All right. Good afternoon, everyone. I'm Stephen Willey, one of the senior biotech analysts here at Stifel. Glad to have with us, in the next session, the Chief Strategy Officer of Adagene, Mickael Chane-Du. Thanks for having me. Thank you for the time today. I think this is the first time we've connected in a forum like this. It's good to see you. You know, maybe you can just start us off with a brief overview of the company, quick introduction, and then we'll just jump right into Q&A. Yeah, thank you. Adagene is a global biotech company. We're focused on the development of novel antibodies ranging from monoclonal T-cell, T-cell engagers, ADCs, but more importantly, including masked ones. We can mask monoclonal antibody T-cell engagers, ADCs. Our lead program right now is ADG126. It's a masked anti-CTLA-4. We believe to have encouraging preliminary evidence of an improved therapeutic index versus the first generation of anti-CTLA-4. Are you on mute, Stephen? Unmuted. ADG 126 as you mentioned, muzastotug, is that how it's pronounced? Muzastotug, yeah. Muzastotug. I see, I still You know, I'm too used to saying ADG126. Sorry. Yeah. I'll probably stick to ADG 126 as well. This is obviously the centerpiece of the story here. You know, maybe you can just kind of talk about how the clinical profile of this asset compares to other next gen CTLA-4 antagonists and what you would emphasize as being kind of the key points of differentiation. Yeah. Two things about the design of ADG126. Number one, we have a differentiated binder. The binder, the anti-CTLA-4 part is proprietary. We bind to a differentiated epitope, which leads to a much stronger ADCC and potency, 10X compared to ipilimumab, and we achieve that without Fc engineering. On top of that, we apply our proprietary masking technology called SAFEbody, and we believe that SAFEbody comes with a much higher masking efficiency rate compared to our peers. Meaning that the antibody is less likely to bind to the target here, in this case CTLA-4, when the mask is uncleaved. Okay. Yeah. I know investors are seeing, you know, a variety of different masking technologies deployed across a whole spectrum of different antibody formats. I think the feedback that we tend to unanimously get is that from an investor perspective, this seems like really difficult technology to diligence. I'm not sure if you agree with that, having been on the investor side before. Yeah. I think in this instance, I mean, I would make the argument that you've probably made that diligence process a little bit easier by delivering with ADG126 what would probably be a near lethal dose of drug were it not masked. I would agree. What is unique about the SAFEbody masking tech versus other protease cleavable approaches? You talked about the masking efficiency, but maybe you can also just talk about how you have leveraged this technology outside of your wholly owned pipeline as well. Yeah. What really stands out is, as mentioned earlier, it's really the masking efficiency. When the drug is intact and not cleaved, we're less likely to bind to the target. Without saying too much, we synthesized some of the other masking, some of the other masked anti-CTLA-4, and we find that when the mask was still present and uncleaved, the drug would be able to bind to the CTLA-4 part, you know, to the CTLA-4 receptors. At high level, I will also mention that we believe that cleavage sensitivity/specificity is also an important factor to be considered. Yeah, the fact that we are delivering what, as you said, what could be potentially lethal dose to patients up to 20 mg/kg in the context of colorectal cancer patients while being combined, even in PD-1, you know, is very telling indeed. Just to give you a few benchmarks, ipilimumab was given at a dose of up to 10 mg/kg as monotherapy. In the context of a combination with nivolumab, the dose is more likely in the range of 1 mg- 3 mg/ kg. 1 mg/ kg is definitely the one with which physicians are more confident with, let's put it this way. More comfortable with. On our side, going back, ADG126 is dosed up to 20 mg per kilogram Q6W, as well as with a loading dose approach, 20 mg followed by 10 mg every three weeks. We have generated, we believe, an ORR that substantially exceeds the standard of care, also what other CTLA-4, you know, the first generation of CTLA-4 have shown, as well as single agent PD-1. The response rate there was sub 5%. Durvalumab, tremelimumab, for example, had a response rate of 3% in the very same patient population, or at least I would say a very similar setting, late-line MSS-CRC and focusing on patients without metastasis to the liver. To answer your last part, the last part of your questions, besides ADG126, I will mention that we have a few masked T-cell engagers, one of them being ADG138. It's a dual masked HER2 CD3 engager. There's a lot of HER2 molecules out there, but I don't believe that there's a lot of masked T-cell engagers binding to CD3 and HER2. Okay. I know you provided an update of the phase Ib/II data in colorectal, I think it was last month. Yeah. As you mentioned, right, you've kind of focused on this combination approach with pembrolizumab and later line colorectal patients who do not have liver mets, which is kind of. The route that we have seen IO take in this, in this tumor type. I guess maybe before we get into any of the data, can you just talk about the rationale for, you know, pursuing this subpopulation of colorectal specifically and, you know, what is the unmet medical need that you think still exists here just in the context of what is currently available in the form of therapy? Sure. The unmet medical need is still substantial across the board. The best center of care options today only yields response rates in a mid-single-digit range, overall survival in the low teens in, you know, and I'm talking about patients without metastasis to the liver. First generation of checkpoint blockers, PD-1 and CTLA-4, I mentioned durvalumab, tremelimumab earlier, are not known to work very well in the context of MSS colorectal with or without liver metastasis. They actually did worse than standard of care in randomized trials. Look at the IMblaze370 trial for TECENTRIQ cobimetinib versus Rego. Look at the phase II randomized phase II trial for durvalumab, tremelimumab. MSS colorectal is not the low-hanging fruit. It's a very cold tumor, a very cold TME, a high prevalence of PD-L1 negativity, a lot of Tregs. Patients without liver metastasis seem to be a little bit more amenable to response evaluation. We have observed it in various clinical data sets from Genentech, from Xilio. The working hypothesis here is that liver mets may be siphoning activity effector T-cells from the circulation and suppress them and activate the suppressive players such as Tregs, MDSCs and macrophages. That's again, it's a working assumption. Okay. I know the most recent data cut, or I guess this phase I/IIb data that you've been generating and which was just updated again last month. You've generated some data across a few different doses and schedules. Maybe you can kinda talk to what you're trying to optimize for in terms of, in terms of pharmacology and, you know, what is driving the enhanced therapeutic index that you seem to be achieving with this induction and maintenance regimen that you're possibly going to be moving forward? Sure. There is one very important working hypothesis before we talk about what we're trying to achieve. Anti-CTLA-4 is a highly dose-dependent mechanism of action. We've seen that with ipilimumab, and we're seeing this with our own molecule as evidenced by the fact that the lower dose of ADG126 at 10 mg/kg had response rate between 0% and 17% with pembrolizumab in patients with MSS-CRC without liver mets. With the higher dose, we came with a response rate of 25%-36% confirmed against with that combination, but with higher dose of up to 20 mg/kg. Again, it's a very dose-dependent mechanism of action. What we're trying to achieve is a balance. It's a balance between the concentration of activated cleaved ADG126 in the tumor microenvironment. That's where you wanna have the highest concentration possible while limiting the exposure of, again, activated and cleaved ADG126 in the periphery. We've done a lot of work on the PK side. We've done a lot of modeling work. We believe that we are achieving that balance. The clinical data does suggest so because, again, we're dosing very, very high. When you look at our rate of serious adverse events, dose discontinuation, dose modification, utilization of infliximab, it's significantly lower than our peers. On the other end, we are able to achieve these, at relevant doses, we are achieving response rates above 15% all the way up to 36%. Small numbers, certainly something encouraging that, and that compares very favorably with peers and current standard of care. Okay. The severe adverse events you are seeing or have seen, I'm guessing those are very consistent with the immune- Correct mediated adverse events that we've seen with CTLA-4 antagonism. Are those Cmax or AUC driven? It's probably a little bit of both. I would say that peak exposure and intensity of systemic immune activation probably matter a lot. I'm more inclined to believe that Cmax is probably the bigger driver here. I would assume so. Okay. I know you talked about the IPI dosing schedule, I think in response to an earlier question. I think in clinical practice, a lot of physicians tend to use that on a Q6W. Schedule just because I think a lot of that drug gets into the periphery, and so you need to give the Treg some time to recover. I'm guessing your ability to dose at the strength that you are dosing at and do it consistently every three weeks kinda reflects that fact that again, you're getting most of this drug into the TME and very little of it into the periphery? It's just about achieving a balance. We believe, as you mentioned, we believe that this ability to dose more frequently is helped by the better therapeutic index. The ability to have this higher concentration of activated, slash cleaved anti-CTLA-4 in the tumor, where there's a lot of Tregs, by the way, while limiting it in the periphery. Okay. I guess when you, when you take a step back and you look at the efficacy data that you've generated, kind of in totality, what stands out to you as kind of being the most compelling part of the story and that which you believe de-risks, you know, a registrational effort going forward? It's a really good question and a hard one because I actually believe that I don't think that one data point will help. It's really the totality of the data. It's the fact that we're giving such a high dose to patients. The fact that we have a very low discontinuation despite the high dose. The fact that we are having a higher response rate in combination with PD-1 versus the first generation of anti-PD-1 CTLA-4. The fact that we have a very encouraging overall survival trend. It's really the totality of the data. Okay. I know you have initiated a randomized phase II trial. Yeah. I believe the objective here is to satisfy FDA's Project Optimus mandate. Correct. Can you just talk about the design of the trial when you think these data might be in a position whereby it could allow you to initiate a registrational effort? This is a randomized phase II trial, randomized 1-to-1, 60 patients, 30 and 30. We're testing two dose levels of ADG126 in combination with full dose of pembrolizumab, doses that are on label. For ADG126, we're talking about 10 mg/kg every three weeks, as well as 20 mg/kg every six weeks. The primary endpoint of the trial is response rate. Obviously this data will inform the design of the future registrational/phase III trial. Okay. If you had to design that registrational phase III trial today. What would it look like? I guess maybe more specifically, what would you use for a control? Very likely this is going to the phase III will be randomized. You have two scenarios. The base case scenario should be that the primary endpoint of the trial will be overall survival. Okay. Randomize 400- 500 patients. Control arm of I would go with physician choice of therapy as we speak, and the choice of therapy would be dictated by how many prior lines the patients got at baseline. Scenario number two, which I see as an upside scenario, we have noticed that a number of biotech companies were able to get two co-primary endpoints in the context of second line and above solid tumors. One co-primary is OS, the other co-primary would be response rate. Response rate could serve as a basis for an interim analysis on a proportion on a number of patients, not the whole number of patients, as well as a basis for accelerated approval. You should think of it again as an upside scenario. Okay. Yeah, I think we saw Pfizer do that with encorafenib in BREAKWATER colorectal, right? Kartos as well. Okay. In terms of best available therapy options, would you allow for TAS-102 Bev to be included in that buffet? If we were to include third-line patients in the study, yes. I would guess that would probably make it an easier trial to enroll, correct? Probably. Maybe we can talk a little bit about the preliminary data that you just presented at AACR. I guess as it's relevant to colorectal, you added fruquintinib to the combo of ADG126 and pembrolizumab. What did that data tell you just about the safety and efficacy of triplet therapy? Is this something that you're interested interrogating within liver met patients as well as the non-liver met patients that you've been focusing on? Okay. The data we presented at AACR came with a small sample size, so take it with a grain of salt. I'll say that the data suggesting that we, number one, can be safely combined with PD-1, with PD-1 and a VEGF multikinase inhibitor, so very importantly. The crossroad comparison suggests that importantly we remain very dose-dependent. The higher dose of ADG126 came with a higher response rate. We had a higher ORR versus the doublet as a whole. Again, it's a small number. We were happy to see a positive trend. Now, to answer your other question, using the triplet, this triplet combination for patients with liver mets, I'll say that this is an option potentially for patients with liver mets. As you know, we will be evaluating a new regimen with Incyte, and we're quite excited about it. Yeah, maybe we can talk about that. You just entered into that clinical collaboration, looking at 126 in combo with an asset that I actually think is really interesting and doesn't really seem to get a whole lot of airtime from investors. This is their PD-1/TGF-β receptor II bispecific. I think 8890 is the acronym. How do you think these mechanisms complement each other? And how does Incyte's ongoing development of this asset, which they're looking at plus chemo in the frontline setting, potentially impact the development efforts that Incyte could be pursuing with you i n later line patients? As you mentioned, this is a PD-1/TGF-β, TGF-β inhibitor, so it's bispecific. We know that PD-1 and CTLA-4 work very, very well together. That part I would say is a given. We believe that ADG126 could help the bispecific as a whole because we can potentially address an important mechanisms of resistance to INCA which is a regulation of Tregs and CTLA-4. Now you can imagine that Incyte wants to generate data in the same setting where they had monotherapy data. For people who are listening to us, the response rate, you know, late-line MSS CRC including inclusive of patients with liver mets was 15%. I believe it was 12% in patients with liver mets and 23% in patients without liver mets at the relevant dose. We think this is very interesting data, as you believe, Steve. We believe that this is a stronger signal than PD-1 single agent. PD-1 single agent has been largely ineffective in the context of MSS CRC, third and fourth line. We hope, we believe that the addition of ADG126 can improve the outcomes for these patients, obviously we need to generate the data. Once we have data and depending on the strength of the data, we hope that the two companies will, you know, sit together and potentially discuss, you know, how the collaboration could look like in the future. Okay. It is important to generate data again in the same setting, make things apple to apple, more in an apple to apple thing. Agreed. Outside of the recent Incyte collaboration, I know you've had a strategic collaboration/relationship in place with Sanofi. You're also looking at ADG126 in combination with their PD-1/IL-15 conjugate. Which I believe is the old Kadmon molecule, just maybe any sense of when we might see some preliminary data from that trial and maybe you could talk a little bit about your strategic relationship with Sanofi as well? Yes. The relationship started in 2022 with a discovery collaboration. Sanofi has been using our SAFEbody capabilities and applied them to a number of antibodies. Very importantly, Sanofi is one of the few pharma players that do know a lot about masking technologies because they acquired Amunix back in 2021 for $1 billion and change. We have since deepened the relationship with Sanofi. We had an equity investment from these guys last year in July. Importantly, this is coming from Sanofi corporate, not Sanofi Ventures. We also talked about initiating a trial collaboration, the trial collaboration that you've been mentioning. We will evaluate ADG126 in combination with their PD-1/IL-15 conjugate in solid tumors. More than 100 patients will be enrolled. We're also very excited about this one. Unfortunately, I cannot tell you when we will have data. Sanofi really controls the timing of the data release, so no guidance at the moment. Okay. That scope of the development program though was in solid tumors and beyond colorectal specifically. The wording is more than 100 patients in solid tumors. Okay. I'll say probably warmer tumors. Okay. You're getting very good at sticking to the corporate speak. You have other tumor types, I guess, you're looking at with the Sanofi collaboration. Then you did present or there was some data presented at AACR looking at the combination of ADG126 with atezolizumab-bevacizumab in liver. Maybe you can just talk about what that data kind of directionally points you to. Again, I know small patient numbers, but I think obviously another indication where we've seen it be, if tolerable, is a drug that can add clinical benefit there. First line HCC liver cancer, it's a tumor type of interest for us. Number one, we were very happy to show that we can be safely combined with atezolizumab-bevacizumab, PD-L1 plus VEGF. We believe that adding CTLA-4 to PD-1 VEGF makes a lot of sense, not just in HCC, by the way. It was a small number of patients in the randomized setting. We observed a trend towards better response, better PFS, better OS with the triplet, knowing that the triplet included a lower dose of ADG126, 6 mg/kg every six weeks. We do know that, based on our data in colorectal, we know that we can go significantly higher than 6 mg/kg Q6W. We can go as high as 15 mg or 20 mg Q6W, we believe, in the context of such triplet. We are excited about it. I will also mention that because you were asking me about the potential of the tumor types. I don't want to commit, but NSCLC is an obvious one. It's a very good tumor type. CTLA-4 inhibitors have been approved for that tumor type. They have been limited by their toxicity profiles. I will mention also that there's emerging data suggesting that PD-1 CTLA-4 VEGF could be promising in the context of PD-L1 high first-line NSCLC. Yeah the data. Again. Yeah No commitments now from Adagene to move forward in NSCLC in the short term. These are two tumor types that, I believe investors should pay attention to when they look at ADG126. Yeah. No, you make a good point about lung. I think we've already seen, right, like there's been a progression from the PD-1 VEGF-A bispecifics to now seeing these PD-1 VEGF-A CTLA-4 trispecifics. Yeah, exactly. I think there's actually a couple of those in the clinic already. Okay. Maybe just last question to finish things up here. I know you recently did a financing. Maybe you can just kind of talk about the balance sheet runway right now and what that allows you to execute on. Yes. We were very fortunate and happy to have raised $70 million with U.S.-based sophisticated biotech investors. The $70 million helps the runway to go into second half of 2028. With that kind of runway and that kind of balance sheet, we are fully funded to execute on the randomized phase II trial. We can potentially do some smaller phase I trials. We are partially funded for a randomized phase II trial in late-line MSS-CRC. All right. That's all we have for time, Mickael. Really appreciate it. Thank you, Steve. Appreciate it. Great questions. See you. Thanks everyone.