This is Daina Graybosch. I'm a senior equity research analyst here at Leerink Partners, and I'm excited to be hosting again at our global healthcare conference, Adagene. This is the first year we've hosted Adagene that I covered the stock, so that's exciting. In past years, it was a fireside of uncovered stock. I wanna thank Mickael Chane-Du for joining us. He's the Chief Strategy Officer at Adagene. We have 30 minutes, and I think we'll jump right in. Thanks for having me. Awesome. Your lead program, Muzastotug, I call it Muza. What do you call it? 126. 126? That's the old name, ADG126. Okay. 126. It's a next generation masked conditional CTLA-4 antagonist. I thought we would start just setting the baseline with it, which is how is it differentiated from other next generation CTLA-4s, masked or otherwise? Sure. There are three levels of differentiation, I believe, versus other CTLA-4, be it the first generation or the other masked anti-CTLA-4. Number one, we have our own backbone. Our CTLA-4 antibody binds to a different epitope compared to ipilimumab, which ultimately leads to a significantly stronger ADC, ADCP versus ipilimumab. We believe that we are 10x higher compared to Ipi. That's factor number one. Factor number two, we use our proprietary masking technology called SAFEbody It's a protease sensitive peptide, we believe that our masking efficiency is significantly better than a lot of our competitors. As evidenced by the fact that with our anti-CTLA-4 ADG126, with the mask, we are able to dose patients at very, very high dose levels, up to 20 mg per kilogram. Can you tell me what it means to have a high efficient mask, specifically? When we talk about masking efficiency with, when you have the mask, you want the antibody to not bind to the target, right? There's a certain level of efficiency to that, and we believe that we are significantly higher compared to a lot of company, including Exelixis, for example. You don't bind the target until you're unmasked? Yeah. Or even when the mask is present, you know what I'm saying? Right. Yeah. I think that some people would say that binding the target when masked has some positive benefit, I'll try to play devil's advocate for a moment, in that you're building local concentration, and then you can cleave at a higher concentration if it binds but isn't particularly active when it binds when masked. Sorry, can you elaborate on that again? Yeah. If you can bind the target, but you, it's weak, that you would develop local concentration where there's high target expression, and then when you cleave, you unleash the more potent activity. I see what you say. We are believers that you need a balance. You know, you need a balance in terms of how strong you wanna be in terms of, in terms of potency. Obviously, you want a high, you want a high concentration, but you don't want too high of a concentration and too high of an antagonism of the target because you, again, you want to have this balance and therapeutic index. We believe that as we speak in the, in the clinical setting, with, again, very, very high dose that we're giving in combination with PD-1 up to 20 MPK, we are achieving that balance, as evidenced by the fact that we don't have grade 4 or grade 5 treatment related, and our incidence of grade 3 is very much under control as we speak. More importantly, besides the number in terms of grade 3/4, grade 3/4/5, our discontinuation rate due to treatment related adverse events is fairly low, less than 10%, again, in combination with full dose of pembrolizumab. Yeah. Okay, let's talk. Yeah, we could go theoretically on the kinetics of what's happening all day, but what matters in the end is the clinical data. Mm-hmm. We have a lot of clinical data, with 126 and Pembro in MSS CRC, and I wonder if you could talk generally about what's exciting about the data you have so far? Yeah. Let's talk about the MSS CRC indeed, and I'm sure that later in the conversation, we will talk about non-CRC indication. Just for background, for late-line MSS CRC, with or without liver metastasis, unfortunately, the standard of care has very poor outcomes. We're talking about a response rate in the mid-single digit, right? Median overall survival in the low teens. If you talk about fruquintinib, for example, the median OS has been 11-12 months, right? If you look at the sunitinib regimen, it's a little bit higher, but not significantly higher. Number two, it is important for people to remember something. Keytruda or any other PD-1 inhibitors, they don't have a label for MSS CRC, be it in the first line, second line, or late line setting. It is an extremely cold tumor, right? Very high prevalence of PD-L1 negativity, a lot of T-egs, et cetera. PD-1 doesn't have a label because unfortunately the responses have been very, very poor. I will also mention, by the way, a data point about PD-1 CTLA-4. We know from a randomized Phase 2 that nivolumab, ipilimumab had a fairly low response rate in our population of interest. Population of interest being late-line MSS CRC without liver metastasis, their ORR was 2.5%. Wow. Okay? 2.5%, around the same number again for PD-1 single agent. Our response rate so far, depending on the dose you look at, the relevant doses is between 15% and 29% confirmed. I'm referring to the data that we presented last year at ASCO. 15%- 29%? Yeah, confirmed response rate. What is the unconfirmed? Unconfirmed, that would be 17%-29%. The upper end. What's giving the range? Say that? What's driving the range? Why are you giving me a range? We see a dose-dependent response profile, the higher the dose. This is something, by the way, that you want to see with an anti-CTLA-4. The higher the dose, the higher the concentration, especially in the tumor microenvironment, we believe that this is going to drive a higher response rate. We have seen data from the ipilimumab of the world as monotherapy in the P hase 3 randomized, looking at 10 MPK versus 3 MPK. The higher the dose, the better. You see a longer survival benefit with Ipi. We combine with Keytruda, and we are seeing something very, very similar. The higher the dose, the higher the concentration, and we're seeing a higher response rate. Got it. As of then. That's what we've seen at ASCO 2025. We will give an update to the, to the street, with regards to our doublet combination, Keytruda plus ADG126, again, in late-line MSS CRC with Ipi/mets, in the coming weeks. Wow. So it'll be like an investor update. We wanted to. At a conference. No. We wanted to have some flexibility. Got it. Help us understand because, I mean, you've done an incredible amount of dose exploration and optimization. I think really impressive to understand the PK and really understand the therapeutic index and how much active moiety is in the tumor versus not at various dose regimens. Admirable. I always get confused because you've done so much. Help me understand like what is the latest in terms of this data set, the latest dose and regimen that you're most excited about, and how much of this next update will be at that dose and regimen? As a reminder, at ASCO 2025, we had 41 patients across the two lower dose cohorts. When I say lower, but we're talking still about 10 mg per kilogram. 10 mg per kilogram Q6W and Q3W. We had 41 patients who were efficacy evaluable. All right? Yeah. We had 21 patients across two high-dose cohorts. We had 20 MPK followed by 10 MPK every three weeks. We call it the loading dose. We had 14 patients. All right? Again, at ASCO 2025, we had seven patients who were efficacy evaluable from expansion cohorts for the 20 mg per kilogram every six weeks. Mm. In the upcoming data set, we will have five more patients at 20 milligram per kilogram every six weeks. Okay? The total number of patients from the higher dose is going from 21 to 26. We're getting With the same medium and high doses- Mm-hmm ... four regimens, we're gonna get a lot more follow-up and adding five more patients at the 20 MPK Q6W. That is correct. I believe that investors should pay a lot more attention to durability. At ASCO 2025, the follow-up was a little bit too early for the higher dose, at least, to show. We couldn't show mature data in terms of duration of response, PFS, and OS. In the coming weeks, investors will be able to draw some conclusions with regards to durability of ADG126 from the higher dose. Got it. I want to emphasize, by the way, something about 10 MPK and 20 MPK. We just talked about the higher dose. I want to reemphasize one data point. At ASCO last year, we presented a combined data set for 10 MPK, Q3 and Q6W, 41 patients. We reached a median of 19-20 month. We have a median follow-up close to 18. Okay? That number already compares very nicely favorably versus historical controls, versus durvalumab, tremelimumab, versus standard of care. All right? We will have a longer follow-up, so people will be able to see our... You know, we talk a lot about tail of the curve with immuno-oncology agents, so people will be able to see that and draw conclusions with regards to long-term survival benefit with ADG126. Mm ... at 10 MPK/lower dose plus pembrolizumab. This is a 10 MPK. We will also have data in terms of durability, PFS, and OS from the higher dose. We will share some landmark analysis. If you look at fruquintinib in a very similar setting, the 12-month OS rate was around 45%-50%. Okay. It was 70% for the lower dose of ADG126 plus Keytruda. Seventy. 70%. We will share the 12-month OS rate for the 20 MPK cohorts. All right? Got it. Remind me why the loading... well, you also have ongoing a Phase 2 of two dose cohorts- Mm-hmm right? For optimists. Are those two dose cohorts repeating two of the dose cohorts we're seeing of the four ongoing, or are they new? They're repeating with a slight adjustment. We are testing two dose cohorts, 10 MPK and 20 MPK. We've one slight difference. We are using an induction/maintenance schedule in the sense that we encouraged the investigators, especially for the first two cycles, to. For example, let's talk about 20 MPK Q6W. For certain patient, and especially the responsive one, we encourage that the patient stay on 20 MPK Q6. If it's especially if the patient is doing well, we encourage the investigator to switch to 15 MPK Q6W. All right? Keeping in mind that the vast majority of responses that we have seen in these two, in the vast majority of cases, we see responses happening within the first two scans. Mm. Having this induction maintenance, we believe is a great way to find a balance in terms of efficacy, safety, keeping in mind also long-term benefit of the patients. Yeah. I also want to, because some investors have asked a question, does it mean that we're worried about the safety profile? I wanna say that not. It's not that we are worried, we just want to further improve what we have. Yeah. Got it. We, we did see last year readout of the first, I guess, positive IO regimen in MSS CRC with the Zanzalintinib atezolizumab versus a TKI. I'm drawing a blank what TKI was. I think that was regorafenib, right? regorafenib. Thank you. Assuming approval, that will be the first sort of IO regimen approved here. Can you just put in context, one, what you think about your doublet versus that doublet? Also you're working on a triplet, how you're thinking about adding a TKI in your case fruquintinib, and why, you know, could you swap in the approved Zanzalintinib atezolizumab, if that's the case, to sort of add on top of approved doublet versus going with the triplet where you're gaining your own data? Okay. Let's talk about what we know as we speak regarding our doublet versus zanza atezo. I believe that in The Lancet paper, zanza atezo had a response rate of around 5%. Is that correct? In ITT. I believe that if you assume that the vast majority of the responses happen in patients without liver metastasis, we're talking about 8%-9%, if I remember correctly, in terms of ORR. If you assume that, which might not be true, right? We don't know. Which might not be... Again, I'm being- Yeah. That's the best. Let's say between 5% and 9%, right? For again, patients without liver metastasis. As we speak, I mean, at ASCO 2025, our response rate, confirmed, at, especially at the higher dose, was close to 30%. Right? Yeah. I think this is one area where we can differentiate. Very, very soon, we will again, give an update, share what kind of long-term survival benefit we can see starting from 10 MPK, and a trend in terms of how the 20 MPK cohorts can perform. That's the efficacy. I believe that safety is very, very important because. Mm. Zanza atezo is not the easiest regimen on the patients. If you look at the incident of grade 3-4 discontinuation rate, et cetera. Okay? We believe that it is important to induce, you know, responses, but if you can maintain patients on treatment for as long as possible, obviously, this is important for the durability outcomes. Yeah. yeah, talk about your triplet of fruquintinib, why you chose fruquintinib, when we'd see that data. We chose fruquintinib because fruquintinib is part of the standard of care for late-line MSS CRC. Right? That's number one. Number two, we wanna combine with it because again, besides the fact that it's part of the standard of care, it's a multikinase inhibitor that is more selective for VEGF. We're believers that combining PD-1, CTLA-4, and VEGF is a good regimen and relevant for patients with late-line MSS CRC. Mm. without liver metastasis and potentially down the road for patients with liver metastasis. We will have data around mid-year. When I say mid-year, it could start as early as AACR 2026. I think it will be important to show that we can have a very safe regimen knowing that we are going to use ADG126 at, you know, reasonably high doses. Again, with full dose of pembro and a starting full dose of fruquintinib. Right? I think it will be important to share beyond safety, a, you know, good trend in terms of early efficacy data. Got it. Are you considering parallel path of a triplet and a doublet in registration? Or you'll pick the best of these? Or is it too early to have that conversation? Let's publish the data- Yeah. number one. We shall see where let's see what we can do. The good thing is ADG126 at high dose is a very well-tolerated agent in combination with PD-1, and we will share in the coming month that we can be safely combined not only with PD-1 fruquintinib, but also PD-1 bevacizumab, et cetera. We believe that ADG126 is a safer CTLA-4 that can be dosed high and can become a very natural combination partner as part of a lot of novel regimens. Yeah, I think it's worth pausing on that, in that this has been tried, right? We tried Ipi, nivo, cabozantinib in RCC. Mm-hmm. to the detriment. I mean, that failed on OS in a randomized study, and you had lower dose exposure of both the TKI and the IO agents. In addition to safety, you'll be looking at dose exposure of all the agents, right? Mm-hmm. Mm-hmm. To see if you can maintain the duration of treatment. That is correct. Should we expect to see that kind of data, the dose exposure data in the first readout? Dose exposure data, Yeah, what was, for example, the median dose of each component? Yes, exactly. We may. Okay. Got it. Another company shared some promising data. It was a post hoc signal that suggested that baseline plasma tumor mutation burden, not tissue tumor mutation burden... Mm-hmm. In MSS CRC enriched for patients sensitive to their CTLA-4, another MAST in combination with PD-1. I wonder if you've looked at plasma TMB in your trials, and do you see that as a potential way to enrich for even greater efficacy? As we speak, we don't have plans to enrich for such population. I can share with you that we don't have data for all the patients, unfortunately. That being said, we were able to extract some data looking at plasma TMB high or low, and we have seen responses in patients with plasma TMB less than 10. We believe that there are probably other factors involved in behind so these responses. Got it. More heterogeneous than a simple cut. Right. Compared to the other CTLA-4, you would have more Treg depletion, potentially, mechanistically. Hard to- Hard to know? Yeah. I mean, we are very proud of our ability to deplete Tregs, obviously. We believe that when we compare, for example, to an ipilimumab, I can certainly say with confidence and conviction that we do deplete Treg- Mm. in a more significant manner. How do we compare to botensilimab or XTX101? That I have probably to come back to you. Yeah, got it. Let's talk about the potential for 126 beyond CRC. I think there's currently a cohort in collaboration of Roche testing it in hepatocellular carcinoma. Mm-hmm. I wonder if you could give an update on that and just the broader potential and other indications. Yeah. We will have data pretty soon. We plan to present this at a medical meeting. Okay? We believe that this is an interesting data set because it's a randomized data set. You will see ADG126 in combination with atezolizumab and bevacizumab. There's a control arm of atezolizumab, bevacizumab, right? It's a moderate number of patients. The dose that we use for ADG126 is a dose that is higher than what that you have seen with ipilimumab. All right? We believe that investors will be able to draw some conclusions looking at response rates, duration of response, PFS, and OS. The median follow-up for the patients in that data set is pretty long, more than 20 months. Wow. Yeah. Roche shared that data set with us last year. We have the authorization with them, you know, to release it. We decided to do it again, very likely at a medical meeting. Got it. I want to emphasize also something. MSS CRC, as mentioned earlier, is a tumor type where PD-1 doesn't work. PD-1, CTLA-4 have not been able really to get a label there, right? Again, very to a cold tumor. HCC on the other end is a warmer tumor type, let's say. Mm-hmm. we know that PD-1 single agent has some level of activity. PD-1, CTLA-4 have been able to. Yeah. grab a label there, right? certain companies, and notably AstraZeneca, if I remember in the HIMALAYA and STRIDE, in the STRIDE trials, they evaluated tremelimumab with a single dose high induction. Right? Yeah. I forgot the exact, the exact dose level, but the hypothesis was they need to dose very, very high with, one cycle of CTLA-4 and then have more PD-1 embarked. Right? We are dosing again, we are dosing ADG126 with atezo and bev, until progression in that data. We believe that, giving an anti-CTLA-4 continuously as many times as possible is important to deplete Tregs. Treg, we believe, is an important mechanism of resistance to immuno-oncology agents. Got it. The difference there you attribute to the Treg side of the mechanism, potentially. It's about the dosage level. It's about Treg depletion. It's about treatment until progression. Yeah. What's the dose? Have you given us the dose? We have not really said, but it's a higher dose than Ipi, but it's a lower dose. Ah. than what was, than what we have in our MSS CRC data. Got it. You're right, 'cause you started this one early on. Yes. Got it. We believe that it's an interesting data set. It's randomized. We believe that CTLA-4 via PD-1 VEGF, you know, the addition of CTLA-4 to PD-1 VEGF should be, you know, should bring something to the table. In a capital unconstrained world, where else would you guys take ADG126? Good question. We are looking at late line MSS CRC without liver mets, but rest assured that we have our eyes on patients with liver metastasis. Okay? We believe that we can address that patient population with broader regimen or novel regimens. We also have our eyes on earlier lines of therapy of MSS CRC. You have seen a number of companies that had some good data, good signal in late line and then went to first line, right? This is MSS CRC. MSS CRC again is a cold tumor, et cetera. There's a lot of other tumor types where we know that CTLA-4 does work. We believe that we could be differentiated thanks to our masking, our enhancer particular index, and our ability to dose significantly higher. Mm. A lot of other CTLA-4. Again, CTLA-4 is a dose dependent. We believe that it's highly dose dependent. The higher the dose, the better. We know that Ipi Treme have a label for melanoma, RCC, HCC, lung cancer, et cetera. That's in a world where we're not constrained by capital. Yeah. You have done a lot of interesting collaborations. Some you've been extending, some there are new ones, and maybe people haven't paid attention, but could you just give us an overview of the ones you're most excited about or the ones that are most recent? Yeah. Last year, we last year in July, we announced that we got an equity investment from Sanofi, a commitment of up to $25 million. We received the first tranche of $17 million at the cost of $2 a share. Okay? We have had a very long relationship with Sanofi, which started back in 2022. It was a discovery collaboration. They wanted to have access to our SAFEbody, so our proprietary masking technology. Last year, they expanded that collaboration, which triggered the milestone payment. They advanced a third SAFEbody, third masked antibody as part of that collaboration. Not only that, equity investment, amendment slash expansion of the collaboration. They also wanted to initiate a Phase 1/2 to evaluate a novel combination, and that novel combination being ADG126 plus their, now we can say what it is, it's, their bispecific PD-1/IL-15. Mm. The fact that we are combining our CTLA-4 with a PD-1/IL-15 tells you a lot about how they envision or see our safety margin. Yeah. That trial will enroll more than 100 patients with solid tumors. Right. That's started? I believe this should start soon. We are very excited about this ongoing collaboration with Sanofi, but we also have an existing collaboration with Exelixis. As part of that collaboration, Exelixis is also using their, our SAFEbody capacities and apply to a number of biologic biologics. Okay? Last year we also announced a licensing deal, a small collaboration with a company called Third Arc Bio. Third Arc Bio is about developing T-cell engagers, and they wanted also to have access to our SAFEbody capacities again and then work on TCEs. Got it. Yeah. So- I think I can say it's in solid tumors. You have your own, I mean, you have a lot of MAS programs. I knew the company first 'cause you had a MAS 4-1BB, in addition to the CTLA-4, which I think is still sort of trucking along somewhere. You also have MAS T-cell engagers. I wonder if you could talk about that platform and your lead, your leads, which I think are targeting HER2 and CD20. Correct. That is correct. We have these two assets in the preclinical setting. Let's talk first about the ADG211 CD3 compound. This one, again, at preclinical stage, according to our preclinical data, including in monkeys and HPs, we have seen that we can significantly reduce the incident of cytokine release syndrome in this in vivo and in an in vivo setting, right? We believe that this is a TCE that we can dose fairly high, and it's a TCE that can be very potent. It's a double MAS, right? Yes, and it's a double MAS. Sorry, actually I forgot to mention that. The other compound that we have publicly talked about is a CD20 CD3. This one may, also with a, with a double MAS, could have applications in autoimmune disorders. Yeah. How close is that one to the clinic? The first one could be, is closer to the clinic, the closer to the clinic, than the other one. Ideally, this year, these are programs that we would rather move forward as we speak, given the state of the balance sheet, that we would move forward with a partner. Got it. I think that's all we have time for. Thank you very much. I appreciate it. It was great. Thank you, Daina. ...to catch up.