Hello, everyone. My name is Daina Graybosch. I'm a Senior Analyst here at Leerink Partners, covering mostly companies working in immuno-oncology. I'm excited for, I think, a few years running to be hosting Adagene and their CEO, Peter, to talk about their programs and the company. Welcome. Thank you, Daina, to have us. Awesome. Your lead program, ADG126, is it muzastotug? Is there a nickname? Yeah. Muz is targeting CTLA-4. I think I want to spend most of our time talking about that program and at the highest level, and then we'll get into the nitty-gritty details, which are really interesting because of all the clinical work you have done. First, why should investors still be excited about CTLA-4 for colorectal cancer in particular? Yes. Daina, the CTLA-4 is a de-risked target in all tumors. I think for the MSS CRC tumors, the CTLA-4 is essential, especially through this Treg-mediated or CTLA-4-mediated Treg depletion in tumor microenvironments. This could make this tumor, which we know PD-L1 negative population accounts for 82%, and the TILs very little in the tumor biopsies. By depleting the Treg, you can not only upregulate the PD-L1, also bring the T effector cell into the tumor environment to make it warm again. You say 80%, 80 of tumors is Tregs? Oh, no. The PD-L1 negative populations. That is why PD-L1 therapy has very minimal response for this tumor, right? Low TILs, PD-L1 expression is very low, and the Treg expression is about 40%. Interesting. Like your competitors in CRC, the other competitors with CTLA-4s, Adagene's focused on patients without liver mets. You have also looked at a subpopulation without liver mets and without liver and peritoneal mets. Sort of why is it reasonable to develop a therapy for these particular clinical subpopulations? Can we trust that the activity in the subpopulations is sort of predictive, or are they post-hoc groups? Yeah. I think for the lung liver met, and it's very well documented in the literature and the clinical data, shows for immuno-doublet, this is the population that is going to respond to the immuno-doublet well. In fact, we know a company talked to the FDA, FDA also agreed with the proposal to do the trials in these populations. In terms of peritoneals, it really depends on the stage of the tumors. As we know, the peritoneal mets also are pretty resistant, especially in the late stage, I believe stage 4C, and you saw a lot of peritoneals. That, in general, don't respond to immunotherapy well. That's why we explored to exclude those populations in our 20 MPK loading dose. If you look at the data we show at this 10 MPK, we did find that certain populations with peritoneal can benefit from this therapy for survival. For simplicity, you can rule them out. We think a meaningful strategy, if you look at the OS benefit, you can include part of this population in your trial in the lung liver met in general in that category. The peritoneal is maybe a proxy for disease burden, late-stage disease, all these factors that we know are very challenging for IO, whether it's PD-1 or CTLA-4. Does that mean as you move to register other trials, by moving to earlier lines, you'll just naturally have less of the peritoneal mets populations? Absolutely. You're right about that. Let me go back to the liver met question. I think you answered it by answering that you have some precedent that regulators are OK with using this to carve out a population. You answered it based on lung cancer, that they were OK there to carve out a drug for liver mets. We know with Agenus, they also carved that out. Regulatory-wise, it seems like a path. Sort of biologically, why is this a reasonable place to exclude those patients? Yeah. I think biologically, people look at this really hard, right? Not only in MSS CRC or CRC patients, also in lung cancers. Basically, this is a highly immunosuppressive population with liver mets. That's why people tend to restrict or leave them out in those trials. Especially if you look at that subpopulation in other standard therapy approved, the liver met always is less responsive for the IO therapies. If you combine with other standard therapies, small molecule or those TKI inhibitors, they can definitely help to control the disease progression in those populations. Yeah. If you move to the early trials, even in neoadjuvant settings, that's lesser issues. Yeah. Got it. The first-gen CTLA-4s, ipilimumab and tremelimumab, had pretty much zero to negligible activity in MSS CRC. What mechanistically is different about your CTLA-4 and the other ones that have also shown activity in this setting that's driving the activity? Is there something biologically different, or is this simply the result of better dose exposure that you're getting with an improved therapeutic index? Yeah. We think it's both. Because if we talk about Treg for depletion, you definitely need an Fc active design. That's why you saw second-generation CTLA-4. They all have this Fc engineering. In our case, our Fc activity is through this epitope-dependent ADCC effect, which is about 10-fold higher than Ipi, without any Fc engineering. Of course, the second part of it is the dose dependence. Because by masking, we can deliver 10- or 20-fold higher dose, like a 10 MPK or 20 MPK compared to the Ipi. This really allows the drug to penetrate into the tumor, get more drug exposure, especially for active species in tumor microenvironment. The combination with both higher drug exposure and more active Fc functions can drive this kind of a cold tumor, MSS CRC, yeah, effect we show there. Is that similar to the other CTLA-4s that have shown activity in CRC? They have both of these elements. What is differentiating about yours? The novel epitope, I think you said, is different because you are not using Fc engineering, you are using the epitope. The therapeutic window, are the others also getting a similar therapeutic window? How do you think you compare there? Yeah. We think it's similar in terms of Fc enhancement that goes through this Fc engineering. We go through this epitope-driven. The reason for that, through Fc engineering, you also make the normal tissue Fc gamma expression become sensitive to this kind of approach. Therefore, you really increase the toxicity related to that. I think if you look at lots of Fc engineered anti-CTLA-4, the toxicity level is also increased significantly. That's why when they try to dose it up, it's very difficult, right? If you look at those Fc engineered ones, if you ask the body-based dose level, they barely go beyond 2mg per kilogram, right? This very limits how much they can push the drug exposure for this concentration increase. Of course, by having a strong ADCC effect, therefore, at the low dose, they can see some of that Treg depletion effect. Of course, the threshold against the normal tissues also enhanced. That is why you find a lot of Fc engineered antibody, even with masking, can hardly go beyond, say, 100mg, even try to struggle to reach 150mg in flat dose, right? That's really interesting. I actually never, we've talked many times, and this never dawned on me, that your two differentiations in the molecule sort of act together. So not only do you have masking and conditional, but the epitope increase of Treg depletion is also contributing to your therapeutic window. Yes. We actually tried those Fc enhancements. You can clearly see in the monkeys, the tolerability goes down significantly. That is the price you pay. Beyond CRC, where do you see potential for Muzo? Is there an archetype indication based on these attributes that stands out? I think the indication we pursue with MSS CRC, right, was we talked about. Because of all those three features, high Tregs, no PD-L1 or negative PD-L1 expression, and a very little TILs, to me, all those features are important for you to think about the indications, which will be very sensitive to this kind of anti-CTLA-4 therapies. Of course, in terms of combination, you can think about other modalities, just more than just PD-1, right? We are thinking about those. I think at one time or two, we will discuss those indications. Will you go after any of the Ipi indications? AstraZeneca has a next-gen CTLA-4, very different bispecific. They seem to be sort of going after all the places where Ipi and Tremi. Will you try to compete in that realm, maybe because you can combine better with standard of care? We have to wait and see. I think that's a really good question. If you look at the Astras, right, they have this Tremi, they have CTLA-4 PD-1 bispecific. That really shows the conviction in these targets. Most of the indications, if you look at this, they're still going after the indication approved for the first generations, right? They just try to expand that. What we're going in terms of our development strategy is for those cold tumors, you really need this strong Treg depletion and Fc active components, which are not in Tremi or in the bispecific. That's kind of a very different positioning for our CTLA-4 development strategies. Yeah. Definitely. We got through many questions. To jump down, let's talk about dose, because I think dose is absolutely critical for CTLA-4. Dose and therapeutic index are absolutely critical for what you're doing. You've pretty exquisitely mapped out the dose relationship of your therapy with dose arms. You had data at January at ASCO GI, and you had this beautiful slide. What really struck me is that you are showing dose responsiveness in efficacy, and you're showing dose responsiveness in toxicity. It does look like your therapeutic index is relatively wider than some of the competitors, but I'd say it's still pretty narrow. You have this loading dose strategy of you start with 20 loading dose, and then you go down to 10 MPK. The activity is pretty exciting there, but you also tick up the grade 3 tox. Can you talk about sort of how you're going to find that perfect window? Because it seems you can't get away with it with CTLA-4 and still having the dose selection be really challenging. That's a really good question, Daina. We really think it this way. I think that in terms of normal tissue exposures in the blood circulation, the window is really well defined by EP or others, right? There, basically, if you look at the plot we show you, right, there is a very tight boundary you don't want to go beyond for drug exposures for normal tissues. On the other hand, if you look at the tumor exposures, you have room to really improve that. I believe the superior window really comes from combination with both. Let me give you examples. If you look at the 20 MPK loading dose we show there, even what 20-fold higher than Ipi at the 1 MPK, if you look at Cmax of Ipi at the 1 MPK every six weeks, we actually reach the same level for peripheral drug exposure for activate muscular antibody. At the 20 MPK, the active species is the same concentration as the 1 MPK of the Ipi there. We believe that's the limit in the normal tissue exposures. If you look at our drug exposure at the 20 MPK inside the tumor, there we are more than 20-fold enhancement compared to what the Ipi can get into the tumor. If you believe the Treg depletion, the CTLA highly expressed in tumor micro and Treg, that's what the big difference comes from, more than 20-fold. You still maintain the drug exposures in blood at the same levels, even you enhance the 20 MPK fold. That is a big increase in the windows. It's interesting. You have a big, rich, to make sure I understand, rich set of data from Ipi on the systemic exposure. You just basically dosing up right to that. You're sort of, in a way, equal on toxicity systemically. You can see that you're this 20-fold higher in the tumor. That's where you think the efficacy is really coming from. Exactly. That's a window, so if you want to equate. Do you think that is it going to the other thing I noticed is there's, especially over time, you have a pretty high variability on exposure MPK. You sort of exquisitely managed this. Like, where is that variability patient from patient coming from? Do you expect variability tumor to tumor? Is that going to require additional optimization or down-dosing strategies? Yeah. That's a, again, I love this question a lot. We think that variability could come from both. There's two factors. If you look at a normal IgG antibody, the PK variability is about 2-3-fold. That could relate to target-mediated pathways or the Fc part with the neonatal part, right? If you actually look at our SAFEbody, muzastotug one, the variability of the PK is about 5-fold. That means we only add less than 2-fold compared to normal IgG PK variations. It is just a but it is more variable. Yes. Of course, you can speculate that variability could have cloned the tumor cleavage process for that, right? Maybe it's related to different tumor type. Based on the data so far, we generate a lot of data in MSS CRC and that kind of intra-tumor or intrapatient variabilities. Also, other tumor types. We didn't see such an obvious difference between different indications. We think maybe relate to the tumor load of that activation process. By the way, we do look at the tumor size loading based on our dose escalation there. There's a wide range of the tumor distribution there and all that. We think this 5-fold we're talking about includes all those cases. Therefore, in terms of the dosing regimen and the kind of control, we show 20 MPK loading dose could reach kind of the limits of that. On the other hand, if you look at 10 MPK to 20 MPK, we still have a wide range to play with. And if you actually look at our 10 MPK Q6W, it's extremely safe in that combination. We barely see grade 3 toxicity there. You have lower efficacy there too. It's only for MSS CRC. In fact, in the head and neck, we have a complete response. We previously reported for that indication. Yeah. Does that give you a sense of which indications are more Treg dependent? Because do you think the more Treg dependent, the more you need to get to the higher dose? Exactly. The more aggressive you want to push that. Of course, that's just we talk about immuno-doublet. If you consider if we're going to combine with a standard therapy, you may not need to be so aggressive to push that, right? OK, yeah. What I was trying to say is we do have a pretty wide range of the dosing regimens given the superior window we created there, which really allow us to come up a nice range of dosing regimens, either by immuno-doublet alone or when we do combination with standard therapies. This, we feel pretty comfortable to look at this. In fact, if you look at the DLT, in the loading dose part, extremely low, right? We really believe, after you have this induction phase followed on the maintenance phase, you can really need to adjust the induction phase. For the maintenance phase, we feel really comfortable to what we have shown, right? 10 MPK Q6W or something, even a little higher. OK. So you have this loading dose and maintenance. Do you need any dose and maintenance? I mean, we have several clinical signals that one hit with CTLA-4 may be sufficient. Astra had a single Tremi dose in HCC. And my read of the COSMIC- 313 data, where the triplet arm, you had lower Ipi exposure because you had the toxicity of cabo. But those patients and overall survival did just as well. So it didn't seem to and somebody asked to ASCO GU, hey, did you break out the lower exposure? And did they get worse? I'm like, oh, we haven't broken it out. That to me means that they probably did fine. So why continue giving it at all? OK, yeah. I really think maybe I can share some data. We look at this. Those cases you mentioned about, we call them in general, are IO tumors, right? Yes. HCC or lung small cell lung cancers. There, you can see even the Himalaya trial you were mentioning about, AstraZeneca, they gave a priming dose, right? One dose. If you look at the lung small cell lung cancer, they actually gave four doses, which in fact, sometimes you see people at the 12 weeks, three months, they give another dose. This really says some of the extra dosing of CTLA-4 could help control the long-term benefit. At least in MSS CRC case, we really observed is if you stop dosing for whatever reason, sometimes you can see the CEA bounce back. Oh, so you have some case studies. Yes. Where they accidentally or they stop dosing. Yeah. We have actually quite a few cases like this. You can see the CEA are very sensitive. If you add back our 126, you can see the CEA can jump right away. In fact, in the cases we share in those four responders in our loading dose, you can see if you look at very carefully, some CEA, if you stop dosing for whatever safety reasons, the CEA began to come back a little bit. Once you bring the maintenance dose, the CEA jump again. OK. Does that mean are we going to see the same tail of the curve? With IO therapies, PD-1 combos, you can stop dosing at two years. You get these patients who look effectively cured, if you allow me to say that. Does this bounce back indicate that it really supports the Treg hypothesis? Does it tell us that that's not going to have the same tail of durability because you have to keep suppressing that versus stimulating T effector cells and effectively clearing all the tumor? I think if you look at the, say, MSS CRC, the adaptive increase of Tregs are pretty strong because to start with, they are really high. That's why we believe a maintenance dose to completely control, to maintain control of the Treg level, will be important. Otherwise, you will see new lesion might slowly coming up. It is more a matter of time to really get that full depletion. Once you do that, the same normal mechanism of T effector cells really clearing and giving that long tail, you expect to see that? Yes. We believe, you know, I think one of the things people want to maybe want to show, as you continue to have T effector cells into there, could this also introduce some Tregs in the process? We like to see that, right? We tend to believe for cold tumor, that could be the case because that's how the Tregs hijacked by tumor to outgrow the T effector immunities, right? Of course, we also introduce ctDNA to monitor that process. The CEA, if you have that marker, it's always a convenient marker to see what's going on there. Do you see a correlation in Treg depletion and the clinical benefit? Yes. We definitely show nice examples actually in HCC, where we show how patient progressed from atezolizumab and followed by lenvatinib after we dosing our drug 126 alone, how that Treg before and after dosing depleted by more than 50% and all that. Those are limited examples. That is why we just initiated the new adjuvants for MSS CRC and the Singapore. We just announced that. We are going to enroll 20 patients. In this case, we will systematically collect those matched biopsies to show how Treg depletions relate to the benefit of the patient clinical benefits. Of course, including the tissue biopsy PKs. We really want to generate that data because, like you said, a lot of people are interested. Yeah. When's the next clinical update from the program, particularly the 20 MPK dose? Like, when can we get bigger cohorts and more follow-up from that? Yes. We are adding additional patients to this. We also want to update, it is extremely important for DOR because of the latest cut of when we published those data, those patients still remain on treatment. We really want to show how the loading dose and the maintenance dose strategy could maintain, not could drive the ORR, also could maintain the DOR. We think that will be a very important data set. Other than that, we also have this 20 MPK every six weeks repeat dosing going on. We will also provide that data once the data mature. There, we are considering combination of this immuno-doublet with the standard therapy. Most standard therapy, as you say, they are basically on the two or four-week schedules. I see. In fact, yeah, we also have trials going on to combine our immuno-doublets with the standard therapies. Which standard of therapies are you considering? I guess that gets into what's the regulatory path in CRC. Yeah, yeah. We are doing some third line or fourth line basically with a SUNLIGHT combination and also fruquintinib. We believe that's important for this population, not only potentially allowing us to go beyond liver metastasis, right? Liver-free metastasis to go to liver metastasis. Because that's where standard therapy applies for these entire populations. Could you remind us what the SUNLIGHT combination is? It's TAS-102+ Beva. Yeah. Are you considering a VEGF PD-L1 bispecific instead of Pembro? We're definitely looking into that. That's a very good question. Because if you look at all the MSS CRC, they're all from fourth line segment to third line. They all have a Beva component in that. That's a very large extension, yeah, to look at that. Is the plan so you're going to we're still doing some dose exploration of the doublet. You're going to do these combos. After all that, you'll decide on the registration path? When will sort of the timing of when that will happen? Yeah. We're preparing a package to talk to FDA and CDE to get their feedback in terms of our dosing regimens and our trial design. As you know, the baseline for third or fourth line MSS CRC so far has been based on the OS benefits, right? That's the baseline. In my opinion, it's again, it's personal, right? We think if you can reach for this immuno-doublet for this population to 30%, it could be meaningful to have some conversation with the agency if there's a possibility to concede potentially some accelerated paths without the ORR or potential DOR with those kind of dosing regimens. Why would they, like, it didn't seem possible for Agenus? Should we just think about Agenus as that's the standard path? Or it was possible for them to get accelerated privilege, just didn't have the activity to reach that bar? I think it's safe to assume the baseline has been always OS. If you look at all the standard therapy approved so far, right? If you look at the current standard therapy, the ORR is less than 10%, even for this population. We're talking lung liver mass. Could this say something 30+ is a very meaningful improvement over our current standard therapy? Could the agency open to that conversation, especially if you consider the treatment-related toxicity a lot lower than what people reported, either in the standard therapy or for people achieve I think nobody yet achieved this kind of ORR we reported. We'd like to hear from the agency firsthand. OK. We're over time. Thank you very much. A good conversation as always. It's been a pleasure. Thanks so much.