Good afternoon, everybody. My name is Wayne Wu. I am the large cap pharma associate here at Cantor Fitzgerald. Welcome to our fireside chat with Adagene this afternoon. With me is Peter Luo, CEO and president of R&D, and also Raymond, the CFO. Maybe to start, can you give us easy question for people who may not familiar with the story. Can you give us a brief overview of the company and your business plan?
Sure. Our story is very easy. We have three platform to make a very unique antibody. We hit a very unique epitope, and then we can make that epitope. We have generated a unique biology, have very safe and potent antibodies. So we call the SAFEbody and the POWERbodies . And the bottom line is, every drug we put into the human, we want to be safe, potent, and unique.
Okay, maybe to start. We can start with the NEObody technology. Can you explain that, and with the unique epitope and what dynamic binding means?
Yeah. We pioneered the ideas back one hundred years ago, 'cause Linus Pauling basically say, "Why antibodies are so diverse?" Because the conformation are very different. So since the genetic come up, people forget that lesson. People try to fit one sequence, one diversity. No, one sequence, you can have multiple diversity. Because those CDR, like our fingers, they can change the conformation. That's why our finger could capture different objects. So what we do is, one sequence, we can generate multiple conformations. So this we call the dynamic libraries. In fact, we get a U.S. patent, global patent, for that unique design. Instead of making big library, our idea is we make a small library in a given physical size. Once you increase your physical size, you can exponentialize your diversity because of that conformation.
Great. Moving to the SAFEbody platform, can you elaborate on how the SAFEbody platform provides a competitive advantage in terms of safety and efficacy compared to other conditionally activated antibody platform?
Yeah. I think the simple idea is really easy, right? Not every platform are created equal. Look at the ADC. Look at Daiichi Sankyo compounds. The same antibody, different ADC, changed, transformed the field. Everybody want to have ADC. Before that, Genentech already have a same antibody, different ADC, but didn't perform as well. Very simple spirit. Our masking technology performed totally different from other technology there. And in fact, I'm going to show you the highlight from ESMO. We show for the first time how that dose response coming up from our anti-CTLA-4, which is really a showcase for all the masking technology. Thinking about CytomX play for 10 years, failed BMS, terminated all programs, right? Then we are forced to show how you can dosing it 10, 20-fold higher than what the Ipi or Agenus molecule, like in combination with PD-1.
We still have a robust safety comparable in the dose level we're using, like a monotherapy, pembro monotherapy, the historical safety data. I'm going to show you the highlights, right? We'll also show mechanistically in human how that actually works.
Okay, great. Since you mentioned the ESMO highlight, why don't we just do a couple of the slides, so you can walk us through the data-
Absolutely
... and the clinical significance.
Yes. We- I'm pretty excited about that. In fact, our partners also, I'd like to highlight three points here. First, potency, dose dependence. If you look at on the far left, we show two dose. Actually, 10 mg same dose, different frequency, six weeks and a three weeks one, right? You can see on the top, the six weeks one, you can see, you can see patient remains stable for a while, then become progressed. Then look at the down, at the three weeks one, in green. We double the patient size because we saw the confirmed confirmed response. There you can see most of the patient were pushed to stable disease, confirmed PRs, right? There's no such data was strong as we've shown here, strong dose dependence, right? With that kind of a response in spider plot. Nobody can deny that.
Then look at the second, the safety profile. Well, not just to show you the number. We show you over a year period, when you are dosing the patient at the 10 mg six weeks, the Grade 3 in orange color, you can see there's a little on the top, but there's a Grade 2, yellow one, Grade 1, right? And then if you look at the three weeks one, there you can see more Grade 3 coming up and stay there. They not just disappear, because you keep challenging the patients with that dose. And also, you see Grade 2 and Grade 1 come up earlier on the right with a high percentage. But what it says is the clinical response, right, the data you saw, the spider plot, correlate with the safety profile nicely.... Right?
If you push the human immune system up higher, you are going to have a response, and also, you are going to challenge your immune system a little bit, so that Grade 3 toxicity at the three weeks one, very manageable. 15% discontinuation rate is 8% over a year period. Okay, and then we show how actually this drug works. We show the active drug, the blood circulation. Consider this drug is optimal or is activated, the tumor, small volumes. Then they build that, and it diffuse into the blood. They slowly build that steady state in the blood. As you can see, six weeks one, the black line means this active concentration, the active species. If you go to the red line, you are likely to trigger Grade 3 toxicity. Look at the three weeks one. There, most of them coming into that boundary, nice boundary, right?
Together, that green line was a population average. They do have some patients, the active concentration go beyond that red line. So that's how you get that 15% of Grade 3 toxicity. Everything linked. No one ever showed this kind of data with one year's accumulations. Efficacy, safety, active species in the blood. I think, I don't know why people didn't understand or read that. So you go to the next ones. We show you, in this population, a lot of people complain about because the immunotherapy, we all start with liver-free metastasis. There's a very simple reason. If you have a liver metastasis, disease progress too fast. We know immunotherapy needs time to respond. To get that drug, the cancer are racing against your drug. Until your drug, your cancer progression can match with your drug, then you will see that response.
So that's why we choose this population. Look at here, the standard trial, approved trial, fruquintinib in the FRESCO trial. Look at that OS rate. Approved the one, right? Subgroup. That's the bottom one there. You can look at it here. I don't know how to turn on this.
Um.
No, laser. See. Well, oh, laser point here. How to put a laser point?
Um, uh, uh-
Okay.
I don't think there's any laser.
Doesn't matter. As you can see, the fruquintinib drug, the survival rate, as you can see, is the lowest one. SUNLIGHT is better for the lung liver metastasis population. And then look at our drug. We basically combine six weeks and the three weeks out. You can see our survival curve nicely beat the standard. The data is still not mature beyond the twelve months, but you already, you see the trend. Any surprise? OncoC4, PD-1 combination is the best combination for long-term survival. So far, there's no drug ever beat that record. I challenge you, right? That's all immunotherapy about. Then I show you something interesting, right? Here you can see, in those data, even those are not the same, head-to-head comparison, but if you look at those controls, they're quite reproducible, okay?
If you look at TAS-102, conducted by the SUNLIGHT, compare the TAS-102 approved, you can overlap those curves. So those populations don't change that much, okay? So then let me show you one more thing, another key point. If we put the Agenus survival data, you can see initially, they actually are falling behind the SUNLIGHT, of course, also behind ours. Only at a certain point, they begin to cross that SUNLIGHT population. Look at that middle, the purple color here, right? Because in the end, it's immunotherapy that shows that survival benefit. But look at our curve in comparison with them. We're still beating them, right? In the same population, no subgroup analysis. Okay? Lots of data. All right, we achieve this with amazing safety profile because as you know, Agenus, they're pushing back by the FDA.
They try one milligram per kilogram, two milligrams per kilogram. FDA only allows them to do one milligram per per kilogram, right? Only up to four doses. We're dosing at the 10 mg per kg continuously. Look at the safety we show, the Grade 3, the green one. We don't have Grade 4. And the Grade 1 and Grade 2 there, look at the historical pembro data, monotherapy. We're compatible. Look at our news release. We'll go through that very carefully. With this, we're ready to set a new standard of immunotherapy. You combine with our masked anti-CTLA-4, with PD-1, which are going through part 1 in the clinic. And this, of course, you can combine with that bispecific VEGF, because we already know our combination with PD-L1 and the beva, very well tolerated in Roche trials.
There, we open the door for those proven combination, immunotherapy doublet here, to combine the beva and the chemo from third line, second line to fourth line. Safety is very important, and this is the efficacy data we show you. Of course, you should stretch your imagination, not too much. You can combine with cancer vaccine, ti-, TCE engager, ADC radioligands. That's the space we talk about cancer cure, and that's the standard we're creating. Yeah, thanks.
Great. So what are the next data readouts for your trial and potential catalysts, and what data will you be presenting any at conference anytime soon?
Yes. We already announced, we actually showed the safety data for 20 MPK combination with, like, combos. And we show if every three weeks, you definitely hit that red line. You hit the roof, right? You know you reached at this limit. Then we go to 20 MPK , and we can loading those in our poster, the nicely along that red lines. So we already enrolled 12 patients. We are gonna report in that data. And you know, if safety efficacy, all those things, put any trigger indication for this ORR, we're happy to see something going on there. And we're gonna provide those data in SITC, and also other meeting coming this years, and, or any next years. We'll continue updating our OS survival curve, and also how we can continue moving that dosing regimen.
Because here we are basically saying, we are creating the best therapeutic window ever for anti-CTLA-4, and this allow us flexibility to dosing at the ranges people never done, 10-fold, 20-fold, to pushing that efficacy limit. If you are the people, you are trade those target sort of chemo sort of, you like to say, "ORR," we say, "Okay, here you go," but you just need to tell us what's your safety limit. You want to put that stop. If you are the people, you say, "I want to survival be benefit. Don't want to push people too much," then we say, "We have a dose for you," so we create that wide range of selectivity, then you come with whatever combo you got to do your further trials, and we definitely will go with the standard therapy for large patient population.
We can see a bunch of very niche populations and a mechanism for ADC and the radioligand, other opportunity there. But what I really want to say in the end, while those ADC radioligand lock down the tumor as quickly as possible, you can sleep well, you know with this combination as a backbone, your OS will win, right? The summary of the trial, people, nice, beautiful, PFS data, right? Just like some ADC molecule show, nice PFS data. Could that is translated into OS? We already say even Daiichi Sankyo compounds didn't translate because that chemo and this ADC cost. But with this combination, you can sleep well. You know your OS will translate.
Great. So what results would you consider a success for the 20-milligram loading dose cohort?
So with that, all the time, yes, what I already says, as you continue pushing that dose range, you are giving some safety, more safety signal. In the end, there is all the negotiation with FDA, of course, with yourself. What kind of safety tolerability you like to see? We have seen FDA-approved drug for Ipi label at 3 mg/kg, more than right? At 56%, close to 60% of Grade three toxicity and higher, discontinuation rate 30%. For those unmet medical need, right? Like a very advanced melanoma. Recently, we are going to see the first-line HCC. Definitely, there's a nice OS there, but the toxicity is very high because, by the way, toxicity, I mentioned colitis, Grade three. Agenus molecule, they report 14% for colitis, Grade three, even on the heavy management of infliximab.
We don't have Grade 3 at the 10 MPK Q3W we're talking about here.
So are there any plans to expand the platform to target other types of cancer or even non-cancer indications in the future?
Absolutely. Yeah, that's almost like a set-up. Absolutely. We think this is the most advanced clinical program on a very challenging target, and people have really failed, failed again, right? Look at all the CTLA-4 for safety. Look at all the claim, right? Look at the BioNTech, the data, they're talking about this, OncoC4 , right? They go through the combination, those are 1 mg/kg, 2 mg/kg, and the toxicity is really high. You know where, right? So with this technology, we definitely are moving into T-cell engagers and with other very challenging target. We love toxic targets. As far as the fundamental biology shows they can help patient solve those fundamental biological issues. CD28, CD3, all those are the sweet spot we like to play because we think our platform really allows us to solve those issues.
Got it. So before we move to your other assets, like the T cell engagers mentioned, I'd like to ask audience if you have any questions?
Can I ask you a question? I wanted to know, your presentation at ESMO, what was the physician reception to the data that you presented?
Oh, my God! We get a lot of physicians just want to do our trials, all right? The leading investigator, actually, in CRC, maybe I can mention his name, Marwan Fakih. He's an opinion leader, talking about the metastasis site and all that stuff. He really want to use this combination combined with standard therapy, right? And he links us to the companies. And in fact, our friends at HUTCHMED, he has been pretty resistant so far. He come to our site, look at this, he said, "We should do a combination on this." Okay. Because here we go. This combination, immuno doublet, has been a foundation for so long. Basically, the question is, can you combine with standard therapy? Then you beat the standard therapy, you know the survival benefit will be there.
Also, you go to a large patient population, because those standard therapy has shown they can control those liver metastasis-free and liver metastasis patients. Really, they don't care where the metastases are. You just put those patients in.
Can I also ask you, how did you come up with this new backbone therapy when other people weren't able to do that? What is it in your science, your team?
So, Louise, can you... Sorry, I just, is that-
Okay, ADG126, how did you discover this?
Oh.
and what, what makes it unique?
I think, you can give a long story about this. I think that the reason we do this is because, you know, I'm a protein designer, right? I'm a protein, hardcore protein folder. Well before AlphaFold and all that stuff, right? By the way, the Google, the DeepMind, AlphaFold guy is trained at U Chicago. Actually, he was a professor who teach at the class and all that stuff. So basically, I think that every molecule is different. They have their very interesting personality, and every target has its unique biology. Look at the CTLA-4, right? That biology, if you look at that story, it's so interesting and also complicated. But to me, it's so interesting than the PD-1, PD-L1. Everybody can make a PD-1, PD-L1. They perform more or less the same. But look at CTLA-4, how different. Because there's some very unique biology about CTLA-4.
Even up to this year, June, Sloan Kettering published, CTLA-4 is linked to the pathway IL-23 inflammation pathway because it's highly regulated in an immune cell called ILC3. That immune cell is distributed in our gut, and the CTL are highly upregulated when the inflammation coming from IL-23. Therefore, those guys suggest, if you target CTLA-4, you better don't destroy that immune cell. If you destroy, you'll get a lot of colitis, and our masking technology don't allow us to targeting that because in your gut, you don't have that environment. So that's why we don't have a high-Grade colitis. We don't understand that previously. When these people come out and look and say, "Oh, God, someone did the biology for you.
Louise, just to add on, you asked why is ADG126 unique? Our strong ADCC is purely driven by unique epitope. We have no Fc engineering at all, which oftentimes is associated with toxicity. We don't have that burden. On top, we have the unmasking technology. And to your point as to why our IO doublet 126 plus pembro has the potential to become a backbone therapy for future cancer care, this is because, as Dr. Peter Luo highlighted, the safety profile of our IO doublet is comparable to that of pembro monotherapy based upon the historical data. And this is essentially why we can go for a combination with other SOC and/or different modalities, but many other CTLA-4s cannot achieve that.
Yeah. Essentially, you can think about any PD-1, PD-1 combination, you can replace by the immuno doublet. But the CTLA-4 allow you to do two things PD-1 alone can never do. As we know, even Keytruda or some of the trial is so wonderful, they're all in PD-L1 positive population. In lung cancer, PD-L1 less than 1% is 48%. That means... But the CTLA-4 can take care of that population. In MSS CRC , that population is 82%. That's why this cancer is so cold. PD-1 do very little about that. The second thing is T-regulatory cell expression, and it's definitely the CTLA-4 mediated, highly expressed there. PD-1 can do nothing about it. You need this, remove that CTLA-4 mediated process. Third, another paper just come out from UPenn. They show you need a CTLA-4 to reinvigorate those exhausted progenitor T-cell. PD-1, PD-L1 cannot do.
Therefore, if you look at survival curve, you will find very interesting, about three years, those T-cell die. But if you put a CTLA-4 there, you can reinvigorate that, expand that. That's why you have long-term benefit. This is essential, I think, you know.
Given the time constraint, maybe can we briefly touch on your T-cell engager candidate, ADG138 and ADG152? Can you explain how your proprietary bispecific antibody format contributes to the stability and efficacy of these two candidates?
Yes. Great. Again, that's really the topic we love a lot. We basically design in such a way, almost like a cassette on the CD3 arm, and we optimize everything in terms of the binding affinity, masking efficiency, and all activation conditions. And then the next thing is just plug and play. We basically say, "You plug in the CD20, and then you put this, and it go to the animal." We actually publish those data. Again, we talk about the same thing. You talk about big therapeutic windows. Well, dosing this drug one hundredfold, from 0.3 milligram per kilogram all the way to 30 milligram per kilogram. If you look at the molecule, recently, Merck licensed from Curon, from our friends, CD19, CD3, the highest dose reached the 90 milligram.
If you divide the 90 mg by 75 kg, typical U.S. patient weight, it's less than 2 mg per kg. Right? Even that dosage, if you look at the dose escalation procedure, it's taking years, step dosing and all those tricks. We just go straight dosing monkeys.
So-
And we have that window, and our cytokine release is still lower than the 0.3 milligram per kilogram or the benchmark by Xencor molecule, CD20, CD3. Novartis licensed it first, and they returned that. Johnson & Johnson come in to license it, then because they believe SAFEbody could help to solve that, they return again. No trick. If you look at even Roche molecule, they still do pre-medication. We don't. We just dose in the people. So if you think about step dosing, what's better than your molecule slowly release continuously? How many step continuously, right, to reach that step dosing? You just dose it in the people. They just control that release all the way. That's the tricks.
Okay, so what are the key milestones or catalysts expected in the next twelve to eighteen months?
So I think that. Of course, clinically, our focus is really on the CTLA-4. We really think this is an unbelievable opportunity here. You can turn on the cold tumors in combination with PD-1, and then we're looking at this. Right now, we look at this basic dosage. We're going to release that 20 mg, the loading dose strategy and the data there, so people can see how wide a range you can dose in the patients, right? The second we want to show, can you go to a broad patient population with liver metastasis, right? So therefore, we already get the protocol revised, working with our Merck colleague, are very passionate about it. So we're going to dose in the patients to show that.
By the way, we show in our six-week one, even we have no confirmed ORR in that patient, we have a PFS, like, six months, and OS rate very nicely. So basically, we say, if you combine with the standard therapy, they have very little response in those, you know, because single digit or 5% or less than that, right? If you combine with our immunotherapy, you don't even need to worry about the ORR in our population.
Mm.
You just wait that PFS, OS. Why? We show our data, subgroup analysis, we show. If you look at those patients receive one cycle, two cycle, three cycle, four cycle, you can see the benefit in survival those patients show. Phenomenal thing, right?
Yeah.
So the idea is, if you can control, but your standard therapy control the disease progression for those liver metastasis, pulmonary, whatever metastasis that makes it aggressive, if you can control, give that window to receive immunotherapy, don't let the doctor worry about treat the patient beyond the progression, they will get a survival benefit. So that's the thing. We are very excited to do and, you know, with our PI and all that. Yeah.
Okay. So how do we envision monetizing your proprietary platforms beyond your internal pipeline? Are there any plans for licensing or partnership to expand those?
Yes. Yes. We found, because you mentioned, beyond the oncology, there's any other indication we can do. We just use, like, the example, CD20, CD3, because in oncology, people say, "Oh, you guys are too late," and all this. And the safety is less a concern in oncology. But once you come to the autoimmune, people care every bit of safeties. And our that bispecific T-cell engager with such a safety profile. Also, you can look at the B-cell depletion, at the high dose, we completely wipe out those B-cells, and the tissue is so clean. And the Genentech actually published a paper in the CD20, CD3. There's a relapse time. If you don't remove those B-cells clean, it will come back. So we can really make sure that's the case, and those indications become a sweet spot for a lot of pharmas.
You can see recent licensing or biotech financings, and we think that's a very interesting field. We're getting in, and the mechanism of action, we already figured out, because in the end, how our tissue, like a tumor or in autoimmune, if you get a swelling tissues, there are some common mechanism that play a role there, and we think that's a wide-open space. We're pretty excited for that.
Great. Perfect timing, so we are at the top of our hour. Thank you so much, Peter. Thank you so much, Raymond.
Thank you.
Thanks for your time.
Thank you.
Thank you.