GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - ADAGENE INC

Guggenheim and I'm very pleased to welcome our next presenting company Adagene and with us is Michael Chaindut, Chief Strategy Officer. Michael, thanks for joining us. Thanks for having me. So maybe just to start for those who are newer perhaps to the Adagane story, could you provide a quick overview of the company, your platform and your lead asset Ms. Asatog, also known as ADG126. Sure, so Adagne is a company focused on protein engineering and we are notably known to develop. We have our own proprietary fully-owned mask and masking technology, and as you mentioned, we have a lead candidate called Musa, or ATG126, I'm going to say 126 for the remainder of the chat. ATG 126 is a mask-anti-CTLA-4. We believe that it is a very differentiated CTLA-5 and a differentiated mask antibody. We will talk more about the data, but we believe that we have expanded the therapeutic window of CTLA-4 inhibition with it. Great. So as you mentioned, CTLA4, a proven IO target, but Immune Tox has always limited it to some degree. So what was built into Muza to widen that therapeutic window, and how is it fundamentally different from first-gen antibodies like epilimumab? Sure. Number one, we bind to a different epitope compared to epilimamab, tremolimumab, or the borobotan-cinnamab of the world. That differential epitope binding leads to a much stronger ADCC compared to EP. We believe that it is 10x higher, and this is data that has been replicated by third party, so we feel very good about mentioning that number. That's number one. Number two, we are using our safe body, our masking technology to it. Two things about the safe body technology applied to 126. A, we are protease sensitive and we believe that our masking efficiency is best in class, which is very important. You know, you don't want the CTLA-4 inhibitor to bind to the target when the mask is supposed to be there. And when the mass is supposed to be cleaved, you want it to bind the target. So the whole concept about the masking efficiency is very to us. And again, we believe that we have best-in-class masking efficiency. B, I'll mention also that we not only need certain proteases at high concentration in the tumor microenvironment to have activation and cleavage of the mask, we also need high expression of the target here, in this case CTLA-4. So we need these two conditions for activation, which we believe participate strongly in the expansion of the therapeutic index. Okay. So, you know, you've reported some very meaningful phase one update this past spring for Moza plus Pembro in late line colorectal cancer patients that do not have liver metastases. And so could you just walk us through the data you've shared to date and how that emerging clinical profile compares with the standard of care? Sure. So I'm going to start with the safety. So we have generated data for ADG126 in combination Prambolizumab in the setting you just mentioned. Let's start with the safety. Our discontinuation rate due to adverse event is less than 10%. It's very close to what you would expect from Keytruda single agent, even though we are dosing patients all the way up to 20 milligrams per kilogram. For people who are not aware, the first generation of CTLA-4 antibodies usually are given between 1 and 3 mcg per kg, for example, when you look at the pilumumab. So the fact that we're giving such a high dose without patients dropping out is very significant in our opinion. Number two, let's turn to the efficacy side, OR, RPFS, and OS. So at the relevant doses, which goes from 10 mg per kg Q3W all the way up to 2 cohorts at high dose 20 mpk, You have 20 MPK Q6W, and we have something called the loading dose, 20 followed by 10 with a schedule of Q3W. At these relevant doses, our response rate in the setting you mentioned is between 15% and 36%, and we're talking about confirmed responses. This is quite an important, this is quite a substantial range, keeping in mind that single-agent Keytruda is known to have a response rate close to zero percent, and Gervalumab, Tromalimumab in the very same setting had a response rate of two to three percent. That's in terms of response rate. Our median PFS is four to five months, and importantly, at the combined 10 MPK cohorts, we have generated a median overall survival of close to 20 months, followed by a plateau, which you would expect from immuno-oncology agents. So we believe that that kind of data set compares very favorably versus not only Keytruda single agent, the first generation CTLA-4 PD-1, but also compared to the standard of care in the same setting. And again, setting of patients without liver metastases. Okay. So, yeah, based on the data to some degree, you're also evaluating MUZA now in a phase study, which I think updated today, has completed enrollment. So can you remind us of that study design and your line of sight into the first clinical update from the phase two? Sure. So this is a phase two that we're doing to comply with the project optimus of the FDA. We have 60 patients randomized one-to-one between two doses. Dose number one is 10 milligram per kilogram every three weeks in combination with Keytruda. And cohort number two is 20 MPK Q6W, also in combination Ketruda. And just to be clear, we're talking about dozen schedules that are unable for Keytrude. The primary endpoint of that trial is response rate. And there's a number of important secondary endpoints, safety, et cetera, duration of response that we will be looking at. In terms of timing, you should expect data in the first half of 2027. Again, keeping in mind that the primary endpoint of the trial is response rate, but we obviously want to have a view also on what could be duration of response, early PFS, but it will be too early to make a call on survival. OK, so then at what point would you be comfortable pulling the trigger on to phase three? Do you need to see more maturity on the PFS some early survival data or is that early read sufficient given what you've seen already in phase one i think the the early reader should be sufficient we plan to generate we plan to have a readout again in h127 the next step would be discussion with the FDA and a phase two meeting to discuss the design of a potential phase three in the setting of late line MSSCLC without given metastasis and the official guidance is that we hope we we expect to have that phase initiated in the later half of 2027. Okay, and how do you think about the phase three design? Would this be conceivably randomized versus long-served Bev or a slightly later line with Rufruquitinib? So in terms of design for the phase 3 or for the Phase 3 trial, you should expect a randomized trial, obviously with overall survival as primary endpoint for the trial. There's potentially an upside scenario, and this is something that needs to be discussed with the FDA, we have noticed some precedence of the FDA allowing people to have overall response rate as a co-primary endpoint. And ORR as a result could be used as a basis for an interim analysis and potentially an accelerated approval. But you should really think of it as an upside scenario. In terms of control arm, to be determined, but we have a pretty good view on what it could be. Again, when I say to be determined post interactions with the FDA, we believe that the nature of the control arm would be dictated by the line of therapy. As you mentioned, Lonsdorff-Bev would be something that would be more relevant for a pure third-line population. When you talk about the fourth-line population purely or above, we're talking about the frequentinib or regorafenib of the world. Now, if you have a mix of the two population, fern and for flying you should you should probably expect a physician choice of therapy depending on the line of therapy again lots of bed for third line for continuing graph in it for for flying and above okay and then you'd be theoretically seeking a label that restricts by patients without liver mets which would be a first in colorectal cancer to date so how confident are you that you have the right alignment with the agency and physicians on carving out the segments as a potentially unique indication? We felt confident about that based on our prior interactions with the FDA. We had a very solid end of phase one meeting last year, which led to the initiation of a randomized phase two for Project Artemis, et cetera. We have noticed also some good precedents about it. I mean, before they decided to pivot, Agenis did have a phase three called Batman, looking at BotanCinema, BarCinemab, CTLA-4, PD-1. versus, I believe, physician choice of therapy for later line of CRC. And the population was, actually no, sorry, the population did not include only patients without liver metastasis, but they also had phase two. They also had a phase two in there. So again, based on our own interaction with the FDA, we feel good about the label. Okay, and then colorectal is obviously a very rapidly evolving space, potentially. Currently, standard of care, you know, very poor, but there's a lot of new mechanisms, including ADCs that are moving into the space, but these are more for an all-comer population. So how would sort of the Moussa-Pembro opportunity fit in with this evolving landscape? Yeah, so we believe that CTLA-4, CTLA for PD-1 can offer a great option for the patients. You know, immuno-ecology agents are known to, normally not known to induce a lot of responses. And they really win thanks to an overall survival benefit and what we call the tail of the curve, of the OS curve. We believe that with Adagene's 126 plus PEMBRO, we can not only increase the response rate, but we can also have very durable responses, which ultimately can lead to very differentiated type of survival benefit and curve. Okay, makes a lot sense. So then one thing that we've been really trying to pay attention to is the fact that the opportunity for MUZA extends beyond just the late-line non-livered mets colorectal population. And you have a lot of other things ongoing, including a collaboration with Insights in combination with their PD-1 TGF beta by specific. So, yeah, we'd love to get your thoughts on the main opportunity for this combo and your view on the data that they've reported more recently at ESMO in an earlier setting and how that sort of changed your conviction on that. And we are very excited about this trial collaboration with Insight. For those who don't know, we signed this collab earlier this year with Insights, and Insights is sponsoring a trial to evaluate the bispecifics, again, PD1-TGF-beta in combination with ADG126. The rationale behind it is very, very strong. PD1 TGF beta leads to a progression of CTLFO and Treg, and we are a CTLF binder and a Treg Again, PD-1 secret agent is not known to be super active. Thereby, Specific has shown what they believe and we believe what is a very differentiated kind of response rate, 23% in patients without liver metastasis and 12% in patients with liver metástasis. By adding ADG1 to 6, both companies hope that we will see improvement in outcomes, improvement in response rate, and so on and so forth. This is something that is allowed by ADG126 and the SafeBody platform. We believe that it would be difficult for a unmasked, non-masked CTLA-4 to allow the right therapeutic index with their bispecific. So very excited, very excited about it. We have started enrolling, they have started enrolling patients recently. They've shown a lot of love, and we believe that the enrollment should be quite efficient. And obviously, would they be the ones, I guess, driving the timelines for a possible clinical update, so? They will be, yes. It is their trial, they are sponsoring the trial, so they control the data, the timing of the data readout. Yeah, okay. And then also in an even earlier setting, you're also evaluating Muza plus Pembro in the neoadjuvant setting of colorectal, which is, as you mentioned, one of the areas that your peers has recently moved into for their PD-1 CTLA-4 combo. And so, I guess first, what's the unmet need here in neoadjumant colorextal, and how is a PD-2 CTLA 4 regimen positioned to sort of improve that need? Yeah, so number one, there is technically no FDU-approved therapy for neoadjuvant, neoadjurant CRC. If you look at the trial design of the ROBIN trial from a genus, you're looking at botancilumab, barcinumab given before surgery, and after surgery you have, you know, watch-and-wait or chemo. The control arm is placebo surgery and then chemo or wait-and watch. So there is a very significant unmet medical need there. I mean, it doesn't mean that people do not receive anything before surgery, in the U.S. you have off-label usage of chemo, right? But based on the data from BotPAL, it seems that CTLA-4 plus PD-1 can induce a very high rate of responses and major pathological responses, which could be very relevant in terms of EFS down the road. The data from Agena seems to suggest that, but data from BMS for Nivo-EP also suggests that any kind of response it could help the even free survival of those patients again after surgery and etc etc and we believe and we believed that in that setting having a chemo free regimen could be very very appealing to the patients given the differentiated kind of safety profile on top of the very on top of that you can induce a lot of very deep responses. YUFENG GUO. Got it. Yeah. So yeah, Agenis has been very sort of optimistic about their opportunity there. And they're sort of de-risking the path, if you will, in terms of regulatory front. So right now, Musa is in the investigator-sponsored trial. So I guess, how should we think about when we could see an update from that study to the extent that you can comment on that? And then if you were to pursue this as a path, what would the next steps in theory be? YUFUENGGUO YANG. So, in terms of timing, we have said that our IAST in Singapore, so Investigator Sponsored Trial, should have data in 2027. We have said also publicly that we have amended the protocol for that trial, and we are now testing a dose and schedule that is very relevant, we believe, for that setting, which is something very causing to the loading dose in our Phase 1b, which again is 20 milligram per kilogram followed by 10 milligrams per kilogram with a Q3W schedule. We believe that dosing higher and dosing more potentially could lead to even better outcomes in that setting. Keep in mind that in the ROBIN trial, a genus BOTVAL is given at 1 milligram per kilogram in combination with the PD-1, and the CTLA-4 component is given for only one cycle. We would be giving more than one cycle, very high dose. We have a very potent CTLA4. But we need to generate the data, again, probably in 2027. Okay, and where would the most relevant angle of differentiation be? Would it be driving deeper responses and sort of longer event-future survival, or is there a safety angle as well? Safety is very important because patients, you know, receiver patients, the only cure for the potential cure for patients is surgery. So you don't want to derail that. You don't wanna further delay it, et cetera, et cetera. But at the end of the day, it's really about efficacy. In oncology, it is all about efficacy, right? Having more responses, deeper responses on paper would be great. This is the bar that we set for ourselves in the new adjuvant setting. But let's see what kind of data we can generate. And ultimately, obviously, even free survival. But something that I would like to mention is that If you look at, I believe the name of the trial is Niche from Bristol-Myers Squibb for NIVO-EP. Even partial responses, so we're not talking about major pathological responses or complete responses, but even PRs seem to lead to a benefit in terms of EFS. So we need to look at things holistically. You want to look at responsive, deferred, defer-response, and then ultimately even through survival because this is the primary endpoint of a pivotal trial. Okay. And so could you potentially initiate a phase two study, for instance, after the IST data reads out, if it's supportive? This is a possibility, yes. Okay. Okay, great. So then maybe looking beyond colorectal, you've also generated data for MUZA and other indications including hepatocellular carcinoma this past year at AACR. So can you remind us of what you found in that study, and is this a path that you may pursue either on your own or with a partner? We like first-hand HHC a lot. It is an indication and setting that we consider very strongly. As a reminder, at AICR this year, we generated data, or at least Roche generated data in the randomized setting. We had an arm where ADG12C was tested at 6 milligrams per kilogram, Q6W, on top of the key standard of care, which is etazolizumab, bevacizumib, so PDA1-VEGF. We showed in that small randomized phase 1 B2 that we have potentially improved substantially the response rate, the PFS, as well as overall survival. To give a few numbers, on top of my head, the response rate for the control arm was close to 20%, and we had, in a small number, though, of patients, six, a response rate of 50%. The PFS4 was close doubled, and we have the trend towards better survival benefit versus, again, the control arms with a very good safety profile. Atezobev is, again, a key standard of care widely used for patients in first line. There is no approved regimen including PD-1, CTLA-4, VEGF. We believe that Musa or ADG126 could be very safely added on top of that standard of care and potentially further improve the outcomes. outcomes keep in mind that Nivo EP forgot the name of the trial but generated a response rate of circa 36% I believe without without Bev there are training me I believe we've won those of CTLA for had a response of circa 20 circa 20 percent and and a teaser Bev is known to be in a 20-ish percent so we believe again that adding CTLF on top of PD-1 VEGF makes a ton makes a a ton of sense. OK. And I believe the data was generated in a sort of basket study, or umbrella study, rather, for Roche. So what would you have to see, I guess, or generate in order to have some movement in perhaps advancing into another study? In first-line HEC, right? For first- line HEC given the benchmarks that I just mentioned, Nivo AP is 36%. The AtezoBev is in the 20% to 30% range. So assuming that it's a very large sample size, having something that is in a 40%, 50% or above could be great in terms of response rate. But we need also to look at the PFS, the West Trends, et cetera. CHET HAASE- OK, makes sense. OK, then beyond Musa, you've also been active in partnering around your SafeBody platform in general. Can you remind us of some of the recent activity and perhaps any upcoming milestones that we could look out for? Yeah, we have been very active on the BD front over the last few months. Remember last year we signed, we expanded our collaboration with Sanofi and Sanof made an equity investment. They are currently our second largest equity shareholder. The relationship with Sanoffi started in 2022 with an early stage collaboration, discovery collaboration that we have since expanded. We signed other deals, for example, with Third Arc Bio. The Third Arc bio shows you that we can apply the SafeBody platform not only to monoclonal antibodies, but also to T-cell engagers. And we announced the first deal in 2025, and we more recently announced a expansion of that collaboration with them. So we have been, again, very active on the BD front. We want to remain very active on the different BD. and obviously cannot give any timing or nature of the discussion that we have, but we want to do more of what we've done in the past. Okay. So then perhaps with our last minutes, could you quickly summarize your catalyst flow for the next 12 months, let's say, and your cash runway? Our cash runway goes to the second half of 2028. So if you're keeping in mind that we raised $70 million earlier this year after releasing updated clinical data as well as the trial collaboration with Insight. In terms of calories for next year, expect Project Optimus Phase 2 data that will help our interaction with the FDA in the future of Phase 3 in late-line MSSC-LC without liver metastasis. So we said H1 2027. 2027, you should also expect data from our Phase 2 in Singapore from this IST trial that we've talked about in the new adjuvant setting of CLC. Something also to be determined or confirmed, but more recently we announced that we had clearance from the Chinese FDA for an earlier stage compound called ADG138. It's a double-mask T-cell engager going after CD3 and ER2. We will be enrolling patients in China first before potentially expanding the scope to something more global. But hopefully, we may be able to have some early clinical data for that asset as well next year. Okay, fantastic. So I think with that, we're going to wrap up. So thanks so much, Mike, for joining us and appreciate you all tuning in. Thanks, Paul.