Hello, I think we're afternoon now. Yes, clearly afternoon. Good afternoon, everyone. My name is Daina Graybosch. My team and I here at Leerink Partners cover immuno-oncology companies, and I am really thrilled to have a conversation for the next 29 minutes with Garo Armen, the CEO of Agenus. So thank you for joining us.
Well, thank you very much to for inviting me to your wonderful conference. This is our inauguration, at the conference.
We're back in person, so it's nice to be here in person. So I'm gonna start with botensilimab, your CTLA-4 PD-1, and use that to actually ask some general I/O questions as well, and then we'll move on from there. So you have a second-generation CTLA-4, and I think maybe starting with the value prop, what did the first-generation antagonists, Ipi and Tremi , leave on the table?
So, one correction, if I may, we don't want to characterize our product as a second-generation CTLA4. We don't wanna hide the fact that it is a CTLA4 binding antibody. That's clear. But it does so many other things than just binding to CTLA4. So, we'd like to label it as a multifunctional, immune activator that also binds to CTLA4. Of course, CTLA4 is a very important target, Daina. But so far, the CTLA4s that are out there have been active only in hot tumors. They have not really shown activity in cold tumors. And so, one of the reasons we characterize it as a multifunctional is because the Fc engineering that has been incorporated into the molecule that imparts so many other attributes to this molecule, amongst them, is the activity with dendritic cells, for example.
The myeloid activation, because of the Fc modifications in our molecule, allows largely to convert cold tumors into hot, which is one of its very unique attributes. In addition to that, of course, it does prime and activate T cells much better than the other molecules that are out there. It down-regulates regulatory T cells, which are the bad actors, and up-regulates the memory T cells, which are the good actors. So it's very unusual to find a molecule that does all of these things under one roof, so to speak. And that is our botensilimab.
Is the essence of that multifunctionality about having a better therapeutic window? Or is it about the epitope and the function, or all of the above? What would you contribute to each side?
All of the above, really. All of the above because, you know, what we have shown, as you know, now in trials of 900 patients across 9 different tumor types, ranging from melanoma, which is amongst the hottest tumors, to pancreatic and CRC, which are amongst the, or I should qualify and say, MSS-CRC, which constitutes 95% of the patients with CRC, as well as in earlier stage, MSS-CRC. So really, so far, what we have seen is activity across the board. I'm going to be very careful and not equate activity to efficacy. Because efficacy is a title that is reserved for the FDA. We cannot call a compound efficacious unless the FDA puts the stamp on it, and that's hopefully will be forthcoming. But the activity is profound. And what do we define as activity? Tumor shrinkage, overall response rates.
In patients that have failed all else, I mean, across, I mean, one of the unique attributes of the patients involved, mostly in the 900 cohort, is the fact that these patients have failed everything available. Whether it is in EGFR mutant patients, in lung cancer, non-small cell lung cancer, or pancreatic cancer patients that have failed first-line therapy, FOLFIRINOX. Or in CRC patients in the latest stage of disease that have failed FOLFOX, Avastin . So the patients in our trials are in that category of the toughest of the tough patients. Now, of course, in the neoadjuvant setting, one of the young investigators came to us, a very talented investigator from Cornell, and said, would you be willing to do this under an IST in the earlier stage patients? And he defined a patient population that is stage three, but heavy burden of disease, heavy burden of disease.
We treated these patients from the point they're diagnosed to the point where they're scheduled for surgery, which is about four weeks. About four weeks. With one infusion of botensilimab. Two infusions of balstilimab. And the tumor responses are nothing short of remarkable. In fact, when I showed the data first to a very, very renowned oncologist, he said, of course you're going to see responses in this patient population because you're doing it on top of chemotherapy. And I said to him, no. We're doing it just with botensilimab. And so seeing these kinds of tumor shrinkages, in fact, one pathologist from Cornell sent a report saying in 12 days, a watermelon-sized, small watermelon-sized tumor had shrunk to less than two centimeters.
And so that's a sign of clear activity. And of course, we will wait for the FDA to hopefully graduate that activity to efficacy.
You guys and me and my team, I think we deal with a condition of among investors of I/O exhaustion. And I wonder if you could speak to that and what you think would take it around and rejuvenate interest in mechanisms like a multifunctional CTLA-4.
Sure. So, when you use the term exhaustion, of course, it has two different connotations. One is the investor exhaustion with I/O, and I might say rightfully so. And the other one is immune exhaustion, which is something else that we encounter. Now, when it comes to the first one, of course, you know, I've been in this business for 30 years. I founded the company 30 years ago with the expectation that immuno-oncology in fact, the term immuno-oncology wasn't even coined at that time. Immuno-oncology would be the holy grail to treating and potentially, hopefully, curing cancer. And still, people caution me about the use curing because, you know, how do you determine a patient is cured? It's a very difficult thing to do. Particularly from a regulatory perspective, it's impossible unless you wait for a lifetime and see the patients die of other causes other than cancer.
So, but in this particular case, when I remember when Yervoy was making its way, Yervoy made its way to being approved in melanoma with a lot of difficulties along the way. But in essence, 15%, approximately 15% of the patients that it was working in, they translated to cures, long-term cures . So after that, we had the PD1s. And of course, when PD1s came into existence, people thought that PD1s would be better than Yervoy. And in fact, in terms of revenue potential and applicability, broad applicability, they were better. But they were not really curing patients for the long term. But it was a tremendous revenue potential. And of course, investors care about revenue potential above and beyond anything else. Rightfully so, because that's their business. Now, what happened was then we had a whole bunch of other targets. We had TIGIT.
We had GITR. We had LAG-3 and TIM-3. And many others that were expected to outdo PD-1s and PD-L1s. And unfortunately, that hasn't happened. That hasn't happened. And because of that, investors are somewhat disillusioned. I mean, with investors, it could be the mentality it's either feast or famine. And so I/O has gone from being feast to now somewhat of a famine in terms of new agents. Then comes botensilimab. What did botensilimab do? Well, as I said earlier, in 900 patients across nine different tumor types, tumor responses. Now, we are encouraged that because of the nature of this molecule, including its ability to bind to the CTLA-4 receptor, we're very encouraged that that will translate to long-term benefit.
Now, that encouragement is evident in our CRC data because the responses we're seeing in a fairly significant cohort of patients have been durable and deep responses. And so that is the basis for our enthusiasm. Not only our enthusiasm, but the enthusiasm of our advisors that this should be a compelling package if done right for from a regulatory perspective. So that's where we are.
Is that so you have 900 patients and nine tumor types? So why MSS-CRC without liver mets as the first registration?
That's because we have most of the concentration of the patients in MSS-CRC. What had happened was when we started our phase 1 trials several years ago, and the phase 1 trials were in all-comers, not just MSS-CRC. But because, I remember the day actually when we got the data on about 16 patients that were labeled as MSS-CRC. And we had a handful of responses in them. But the investigators were so excited because they don't see any responses in these patients with I/O and not even responses in failures with targeted therapy and chemotherapy. So that drove us to expand that cohort to what now is roughly close to 400 patients.
And that's the reason, by the way, we're going after that. And the reason for the liver non-liver mets patients is because they are the, well, I should say, non-active liver mets because some of the patients that we have treated that have seen responses are liver mets patients that have been previously treated with ablation and other methodologies. We're seeing responses in those patients. But in active liver mets, even though there may be a survival benefit, it's very difficult to say, of course, in a small population. We're not seeing the kind of responses we're seeing in non-liver mets. Now, interestingly, again, in a small denominator of patients with pancreatic cancer. So pancreatic cancer patients that have failed FOLFIRINOX and are typically treated with Gem/Abraxane alone. And that's, you know, you'll see a modest response rate short-lived with Gem/Abraxane. We're seeing some, again, the denominator is small so far.
We're expanding that denominator. We're seeing some remarkable response rates. Interestingly, Dana, those are patients with liver mets. So there's something unique about colon cancer liver mets that are active, that are accounting for that. Now, also, very interestingly, one of our largest enrollers at City of Hope did an IST or has an ongoing IST right now, with botensilimab on top of the standard of care, which is FOLFOX. It's a dose escalation trial. Of course, you know, there's a great deal of interest in this, because even though these are earlier stage patients, they'll, they'll all fail.
Okay. They'll all fail. In that patient population, on top of FOLFOX, we're early indications of patient activity with liver mets. This is going to be an interesting journey.
I was going to ask about that population, actually. There was another IIT, atezolizumab, which was frontline CRC, MSS. That's atezo-bev FOLFOX/FOLFIRI that showed a benefit over Bev FOLFOX/FOLFIRI alone, particularly in immune subset. Actually, I think the Bev looks like it's adding something in my view. I wonder if you can actually combine in any VEGF targeting and if you've looked at that or any plans to look at that.
We haven't looked at it yet, but I think as you say, that may be a logical next step as well.
Interesting. MSS-CRC, it's been really the standard of care is not great. Very low response rates. It's a short survival. Nonetheless, it's been very difficult to best. I think the latest is Merck's LEAP trial with lenvatinib plus Pembro versus the standard of care. And they had, you know, decent response rates. At least they had initially reported in phase 2 much fewer patients sampled than what you guys have. So why, why is this even when you have regimens that shrink, it's failing on overall survival and how are you mitigating the risks in this indication?
So, I mean, I'd only be speculating here. So it's not based on a comprehensive data set. But the speculation is the following. Clearly, immunology works differently. And clearly, a CTLA-4 binding antibody, historically, in patients where you have seen activity, that activity with CTLA-4 generally, translates to a survival benefit. With PD-1s, it's a mixed bag. It's not necessarily translating to survival. So, we're encouraged by the fact that our Bot, does bind to CTLA-4 among other things. So that could be a very important attribute to potentially translate it to long-term activity. That's one. And the second one, which is more meaningful, is that we're seeing durable responses in our trials with survival curves now with the caveat that this is a single-arm trial. But we're still seeing survival curves, Kaplan-Meier curves that are flattening with about 50% of the patients benefiting for the long term in there.
All of these give us encouragement that we may translate to an important survival benefit.
So you're currently in a randomized study, phase 2. I think that we'll see data this year. Is that correct? When might we see the data? And what signals from that trial are most important for you internally in your continued investment and discussion of regulators?
Sure. This is a five-arm trial. It is not a statistically powered trial. It was meant to address the FDA's question of dose responses, combination of the separation of the elements, the Project Optimus trial. So we had five arms. One would be monotherapy at the lower dose and the higher dose of Bot. That is at 75 milligrams flat dose, 150 milligrams flat dose. The same dose levels in combination with our balstilimab, our PD1. And then we added to it a regorafenib, which is the standard of care. Again, not statistically powered, but just to get a sense of the direction. So what would be a good outcome from this trial?
Well, the good outcome would be to see potentially a dose response in the monotherapy arm. A good response in the combination arm. And then very little or no responses in the refractory arm. And so we are in the process of compiling that data now, cleaning up the data. And we hope to have that data ready for at least FDA review by mid-year. And then, should the FDA give us the green light to file a BLA, then we will use the phase 2 data as supportive to phase 1 data. And so that's the objective.
Maybe you already know this, but I don't. If PD-1 antagonism is if bal contribution isn't super compelling, is there a potential that you go forward of single agents or is this too small? You'd always want PD-1 on board based on the science.
I think, you know, there is no question that Bot alone has some activity. I mean, we've seen that across different tumor types. No question about that. Some activity. But there's also equally compelling evidence from the earlier trials that the combination of our PD-1 balstilimab with botensilimab really ups that activity meaningfully. The purpose of the Project Optimus trial, our phase 2 trial, is to doubly confirm that. Because we haven't done that in a randomized, more formal setting. The purpose would be to confirm that. We're hopeful that we will see that.
It looks, if you compare the adverse events to that of ipi-nivo, that you're expanding the therapeutic window for CTLA-4. That said, I also know that you are doing, you know, monitoring of patients and intervening early for side effect management. How much of it is the molecule and how much of it is how you're managing side effects and being able to get on a bigger dose?
This is a very good question. A very good question because, no pain, no gain here, right? So, so it's almost unthinkable of a cancer agent that has absolutely no side effects. Unthinkable. And so in our case, what we're seeing is colitis, which is diarrhea. Now, sometimes it could be severe and very, very uncomfortable. Sometimes it could be life-threatening. So in our case, we're seeing approximately 20% grade 3 or higher colitis cases. Now, a great majority of that, my estimation is, I don't know, 80%, 90% of that are readily reversible with either infliximab or steroids. And the sooner you use infliximab and steroids, the more reversible it is, quickly reversible it is.
So I think it's very important to also indicate that, when you reverse it, which is the great majority of the afflicted patients, when you reverse it, there's no long-term toxicity associated with these patients. You know, the only long-term toxicity with an agent that binds to CTLA-4 is immune toxicity. But that is a tiny, tiny fraction of the patients, much less than 1% that you see. That's why when you talk about chemotherapy, in fact, there was an interesting article in Atlantic about 6-7 months ago that talked about the painful long-term toxicity of chemotherapy, that patients are afflicted with. It affects their lives, I mean, for the long haul. Whereas in the great majority of the patients, even if they get grade 3 or higher, colitis, that toxicity is transient and not associated with long-term.
Some of these, like neutropenias and other things.
That's right .
Can you talk about the next data outside of MSS-CRC and whether you will pursue multiple indications on your own or if you that would get getting a partner?
So, I think it's we are limited on our own. I mean, can you pursue an approval strategy for botensilimab that is pan-indication? The answer is perhaps. Okay. But there's no way right now, given the financial markets and our own financial circumstances, that's doable. So it's a foregone conclusion that we will need to partner this. And then the next conclusion is what is the profile of a partner that you partner with? Because your partner in this case has to be a partner that believes in the cause and puts in the appropriate resources behind this for it to go pan-indication. If you go pan-indication, perhaps we will undo this investor fatigue with immuno-oncology by replenishing the confidence in immuno-oncology. I think that's doable. If you don't try, it'll never happen. So you have to shoot for the stars for this to happen.
That's what we're doing. So in terms of our activity, our near-term efforts are concentrating on sort of bringing in cash quickly. And we're doing that with royalty slash project financing activities. And last year, we had guided investors in the fact that we will complete such a transaction by the middle of this year. We're tracking that right now. In terms of partnerships, we are in active partnership discussions. I have had interactions with CEOs of 3 major companies. And we have additional 2 companies that were also in discussions. And some of these are more advanced than others, of course. So that would be the impetus for a more meaningful transaction that will allow us to go across different indications. But specifically on our own, I think pancreas is something that we're morally obliged to do.
In addition to that, EGFR-mutant non-small cell lung cancer can also be a potentially rapid way to approval because in those patients that have failed EGFR therapy, there's nothing available. And we're seeing some deep, impressive responses in that patient population.
I'm going to move on in 2 minutes and 50 seconds. Actually, I want to ask about how I first know about your company. And that's as a vaccine adjuvant. So you made the adjuvant in GSK's Shingrix, maybe the driver of that activity. And now you have SaponiQx. I know how you say it. SaponiQx?
SaponiQx is the adjuvant company that we've started.
Yes, SaponiQx. You have a Generation 2. I wonder if you could talk about what that is and your business plan around that.
So as you know, as you remark, GSK's Shingrix and now their next generation products are fueled with QS-21, a very powerful adjuvant. Had I known its contribution to these vaccines, Shingrix will be well over $4 billion in annual sales this year. And RSV will be over $1 billion in sales. Had I known the activity, I wouldn't have sold the royalty proceeds. And I would have probably demanded a higher royalty payment from GSK. I mean, we sold it for a grand total of about $250 million. And yet, the entity that we sold it to is making now over $150 million a year in income. So I'm not begrudging that, but it's a huge success with SaponiQx. And of course, next generation SaponiQx products is still QS-21 based, but it will be from a renewable source that we have validated. So very exciting project.
You'll partner that for infectious disease vaccines?
Most likely, yes. Yes.
Got it.
We have a few minutes for our favorite topic, iNKTs, our MiNK Therapeutics.
Sure. That's my last question. So what's differentiated about MiNK? And I see you're taking it into an autoimmune disease as well.
That's right. So this is a remarkable product as well. I mean, we're starting an IST at Memorial Sloan Kettering that has actually started and enrolled the first set of patients. It is sponsored by Stand Up to Cancer, external funding. And this is a product that has shown profound activity in our clinical trials as well as in our preclinical models, both in combination as a standalone. But most importantly, I call iNKTs, even though they stand for invariant NKT cells, these are T cells. They're not NK cells, invariant NKT cells. These are really intelligent NKT cells. Why? Because they have the innate ability to size up their environment and either tune up the immune response or tune down the inflammatory response depending on the environment. That's why I call them intelligent NKT cells.
We have seen some remarkable activity in lungs clearing in patients that are otherwise on ECMO. I mean, ventilators, basically. So the effort is for us to expand that and show that iNKTs are both viable agents in cancer treatment in combination with, for example, bot-bal, as well as a standalone agent in highly inflammatory lung diseases.
That was in COVID. You saw the.
That's right. I mean, patients that were on ECMO machines are cleared in a matter of days. Yeah.
That's exciting. Well, thank you. It's always nice to talk. Thanks, everyone, for your attention.
Thank you very much, Daina.