells, which helps to generate the right T cell responses that you want in an anti-tumor setting.
This is how they can function in a very synergistic way with other approaches as well as independently have clinical activity and this has been shown in some early clinical trials in various different ways, including a clinical trial that I did with my colleagues in Harvard on autologous NKT cell therapy on which we're now moving into allogeneic NKT cell therapy.
What are the features of NKT which make them attractive? Some of these are that they actually not only don't cause GvHD, unlike classical allogeneic T cells would, but they suppress GvHD.
And you don't need gene editing to use them in an allogeneic context. That makes it a lot simpler to use them. They have the capability to home to tumor sites, makes them very attractive for a lot of solid tumors as well as some hematological malignancies.
They are feasible to use in this context. That's critical because they're very rare cells. One of the reasons, obviously, that they're not fully functional in patients is that there are limited numbers, and they are functionally defective in patients who actually progress, although they have an antitumor activity in probably as near surveillance role in healthy people.
Consequently, because we can expand them dramatically, and this just shows a typical example of what we're doing routinely now in our clinical manufacturing process, is we go from a few million cells of iNKT cells purified with this monoclonal antibody I mentioned that we developed a while back, and that we use to purify them.
We expand them in a proprietary process, and within a month, and given this is allogeneic, that's very convenient, but it doesn't even need to be as short as that for allogeneic use, of course, because you're stockpiling it. We get very reproducible, massive exponential expansion.
This is a log scale, log to the base 10 scale expansion you can see. We go from a few million cells to tens of billions of cells, enough for treating a whole clinical trial phase I in our current process, and we know that they can expand well beyond this, to the 1,000 dose or more patient scale. This is a really practical, feasible, and powerful cell platform to exploit.
In terms of its targeting, we know that we can target a variety of different tumors, and we're particularly excited about those where CD1d is expressed, and CD1d is the target for this iNKT cell population in its own inherent receptor. We can target those even without genetic modification or addition of a CAR or TCR because these are CD1d-expressing tumor targets.
We add to that their ability to target the tumor microenvironment beyond the tumor cells themselves, and then to augment other immune cells and to work in synergy with checkpoint antibodies, then you have a really powerful cell platform.
Of course, if you add CARs and TCRs to that, you can then widen this to include all tumors, essentially. That's the summary of our AgenTus portfolio and its capability, and how it fits in nicely with the Agenus checkpoint antibody approaches.
Thanks, Mark. Hi, I'm Julie DeSander, I head up business development and alliance management at Agenus. In the short four years that I've been here, we have generated over $525 million in cash from partnership transactions. We have an additional $2.5 billion in potential future milestones and royalties.
These transactions are born out of the highly innovative programs, the incredibly efficient research, clinical, and manufacturing operations, the unique suite of technology platforms that you've heard about today. These transactions enable us to rapidly advance novel therapies to the clinic where they offer transformative promise to patients not benefiting from available therapies today.
As you know, we have a number of notable strategic partners today. Last year, we brought in $172 million from Gilead through our upfront payments as well as achieved milestones with an additional $1.7 billion pending in future milestones and royalties.
As you heard about today, Gilead licensed our CD73 TGF-beta bispecific and received options on two additional programs. We also closed a transaction, a $210 million transaction with UroGen late last year. UroGen licensed the rights to use zalifrelimab in combination with UGN-201 for local delivery of urinary tract cancers. Incyte continues to advance four checkpoint antibodies in the clinic and one preclinical antibody, all discovered by Agenus.
Merck is advancing our first-in-class ILT-4 antibody discovered by Agenus, which is expected to enter phase II studies next year. GSK continues to develop vaccines with our QS-21 adjuvant, including SHINGRIX.
That's not all. In 2020, we will continue to pursue new partnerships to grow and advance our portfolio. We intend to retain U.S. rights to the majority of our pipeline to build our future commercial business.
We're in active discussions with a number of large pharma and strong regional players for several assets in our portfolio, including AGEN1181, our next generation CTLA-4. We've also received interest in platform collaborations from companies that want to access our technology platforms to enable their own portfolio.
Like the iNKT platform you just heard about from Mark, we've had quite a few parties express interest in accessing that platform so that they can take their autologous or individualized cell therapies and transform them into allogeneic or off-the-shelf formats.
We've also been approached by a number of companies interested in clinical collaborations to access the PD-1 and CTLA-4 antibodies that you heard about today. These companies believe that Agenus is a faster, more flexible, and collaborative partner than working with big pharma.
Finally, we're exploring research collaborations and in-licensing opportunities to continue to expand our pipeline with complementary technologies. These transactions deliver value to Agenus in multiple ways. They deliver financial value in the form of upfront, milestones, and royalties. They accelerate the clinical development of our programs by expanding the geographies and indications under evaluation.
They enable us to expand the benefit of immunotherapy to more patients through novel combinations within and outside of our portfolio, and they support the expansion and future growth of our pipeline.
As you have heard today, we have an incredibly productive research engine for generating first-in-class and best-in-class immunotherapies. The pace at which we're developing new discoveries is such that we cannot internally develop all of these programs on our own.
Our business strategy is to out-license a portion of our portfolio to generate upfront and long-term financial value and bring these discoveries to patients as efficiently as possible. We will continue to retain a significant portion of our portfolio to build our commercial business, including U.S. rights to AGEN1181 and a number of the programs you heard about today. Thank you, and I look forward to updating you on our partnerships as the year progresses.
Thank you very much, Julie. I'm alive and live here. I just wanted to close with putting things into perspective. We started with Dr. Monk. He gave us the reality of cervical cancer. It is a young woman's disease by and large. The best treatment today that's approved provides 14% response rates in a select population.
These are not all comers. It's a select population. Whereas in our trials, we have taken truly relapsed patients and with monotherapy, with our PD-1, shown 12% response rates. Now, if you adjust the Merck response rates to that overall population, it's somewhere between 11% and 12%. We have to make sure that we put those numbers into perspective.
When we treat patients with our combination agents, our CTLA-4 and PD-1, that's the first generation CTLA-4, by the way, then in the same relapse population that we're showing 12% response rates and Merck is somewhere between 11% and 12%, we're showing 20%+ response rates.
As Jen and Anna alluded to, we wanted to wait to disclose the interim analysis, which was available to us last year, until we were more certain that the continuation of the trial was going to confirm that. Those data will be available in the next few months.
Dr. Drake told us about the importance of CTLA-4. CTLA-4 and the uniqueness of 1181, our next generation CTLA-4, in comparison to other CTLA-4s that are out there. One thing that I think is very important to put into perspective here is Jen talked about 20 patients having been treated with 1181.
I just want to make sure that you understand how we've gotten to those 20 patients. We've treated four patients at the lowest dose, which is 0.1 milligrams per kilogram. Three more patients at the next highest dose, which is 0.3 milligrams per kilogram. Patients beyond that with one milligram per kilogram, both in single therapy and in combination.
We talk about 20 patients, the data on those 20 patients have not matured yet, meaning we're not suggesting that one patient out of that 20 has seen a complete response. The data, as it matures, may, fingers crossed, may see more complete responses even in that 20.
I just want you to understand the perspective of Dr. Drake, that while it's unusual to see anything really meaningful in a dose escalation study, what we're seeing here is a dose escalation study where one of three patients at that dose that has been treated with more than two doses, basically, showed that complete response. That's what gets us excited about it. Dr. Curiel talked about the mechanism of all of this.
It's all deep science. It's high science. What he talked about and what Dhan Chand talked about are how we interrogate the biology, the tumor, the patient responses, so that we can learn from that process. Please, be cognizant of the fact that while the world likes to simplify things, meaning, let's simplify and let's have a single agent or a simple combination that does all the trick.
In cancer immunotherapy because of the complexity of this disease, that's not possible. That's why, Dr. Chand talked about how we are advancing our understanding of the biology so that we can continue to innovate in order to battle this nasty disease. That's the overall perspective on the reality of what we do.
Now, what we talked about also is in the context of our business model. Julie mentioned that we intend on increasingly keeping North American rights to our products for ourselves. On that note, when we have started talking about AGEN1181 with prospective partners, which is currently in active discussions, we have qualified it and said we're only interested in licensing out ex-U.S. rights. Normally, large companies don't like that, but none of the companies so far have left the table because of this restriction.
That's in a nutshell, along with the fact that what Julie presented, we have raised $525 million through corporate collaborations and innovative financing mechanisms in the last four years, which has basically allowed us not to come to the public markets with a marketed offering during that period of time.
It will be, in the next month and a half, five years since we have done a publicly marketed offering. Five years. During this year, our expectation is that we will continue to finance our operations with existing cash, plus milestones that we're certainly to receive, which amounts to about $70 million.
These are milestones that have already been achieved in some format, and we're going to be receiving cash in the next few months, and expected new transactions. That's basically the story in a nutshell. I know that you may be anxious to ask questions, and we invite you to do that. Thank you very much for your attention. Please, Matt.
Hi. Matt Phipps, William Blair. Thanks for all of that data and presentation and academic context. One question on the data presented for cervical cancer. I'm sorry if I missed it, did you disclose the percentage of patients who are PD-L1 positive? Obviously, Merck's data was 100%. Bristol's, I think, was 60%-70%. I guess for Dr. Monk, what would you expect across second-line cervical cancer patients?
Thank you for that. I should have emphasized. Those are on unselected patients. We would suspect that if we would biomarker-restrict it, the activity would even be higher. That just takes time. The initial data cut did not have that information. The tissue had been collected. That will be a key component moving forward.
Thank you for recognizing that, because that actually makes the activity look better because it is unrestricted patients. The number of patients that are PD-L1 positive at 1% is 80%. It is virtually all squamous tumors. About 20%-30% are adenocarcinomas. That is where the fraction of patients are generally PD-L1 negative. Thank you for that.
Great. Thank you. The safety profile of the combination, at small numbers, but actually it almost looked better than monotherapy. Is that just a?
I think it's-
a rare, small number fluctuation.
It's probably false, though.
Regardless, you're not really seeing added toxicity.
That's the point. It's really based on the dose and schedule of the anti-CTLA-4 product. That's right. Thank you for that.
Moving on to 1181. Great to see a CR so early, but we got a lot of different data thrown out at us with the different ways that this antibody could work better than ipi or other first generation CTLA-4s. How do you really parse out Treg depletion, Fc gamma receptor activation of antigen-presenting cells leading to more memory, T cells, these things?
Treg depletion has been tossed around a lot and been tough to really show. You had the CCR4 antibody really not show anything when used in PD-1 combos, which to me made it tough to really try to validate the Treg depletion strategy. My question really being on going forward, you brought up interesting ways to maybe deplete more Tregs specifically with a bispecific antibody.
Is that really going to be enough by itself, or is it really you have to have this whole thing going on where you're getting better priming of naive T cells through antigen-presenting cells, you're kind of making the tumor microenvironment more susceptible-
Cellular therapy.
Yeah, or cellular therapy. Yeah. A long question there.
It's a great point, but to be fair, no agent has really documented clear Treg depletion in human tumors yet. The CCR4 antibody, when we did these experiments with sorted human Tregs, CCR4 doesn't even come up, actually, in TIL Tregs. It comes up in peripheral, but not in TIL Tregs.
There's a number of markers that are more specific for TIL Tregs. While CTLA-4 is a great one, it's a good start, actually, there's other ones as well, actually. I think the proof of the pudding that you're asking for is going to come from on-treatment biopsies where Treg depletion is clearly demonstrated, and that should correlate with anti-tumor activity. The other added features of dendritic cell and T-cell activation will come from those studies.
When we do these studies at Columbia, what we do is we do single-cell RNA sequencing of on-treatment biopsies. Those are really the only kind of data, I think, that will demonstrate that carefully.
The other drugs that are in the clinic have not shown that yet, there's not been a lot of data on any of those drugs yet. That's what you want to look for, right? You want to look for a drug that really shows that it alters the TME, depletes the Tregs, and shows more CD4 and CD8 activity.
I want to add to that. The mogalizumab data anti-CCR4, the complete phase I data's going to come out in Clinical Cancer Research in the not too distant future. Couple of key points there. One is that there wasn't really good data on depletion of Tregs in that trial in the tumor. It was mostly in blood. The tumor data didn't show a lot of Treg depletion. Point number two is most of those patients had pancreatic ductal adenocarcinoma, which is a really tough tumor in any regard.
All the animal modeling and all the correlative human data suggest that Tregs are really important. They're multifactorial in how they impede antitumor immunity. I think they're great targets. Like Chuck said, we'll see in the trials. We have the technology to see that, but don't be put off by anti-CCR4 because of these issues.
Just in ovarian cancer, right? Checkpoint inhibitors don't work in ovarian cancer, and we'll show you that at the SGO here in a month, in Toronto. You guys got to figure this out, and once you figure that out, I'm already your best friend, but I'm going to be your old best friend.
It's happening. It's happening. To answer your deeper question, Matt, I want to ask Dhan Chand to address it. It is, of course, there are so many components that we're addressing with this AGEN1181 version of CTLA-4, but it's very important to know that we're also dissecting every element in the context of the clinical outcomes and looking at, for example, this particular patient.
I don't think we're ready to talk about it because it will be publishable, but we're looking at specific traits of this patient that would corroborate our expectations of the molecule to work in such a patient.
Matt, thank you for the question, and you're right. Treg depletion alone is not going to be enough. We see this in our models. 1181 is designed to not just be a Treg depleting agent, but also to enhance T cell priming. That is a very key factor here because when you think of what CTLA-4 does, it's really a molecule that prevents T cell priming.
Because 1181 is designed to enhance T cell priming, you're going to get better T cell priming, better T cell activation in combination with Treg depletion. You need to have more than one biological activity occurring to get a meaningful outcome. On top of that, as you saw from Tyler's presentation, 1181 is best designed, by virtue of enhancing T cell priming, to also generate better memory cells.
That's where you see the durability of responses, generating those memory cells. 1181 is not just a Treg depleter. It's a T cell activator, promotes T cell priming, and also promotes better memory formation. To your question about the Fc requirement, ipilimumab does not bind well to the low affinity CD16 allele. This is 40% of your population.
Because of that poor binding, as Dr. Drake showed, the activity of that molecule in promoting T cell activation is very poor. 1181, on the other hand, can bind well to both polymorphic variants, and you see consistently, including in the patient report today, activity in a patient that by all means should not have responded. To your second question about the other molecule in the clinic, the one we haven't disclosed, the targets, the bispecific.
While it is designed to specifically deplete regulatory T cells, the other feature that I didn't mention was that it also directly co-stimulates effector cells. You're getting both the depletion of Tregs and the stimulation of effector cells together. You are correct, Treg depletion alone is not going to be enough. You need to have other modalities. We've accounted for that in AGEN1181, and we've accounted for that in our bispecific molecule.
Just one quick follow-up, Dhan. You showed ability to deplete Treg-like cells with that bispecific, 1223. Have you compared that ability to 1181 in similar assays? Just kind of how do they compare?
We haven't directly compared them, but I will say that not all Tregs are CTLA-4 expressing. It's going to be very difficult to say Tregs are all the same. They're not all the same. They are driven by the same stimulation conditions as effector cells.
We've observed that there are CTLA-4 expressing Tregs, which make up a significant proportion of Tregs in the tumor. There's also highly suppressive Tregs that don't express CTLA-4 but express this unique combination of targets that we discovered. Yep.
These molecules could potentially be used in combination as well.
Correct.
Yeah. Other questions, please.
Sahil Kazmi from B. Riley FBR. Congratulations on the progress, and thanks for the great presentation. Can you discuss a little bit about the disparity that we see in the discontinuation rate in the CheckMate trial in both ipi, low dose and high dose ipi, compared to what we're seeing in the combination data today? I believe it's around 18% and 33% in the ipi/nivo trial and quite low here. How does that really translate in the clinic? Maybe as a follow-up to that as well, is there any sort of optionality to go up on the AGEN1884 dose?
Well, to start, if I may, you can't really compare those. It's a bit of an apples and oranges because, for example, in the other trials, you had a mix of first-line patients that were untreated. Even if they were second line, they were untreated with previous treatments.
We don't really know what the tolerability differences would be in those populations. It's too early to really compare because they were not randomized trials and patient populations were heterogeneous. Anna, if you
Completely agree with your statement, Garo. I think right now, this is difficult to make that comparison. This is not a randomized study, so populations might be different. Also, moreover, our data, it's a small number of patients so far.
We continue to observe the required number of patients, so the data is maturing. The reasons for discontinuations might be different. They might be due to the disease progression, or they might be due to the adverse events. There are different combination factors that translate into discontinuation rate.
I would actually just slightly caution you as looking at discontinuation rate as an indication of safety. For example, in CheckMate 650, which is ipi/nivo in prostate, the discontinuation rate is really, really high, right?
You just say it's like 50% maybe and higher, and you say to yourself, "Wow, this is just not tolerable in prostate cancer." That is actually a feature of the way the trial was written. The trial was written that if patients have a grade 3, 4, they just completely stop forever. Yeah.
Which is not what we do in the clinic. It's really hard to compare discontinuation rates as a function of grade 3, 4E. In fact, the other thing you have to remember is when you stop, for example, kidney cancer, the patient has an irAE to ipi/nivo. Those are patients who tend to do fairly well, actually. I think it's one way to look at safety, but I think that you've got to be a little bit cautious in terms of the context of trial design.
Great. No, thank you. Maybe just thinking more broadly in terms of capital allocation, could you just provide some color on how you think about investing in future trials with 1181 in terms of other tumor types versus how that might compare to commercial regulatory preparations for the combination?
If you look at the way we have proceeded so far with AGEN1181, we will be looking at the potential registration of this compound as a single agent, as well as in combination with PD-1 as the next step.
That's one of the reasons, for example, in our dose escalation trial, we've gone from 0.1, which is the lowest dose, to one milligram per kilogram as monotherapy. Now that we have gotten to that level, we're testing it in combination, starting with the lowest dose and upping it. There is an opportunity here.
I believe that based on the performance of this molecule, we may be able to show superior performance with our PD-1 plus 1181 in cancers that are the targets of today's PD-1, KEYTRUDA and OPDIVO, including some of the major indications like lung cancer, for example, non-small cell lung cancer, as well as MSI-high colorectal cancer. Those are certainly targets that we will go after.
Thanks. Thanks for taking my questions.
By the way, just for clarity, because there's been a lot of data presented and a lot of numbers thrown around. The data that we presented for our cervical cancer interim analysis is for a handful of patients, and those patients were completed with enrollment in the middle of last year.
As Anna said, we have enrolled over 100 patients for the registration trial as of the end of last year in each of these trials, the monotherapy trial and the combo trial. We've decided to continue enrollment for a number of reasons.
The most important is for our safety database. In order for you to get approval, you have to have a certain number of patients that are treated with your compounds, and that constitutes the safety database, and that's why we continue to enroll patients in those trials. We expect that by the time we'll file our BLA, we'll be well over the safety database requirement numbers.
Just as a brief follow-up. Sorry. Around that time, we can expect more quantitative data on duration of response, PFS, overall survival, et cetera?
That's right.
Great. Thank you.
Hey, guys. Julian Harrison, BTIG. Thanks for taking my questions. Dr. Drake, Dr. Curiel, thank you for the great overviews on CTLA-4. Beyond PD-1, just curious if there are any combinations with CTLA-4 that you're especially excited about on a mechanistic basis. Thanks.
I have a personal bias, actually. We're going to do a trial of anti-CTLA-4 plus hormonal therapy for early-stage prostate cancer based on the data that I showed. The other clear option that's being thought of is a combination with radiation therapy, which increases regulatory T cells. Those combinations should be hopefully at least additive.
Based on preclinical work in our lab, we're looking at anti-CTLA-4 plus engineered IL-2. Not Nektar, but drugs like that in a variety of cancers, but especially in bladder and ovarian cancer. I also think that 1881 and then the dual Tregs undisclosed, I think that's biologically a really important combination to look at.
Do look out for our AACR presentation that will discuss more extensively combinations, particularly with 1181.
Awesome. Thanks for that. Dr. Chand, actually, I'm just curious where your TIGIT program stands. How close are you to an IND right now?
The TIGIT program is still advancing. We believe that we do have a better approach with our Fc-optimized antibody. We think we do have an even better approach that's also advanced in the clinic in parallel.
Yeah. I think, I mean we have been
Putting information out on the targets and the specific molecules that are in our development pipeline as appropriate. With TIGIT, all I can say is that there is a monotherapy which is Fc modified, which we believe is the best-in-class molecule. I know there has been a lot of noise about Genentech's enthusiasm about TIGIT.
TIGIT has been a molecule that has been under development at our shop for a number of years now. We subscribe to the recent enthusiasm, but it's not something that has come into fashion only recently.
It's been known to us for some time. Also, very importantly, we have a different format of TIGIT, besides the one that you're referring to, that we believe will be a significant improvement over the current TIGIT molecule.
That one will hit IND later this year.
Yeah.
Yep. Great. Thanks very much.
By the way, before you depart, I just wanted to pay compliments to Dr. Exley's efforts in iNKT cells. Just so that we have complete transparency, we have executed in every single area of our IND filing timelines. Every one. In fact, as Jen mentioned, we have filed more INDs with immuno-oncology molecules than any other company in the last four years.
The only one that we missed on our IND filing timelines was with our cell therapy. As you may know, we restructured the cell therapy company a few months ago, and we changed the strategy from autologous cell therapy, which I personally believe is great for patients, but frankly, it is a business that is in the nonprofit category because I don't believe that's a viable business going forward.
I don't mean that that business should be abandoned, but it's a business that will never be able to make the kind of monies that the industry expects. That's one of the reasons there's emphasis on allogeneic cells. We believe that iNKT cells represent the best of breed for allogeneic cells because what we need to do with them, the first generation iNKTs will be used as unmodified iNKTs.
As Dr. Exley said, we harvest cells from healthy patients, we culture them, grow them in significant numbers, and that becomes our product for all patients. It's HLA restricted, so you have basically a couple of categories, but it is off the shelf in that regard. We don't delete anything from those cells. A lot of the T-cell approaches require deletions, and if you forget or overlook deletion of one element, then it becomes grounds for toxicity.
The reason we like iNKTs is that if you look at cancer patients, you see a depletion in iNKTs in those patients. By infusing iNKTs in those patients, along with some of the other armaments that we have in our checkpoint portfolio, as well as a known iNKT stimulator that is in our control right now, and we're replenishing that for both clinical and commercial supplies.
We believe that iNKTs can be universally used across not just hematological tumors, but solid tumors, and that could mean a significant market. Now, along with all of this, we have the ability, because everything is under one roof.
We have the ability to price a whole cocktail of treatments, including unmodified iNKTs, along with our checkpoint molecules and the iNKT stimulator, at a price that is either pari passu or lower than the most expensive checkpoint inhibitor that is sold today. That gives us a major advantage in terms of expanding the market very significantly. Dr. Mark, did I forget anything?
You stated it well.
Okay. Very clear. Thank you very much again. One more question, Dave.
I just wanted to ask a little bit about the financing.
Yes.
Obviously, you expressed a lot of confidence in the molecules and the different things that, our partnerships with other big pharma. Just wanted to get a little bit deeper on that. Obviously, there's a lot of-
If you could pick up the microphone. Thank you.
I speak pretty loudly.
Yeah. That's okay. I got the question.
I'd love to get your color a little deeper on how you're seeing the financing take place over the next year.
Okay. There has been questions and background concerns about our financing needs for five years. As I said, we have not gone to public markets for five years come April. That's a statistic that we're very proud of. Julie showed the slide of us having raised $525 million in transactions that do not include any public financings or market financings at all.
We expect the same trend to continue this year. We do not expect to come to public markets with a marketed offering this year. Based on what we have going right now, the year-end cash plus shoe-in milestones.
For example, we have approximately $40 million worth of milestones coming from the GSK SHINGRIX product that we believe, based on the reports we get, GSK has already exceeded those numbers, so we will be receiving those milestones.
This is not like, if they reach a certain level, then we'll get the money. There are several other milestones that we will be getting this year, so that amount will be about $70 million. That, plus certain other transactions, new transactions, that we expect to consummate, will get us through the end of this year comfortably. I can't make any promises about marketed transactions beyond that, but I'm making a promise that this year we will not do a marketed transaction.
Thank you.
Thank you. Yes.
Jean-Michel Jean from Jefferies. Again, thank you for having us. A couple quick ones for me.
If you can pick up the microphone. I'm sorry. Yes.
Can you hear me?
Yes.
Just a couple quick ones. For the combo cervical data, what were the median prior lines and follow-up time for those patients?
For which data?
For the combo cervical data that you just presented.
Combo cervical data.
Well, this is a snapshot of the information that we provided. I don't have a full analysis, so these are the key results. The full analysis will be available when we will complete the BLA filing analysis.
Thank you. Just on 1181, the current study protocol, does it allow for potentially opening up any expansion cohorts in any indications that you find interesting as the data evolves?
It does.
It does. Okay. Thank you.
They're all comers, by the way, in the dose escalation trial, as you know. Any other questions? Thank you very much for your time. We appreciate you staying over by 30 minutes overrun. Thank you.