Good afternoon, and thanks for joining us to have a conversation with Dr. Peter Luo, the Chairman, CEO, and Co-Founder of Adagene. Adagene is a clinical-stage biopharmaceutical company focused on developing next-generation antibody therapies to treat cancers based on its proprietary platform including NEObody, SAFEbody, and POWERbody. Today's conversation will be focused on their TCE portfolio. Peter, welcome.
Thank you, Arthur.
Peter, maybe to set the stage for our audience, could you give us an overview of Adagene's current pipeline?
Sure. Arthur, thank you for having me, and let me put this. At Adagene, our mission is straightforward: targeting tumor, spare healthy tissues. That's our SAFEbody platform. Our clinical pipeline lead is muzastotug, is a masked anti-CTLA-4 designed to deplete intra-tumoral Tregs. We have extensive clinical data at a higher repeat dose, and with long-term follow-up to assess the response rate, ORR, and the DOR, and the OS benefits. Also assess the late onset toxicities at the 10 to 20-fold higher dose than Ipi used. Our pipeline, in addition to CTLA-4, a rich franchise pipeline and the masked antibody are the focus. We would also like to introduce other masked antibody pipeline. Especially today, the ADG138 is a dual masked HER2 CD3, and using our clinical validated, SAFEbody platform in this HER2-directed T-cell engagers.
We believe this enhanced therapeutic window is essential. I would like today to walk you through the clinical data and the upcoming milestones.
Sure. Thanks, Peter. Maybe before we jump into the asset itself, could you tell us a little bit more about your SAFEbody platform? I guess there is a whole bunch of other companies also doing a similar masking strategy here. So what is special for SAFEbody? How it is differentiated from Alvor and Janux strategy there?
Sure. I think there is a common thing everybody, the technology we mentioned about uses protease cleavable masking peptides.
Yeah
Or the masking peptides. There is a very different twist and flavor for specifically how to develop, design and develop that masking peptide, and with tumor-specific activations. Just like ADCs, it sounds like a very generic drug attached to an antibody. But the differentiation among different ADC we know is a huge difference, right? In HER2, after so many years, people realize we eventually have ADC technology for big blockbuster drugs. I think for masking technology, I believe over the last 20 years or so, eventually we have seen the light for this masking technologies. I think the major difference, if you ask me, I could call a keyword, precision.
Basically, how do you develop your masked peptides in a precision way, which could be tailored to your specific antibody binding interface-
to do that specific masking with precisions. Also, how do you activate this masking moieties in tumor microenvironment in the right time and space? Again, it's a precision to control the other activation process. This kind of difference could make a huge difference in clinics. That's why I'd like to say our masked CTLA-4, a target almost every masking technology originally developed around this CTLA-4 targets. Because there, the challenge is really how can you put your mask on this antibody, allow the mask to stay on and in blood circulation for more than two years or even longer with a continuous dosing, with 10 or 20-fold higher dose. The second, how this mask allow you to activate in the tumor microenvironment clinically, without the leakage while in circulation in the blood, to create that differential therapeutic windows.
I should say, you can describe your technology as much as you could. But in the end, you have to show clinically it actually delivers the kind of clinical result match with what you promised in the very beginning. For this, I could say we're perhaps one of the deepest clinically to develop our masking technology. For example, our muzastotug anti-CTLA-4. Right now, we're working with those patients for more than 250 patients through monotherapy in combination with PD-1, and then in combination with standard therapy in triple combinations, to show how this masked CTLA-4 allow you to dosing at the 10 or 20-fold higher dose, achieve a therapeutic window more than 10-fold higher, and with longer circulation in cold tumor like MSS CRC. We already have the FDA's fast track designations.
Also in first line, like HCC, we have shown a triple combination when we add our drug masked CTLA-4 on top of atezolizumab versus atezolizumab in a randomized trial done by Roche to show a longer, first of all, the ORR almost double, if not triple, the control arm with the doublet. The OS is still not reached after two years follow-up, while the control arm already reached about 18 months. So still with very robust safety profile, for example, is the MSS CRC was going to share with you at the 10 MPK and 20 MPK, and in the first-line HCC, essentially, we can maintain that doublet or triplet, at the 6 MPK, two times higher than Ipi approved in combination with the PD-1, and those are the patient more than two years now, still on treatment, not yet reached the OS.
Yeah. Thanks, Peter. That's very helpful. So in the same essence for we talking about the TCE. So congratulations, you just get the clinical clearance in China for 138 last month, and I believe it's a double masker for TCE, right? Could you walk us through about how you guys designed Enlacquer and why you do the double masking, and what kind of clinical data you tell you pick a right strategy there?
Yes. So here for, as we know, the TCE has been a very hot topic for the last two years.
But if you look in detail, you have found mostly they are targeting liquid tumors, like CD20, CD19, and those targets on a BCMA.
Yeah.
But if you look at the solid tumor so far, target like DLL3, which has really selective expressions in certain specific tumor, like small cell lung cancers, right? Then you will be able to do that, and without the masking. But for other solid tumors, I should say the double masking both the tumor targeting, like HER2 site and the CD3 sites. We have seen some initial data from other related technologies. But what we're doing here is quite different, right? We are based on this clinical validator, SAFEbody platform. We're done right now in randomized phase II globally. And we are leveraging that technology for this dual masking on HER2 and the CD3. And of course, your question is why it matters for the solid tumors. I will share with you a few points here, right?
Because first of all, we know the HER2 is widely expressed in lots of normal tissue, like heart, lung, and others. Therefore, to bring this powerful T-cell engagers to engage these targets, you better make sure HER2 expressed in normal tissues will not be engaged. Therefore, we put a mask, which give us more than 200-fold masking efficiency. Means your target expression has the differentiation by the 200-fold. We can tell that difference. That means in normal tissue HER2 expression, our mask will make the antibody invisible to those HER2 targets expressed in normal tissues, unless you have a higher HER2 expression in tumor tissues. That's number one. Second, the CD3 arm is extremely important, as we know, because you need that potency with a high-affinity CD3 rather than reduce CD3 to extremely low affinity, which makes the TCE less potent.
We put a 100-fold mask on the CD3 arm. So total, when you put these two sets together, we get a log of three to five log on this moiety, which is among one of the highest reported to this moieties. Right. That's second to same. In this way, when you throw this modality into the, say, human bodies, then you will be at least we show preclinical in the monkeys. If they will, we show like a 300-fold kind of a difference, right? Versus the mask, versus the unmasked one. So this will, I think, give you a nice safety margins, for these modalities and the way you do the human test.
Thanks, Peter. So you are moving these into clinic, like this quarter, I believe. Based on your estimate or planning, how these things can be progressed, and what's the path and the timing for moving 0168 into a US clinical study?
Yes, you are right, Arthur. We have had the IND cleaned up by the CDE, and we're expecting the dose in the humans in this quarters and this years. This is our first human TCE test. So although we are quite encouraged by the preclinical safety datas we've shown in the monkeys, and we are also encouraged by the efficacy of this drug, even with the double masking. We show, for example, in HER2 refractory system, HER2 low expression tumor models-
we will be able to achieve complete response at the 0.1 milligram per kilograms in tumor models. We know we have a big therapeutic windows there. On the other hand, I should say, because this is the human experiments, we have to be careful. That is why we have developed those escalation schemes.
which should allow us to dose escalate based on our preclinical data, right? To control that safety and also make sure we also understand how the drug being activated in the cancer patients and how that dosing regimen, for example, at the different dose level and with different dosing frequencies and how that steady state being reached in circulation also, and the mechanism of actions on the drug activation in humans. We believe we have a robust dose escalation design. Simultaneously, because this is the first in human trials, once we get the first few dose escalation data, get comfortable about this, then we think we will be able to decide how rapid we want to ramp up the dose escalation process.
Then also based on the emerging safety and efficacy data, how we are going to explore those initial efficacy readout in a HER2 refractory system patients.
Okay. Got you. Thanks, Peter. I think nowadays another more broad question for you is, yes, you are more focused on the oncology side of the view for the pipeline development-wise, but definitely the reason to, like the BD licensing transaction is all happened in most likely for folks on the autoimmune disease area. My question for you is, do you guys within your TCE portfolio also have some asset or program are intended for autoimmune disease besides the oncology side?
Yes. Arthur, autoimmune is definitely big. I think the T-cell engagers definitely have a nice play in this space. Also lots of people have already shown like for traditional T-cell engager, CD19 or CD20 or BCMA, right?
Our early programs with the CD20, CD3 mask on the CD3 arm in this case will be able to shown this CD3 mask, the CD20 T-cell engagers generate very robust B-cell depletions with significant reduced CRS. This really allow us dosing the drug at the dose level, otherwise hard to reach. There was deep B-cell depletions, not only in circulation, also at the tissue levels. We're quite encouraged by that data. But simultaneously, we know the field are evolving quickly.
We will be able to come up with even novel designs with some multi-targeting T-cell engagers, and with some of the novel designs we engineered. This should allow us not only reach a deep B cell depletion in both tissue and the peripheral levels, also with the kind of CMC and clinical, not clinical, pre-clinical profiles in those autoimmune disease. We are quite excited for those developments, and we are also open for collaborations with partners to move forward with those novel molecules we designed by leveraging our SAFEbody platform and with some novel engineerings to enhance those what we already know out there in clinical space. Yeah.
Oh, thanks, Peter. That's good to know, and I'm looking forward to hearing more progress from you guys on the autoimmune side for the TCEs. Let's move on to the business development side. Since I've been knowing you guys, the partnership is still always the one part or piece of pillar for the company growth strategy there. In September, I believe Third Arc Bio's like the first lead under the amendment deal. Could you give us a little bit more overview about the deal initially, and what's the newest amendment or update to the partnership there?
So yes, as for that. As you know, just like you mentioned here, following the tech license later last years for our T-cell engagers. This September, we amend the collaborations to expand it into a, I call it, more integrated collaborations on the asset side and in addition to the technology partnership. I should say, Third Arc leads and funds the development of those selected programs as we mentioned about by leveraging both our NEObody and the SAFEbody platforms means on the targeting side. Of course, with increased economic terms for less collaborations. What I should say, what we're really pleased is the commitment from Third Arc team. As you know, this is a highly experienced team coming from former J&J oncology leaders like Peter Lebowitz and Debas and Joe and also Sangji, basically the fantastic engineering, early discovery, BD, and the clinical together.
This team, as you know, had the experience to take a T-cell engagers from early discovery through global approval and commercializations. I think that experience speaks tons about the execution of the partner bring to the program we're working with. This economic terms we mentioned, to me, most early programs, it does not make a difference until you get a serious team who can execute and bring them to the clinics and to the markets. We are extremely pleased with that, with the Third Arc team. It's a team people can dream of, right? We still retain, I should say, no cost option to develop and commercialize those candidates in Greater China, Singapore, and South Korean areas. Yeah.
I see. Also another two partner is Sanofi and Exelixis. But it's slightly different kind of angle based on your SAFEbody platform. I think the Sanofi did get the third program in last year with the equity investment into you guys. Exelixis is also getting a masked, the ADC into the clinical. So could you give us a little bit more overview for these two partnerships and maybe also a little bit on how you view the Sanofi or in general for your masked or antibody like CTLA-4 and TCE and also on top of the ADC application as well for your SAFEbody platform there.
Yes. I'm happy to discuss that. I will start, I should say, both Sanofi and the Exelixis, you mentioned here, we already have a long-term collaborations, at the least starting from three years ago. We'll be able to renew that collaborations last years. I was very happy with that because we really treasure the long-term collaboration with the partners and the relationship or the endorsement for the kind of a collaboration between different parties. As you know, early discovery and all those collaboration has been difficult. We'll be able to do so quite effectively with our partners. Also, I should say, for both of them, we have three collaboration projects, discovery projects. I can start with Sanofi.
Because we are working with them, Sanofi is a really strong immunologist, and also, I should say that one of the earliest pharma partners dive into the masking technology. As you know, where the license, those thing, Sanofi early on acquired from Amunix and doing the clinical trial. We will be able to keep the relationship with Sanofi, with our masking technology. We have that relation almost in the same time years ago. We are working with them to develop next generation immunotherapies including mono-bispecific or multi-specific. For Exelixis, we are using our masking technology and could develop ADCs, like called the SAFEbody ADCs. As you know, the target they released this year in AACR is ROR1.
You have seen many, many actually ADC program originally, initially really excited, and then become quite quiet by big pharmas and other biotechs on these targets because we know this target is wide expressed in tissues. By developing a masked anti-ROR1 antibodies and with Exelixis and they put the ADC on and they release some quite interesting preclinical data to show you will be able to spare the normal tissues and with significant, I should say, 5 to 10-fold enhanced PKs and also with very potent dose and can last for 60 days in those tumor models. Basically by enhanced therapeutic windows, we may open a new opportunity for ADC modalities and so far as we know and have shown quite a few toxicity issues for some even well-proven ADC antibodies. That is kind of the collaboration while working with our partners.
I should say, we also announced our milestone reached preclinical $2 million milestone recently with Exelixis for the moving on into the clinics. We also announced a success finish another third project on the SAFEbody ADC with them. For Sanofi, as you mentioned, we also not only received the strategic investment to helping us to do some clinical trial on muzastotug, and we have also supplied the muzastotug for combination with the investigational next generation immunotherapy in over 100 patients sponsored by Sanofi globally. But I also should emphasize, we still retain the worldwide commercial right to our muzastotug and who is our wholly owned ADG138 at this stage. For future TCEs, we will still focus on the clinical, the differentiation of our technology for these modalities and with our partners.
We will keep some core asset for our own development and then otherwise while working with partners depends the ability to accelerate the global developments. Yeah.
Oh, thanks for that. For the sake of time to close, could you remind us what is the key catalyst for Adagene in the next 18 months?
Yep. I think the key milestone should be our randomized phase II trials in MSS CRC for muzastotug in the first half of 2027. Also our emerging ADG138 phase I safety and early efficacy data. We started dosing the patient this year. Before that muzastotug readout, we also expect some updated phase I-B/II data on the overall survival and the duration of the response for our MSS CRC patients at 20 milligram per kilogram cohorts, where we already announced the 10 milligram per kilogram data. Those are ORR and the DOR and the OS data. The 20 mg/kg data are matured in the right directions. Still the OS data is not matured after more than a year half the follow-up. We also could like to highlight the muzastotug data, muzastotug plus pembro data in neoadjuvant settings.
I should say those exciting early stage opportunities for Treg depleting CTLA-4 either new adjuvant settings could be something I think you should pay attention to. Of course, in terms of muzastotug registration strategies and later 2027, well, depends on those selections and the regulatory alignments and what is our phase II data. It is getting matured, or not matured, getting announced next year.
I see. Well, this is great. Thanks, Peter, for coming and I really appreciate, and this is a good information here. Thank you again from the HCW N.Y. team. Thank you.