Alright, everyone. I am Stephen Willey, one of the senior biotech analysts here at Stifel, and glad to have with us presenting in the next session is the CEO of Adagene, Peter Luo. He's gonna be making a presentation. There should be some time remaining for some Q&A. We do have a function, I believe, that allows you to enter any questions into, and we can get those asked and answered appropriately if any pop up. Peter, I'm gonna turn it over to you, and thanks for your participation.
Thanks, Stephen, to have me here. I'd like to give you an overview of the company, and then I'll focus on our phase two program. Here are the company highlights. We believe we have a potential best-in-class anti-CTLA-4 with blockbuster opportunities because these molecules work on, you know, some novel mechanism of action, and with a unique molecular design in terms of masking effect we call the SAFEbody, and also shows nice safety and efficacy profile in combination with Keytruda in MSS CRC patients. We also license our technology to Sanofi and Exelixis to generate safe, efficacious molecules, including ADCs. We do have T-cell engagers in our double-masked HER2 CD3 in IND-enabling, ready stage. We also, you know, announced our cash balance. Yep.
Here is a high-level view about our SAFEbody technology, which essentially allows us to move the molecule, allow them into the blood, you know, injections, and allows them to circulate for a long, long time safely, systemically. They were only activated, as we show here, in disease tissues, in this case, a dimer of CTLA-4 binding, and then cleave the masking by the upregulated enzymes. With this technology, which really allows us to do a couple of things. One, we will be able to do novel combinations, which previously will be extremely difficult because, as you know, CTLA-4 has been a very potent target and has lots of toxicity associated, even just combined with PD-1. It also opens the door to drug targets, which has, you know, expressions not just in tumor cells.
This allows us to help our partners to do those targets, which are hard to target, like TCEs and ADCs. If you look at our pipelines, right now we have a phase two masked anti-CTLA-4 SAFEbody. We also have another program against 4-1BB, masked one, and the T-cell engagers. As you can see, we built our pipeline highly differentiated based on the safety of targeting those very potent targets. The collaboration we disclosed, I already mentioned briefly, includes some early pipelines we are licensed to our partners for development. Here is the focus for today, why we talk about, you know, anti-CTLA-4, because I'd like to share with you this is very important for a cold tumor MSS CRC. This has been called either, some people call it the third largest indication, and so far, immunotherapy is not available.
It also is a second leading cause of cancer deaths in the U.S., and also, you know, developing, developed countries, and the incidence are increasing in younger generations. If you look at the therapy available, mostly are limited to first-line or second-line . Those are the chemo like FOLFOX and the FOLFIRI in combination with bevacizumab or anti-EGFR. The third line therapy, if you look at the kind of therapy, are really marginal effect. You know, therefore, that's the setting we really want to make the break, use our new modality here. We're gonna share with you today how we'll be able to leverage the novel mechanism of the CTLA-4 and the novel modality, modality and the dosing regimen we come up with. First of all, why MSS CRC is so cold?
Here we show your panel on the top, where you can see the TIL, the tumor-infiltrating lymphocyte, and the stroma at the invasive front. You can see three things if you combine MSS versus MSI: a hot tumor, which pembro alone can do quite a bit, quite a bit of approval has been approved. Three facts I'd like to share with you. Number one on the far left is the high Treg percentage. If you look on the left panels, the percentage of Treg is high in MSS CRC versus MSI-high. Second, you see very early T-cells in the tumor site, minimal TIL. If you look at MSI-high, a very high percentage of CD8, absolute amount, as you can see here.
On the far right, you can see the PD-L1 expression, which is a very important indicator for PD-1 therapies, is almost zero. If you look at the MSI-high, highly expressed, all these factors make this tumor so cold. In fact, AstraZeneca has shown very resourceful studies on this patient population, 180 patients, if you look at this enrolled, right? They stratify the patients, right, to receive either Durva plus Treme or just the supporting cares. They further stratify the patient into liver metastasis or without the liver metastasis. The bottom line, you can see in the middle here, only the non-liver metastasis patients show a little bit of survival benefit in the yellow line here. The response rate is 2.5%, marginal, right? That's really the situation for the, you know, current fourth-generation IO therapy.
To summarize, all three factors, minimal TIL, very low PD-L1 expression, less than 1% is 82%, right? Also, high suppressed T regulatory cell. All these factors make this tumor very cold. Our solution, of course, is to come up with a strategy how to recruit more TIL into the tumors and how we can upregulate the PD-L1, therefore make a PD-1 therapy, right, the tumor-specific TIL become effective. All these two factors can be helped on the stream, basically how to deplete T regulatory cell, which are CTLA-4 highly expressed, with this enhanced ADCC effect. Also, to bring in, you know, this activated ADG126 into the tumor site from the blood circulation while keep the circulation of the blood at a minimum. Here is the mechanism of action we call the IO 2.0. We introduce this orthogonal modulation of two independent pathways.
One is T regulatory cell, the other is exhausted T cells. What we're trying to do, if you look at the plot in the middle, is typically if you look at the tumor cells, you can bring PD-1 to do the killing because the PD-1 are upregulated there. CTLA-4, in fact, are highly expressed. This is the data we coded from literature, as you can see. The two in the tumor site, CTLA-4, are highly upregulated in TIL on T regulatory cell. That is why we show in the middle is the red blood here. The question is, how can you remove those T regulatory cells by introducing anti-CTLA-4 on the right?
With three features we introduced here, enhanced ADCC effect, and use masking to help us to deliver enough drug into the tumors and without damaging our normal tissues, and then bring in the PD-1 to do the tumor killings. Let me introduce this design features on the right for anti-CTLA-4, right? Because once you have this anti-CTLA-4 upregulated, then you bring the antibody through the ADCC or ADCP effect, then you can destroy this Treg so to reduce this resistance mechanism to prevent the PD-1, anti-PD-1 to attack the tumor tissues. Right. Here's the design feature I show you here. On the left or in the middle, this is the molecular design. What allows us to do is to mask the antibody. Therefore, we can bring in a lot of drug, as we show on the left, mask the one into our systems without the activations.
Only once they activate in the tumor site, then we'll turn on the activities. You can see the activator four. The activate, because the novel epitope we introduced without the Fc engineering, we end up with a tenfold higher ADCC effect we show on the right. Of course, to leverage this ADCC effect, you have to make sure you have enough concentration of active drug in the tumor, which can go to the saturation site of this ADCC effect on the top plateau regions. Let me show you how we achieve this. Number one, by introducing the masking, we'll be able to dose in the monkeys up to 200 mg per kg GLP tox without damaging the monkeys. If you look at the Ipi, it's 10 MPK. That's 20-fold improvement. Expo clinically, we can introduce 20 MPK every six weeks in combined with pembro in humans.
Ipi, most of the approved dosage is one MPK every six weeks continuously, right? Those are continuous dosing. Second, can we deplete the Treg? We show you here in our preclinical models, yes, you can. If you introduce dosing your antibodies at a high concentration of 126, you can introduce tumor-specific Treg depletions, not outside the tumor. It is dose-dependent here. We also show in human biopsy-matched samples, yes, you have Treg depletions and a high ratio of T effective over Tregs. With this, I'd like to really share with you this top-level data. We will be able to dose in the humans with a loading dose of 20 MPK, followed by 10 MPK Q3W of our 126 in combination with Keytruda. This is our PK modeling, show what's happening inside the tumor. This is active drug, as you can see.
They can reach this steady state with this 20 MPK loading dose really quickly, just within 21 days, and stay there in that steady state compared to the 10 MPK Q3W. That's how we can drive the ORR at the loading dose at the 33%, or it's 10, 23% at the 10 MPK Q3W. Also, as you can see, the discontinuation rate we show here are significantly lower compared to typical anti-CTLA-4 therapies and the low-grade three or low-grade four or grade five toxicity. This is so different from what the EP, the fourth generation CTLA-4, or other second-generation generation. You will find most of them, in combination with PD-1, are limited to one milligram per kilogram dosing regimen in combination with PD-1. Why? Because if you look at the toxicity increase of grade three in red line here, what is the green line ORR?
One MPK gives you better improvement in efficacy versus the toxicity increase. If you go to three MPK, they converge. More than that, it's not tolerable at all. Only the molar therapy can go to 10 MPK. This is the discontinuation rate. This is very different from the profile we just show you here. We believe these kinds of molecular features I'd like to share with you. This is our, again, population PK data in the tumor we modeled in the humans. Versus EP at the one MPK, you can see you barely touch the EC50s or EC90, not along EC90s at the one MPK EPs. Very little gets into the tumors. Actually, a lot in the blood circulation, in the CMAX.
You can see our 20 MPK loading dose, the slowly increase to a CMAX or the 1 MPK EP reaches in blood circulation. Inside the tumor, there's very little penetration there. That's kind of a therapeutic window we created here. As we know, why you need such a high concentration of CTLA-4? This allows the drug from the plasma to diffuse into the tumor tissues and get activated, remove the Treg, and allow the T effector cell penetrated into the tumor to do the tumor-killing job. I hope this kind of a mechanism to give you some idea why we'll be able to really reactivate the cold tumor like MSS CRC, using these novel strategies. This is the kind of the profile I just described with you.
We believe this safe and efficacious anti-CTLA-4 design opens a new door to these very cold tumors, even at the late line, like third line and the plus, right? To reach a response rate like a 33% confirmed ORR still with manageable safety profiles. This follows the fundamental biology of the CTLA-4 overexpression in tumor microenvironment on Treg. Because this active drug has a tenfold higher ADCC effect over the EP without the FC engineering. This combination of safety with an importancy and really have the biology going on inside the tumor tissues allows us to set a new standard among all the CTLA-4 inhibitors, giving the safety and efficacy profile we just introduced here. Here is the milestone for these years.
We're going to continue to provide more data, including the OS data maturing for 10 MPK Q3W and 6W in combination, in comparison with the standard therapy in these lines, in this OS profile in the same similar patient populations. Of course, we're going to continue updating you about our 20 MPK loading dose and especially the duration of the response for those patients remaining on treatment. Also, the new dose regimen we're doing, continuing 20 MPK Q6W. There will also be some regulatory updates about the package we submitted to FDA about our potential registration trial design, patient selection population, dosing regimens, and, you know, all those informations, right, from the FDA. I think that's the end of my talk for today. I'm open for questions.
Yeah, that was great, Peter. Thank you.
I know you showed us the durvalumab and tremelimumab data for AstraZeneca, highlighting the restriction of clinical benefit, albeit small, to that patient population without liver metastases at baseline. I think there's been kind of this long-running narrative of anything using an IO backbone only really showing activity within the non-liver met population. Have you generated much data within the context of patients who have baseline liver mets? Do you see a differential response between the two? I guess I ask the question, right? Because as you move towards registration, do you think about maybe carving out each of those patient populations separately in terms of looking at two separate trials, or do you think that you can consolidate both of those patient subgroups into one registration trial?
Steve, that's a great question.
I think not just us, including others like Agenus and Zai Lab, and all others, we all observed, you know, in the liver metastasis patients, the responding profile, especially in terms of ORR, are quite different from low liver met patient populations. I think the reason for that, of course, people give a lot of reasons. I think Marvin Fakih is one of the KOL in the field talking about why it makes a difference. For us, in terms of drug developments, our strategy is we like to focus the immunotherapy on non-liver metastasis patient populations because there you really can see the response rate, ORR. In terms of liver metastasis patients, because in our dose escalation studies, we did enroll those patients, we get a mixed response for those patient populations. You can see target deletion shrinkage as you're quite significant.
We show those one of the examples previously and the CEA dropped by 90% of others. We also noticed the survival benefit for those patients. They are complicated populations. Our strategy is focus on immunotherapy on non-liver metastasis patient population, but combined with standard therapy, as I just alluded in our catalyst here. Because our combination therapy with such a nice safety profile, we believe we can combine with standard therapy, which has been approved to include those liver metastasis populations. In this way, you'll better deal the entire population in that way. We actually initiate that trial and we'll see how that safety profile looks like. We should be sharing that data this year.
It looks like you also have a SAFEbody version of a CD137.
Is the goal there to avoid some of the hepatic toxicity that has been seen with other competitive compounds in the space?
Yeah. Yeah, Steve, we actually have two. One is unmasked and the other is the masked one in clinics because we did it previously. We will be able to dose escalate to quite a significant higher dose. The other one, unmasked, will go to 10 mg/kg. We really did not see a strong hepatic toxicity, liver toxicity as BMS shows for the, you know, agonist. We still believe that toxicity may be related to some specific epitope involved in inactivating that target. Of course, our idea with masking, we really want to introduce strong cross-linking for the FC regions. In this way, we will be able to give more potency for the drugs.
Since it's still in the early clinical development, we may not have too much information to share there. You're right. We want to control the safety profile, also enhance the efficacy.
Yeah. Okay. Maybe just lastly, it looks like you're developing a CD20 TCE, a masked version of this. I don't know if the intention is to develop this independently, if this is an asset that you hope to partner at some point, but would just be curious as to your thoughts around the utility of that molecule in the setting of autoimmune disease, where we've obviously seen a number of CD20s pivot to.
Okay. Steve, you're right. We have two masked T cell engagers. One is this anti-CD20 CD3, and we mask on the CD3 part of it. We show pretty amazing, actually, safety profile for this drug. I summarize it here.
At 30 milligrams per kilogram, when we dose the monkeys, our, you know, if you look at our cytokine release, it's still far below than the unmasked version. It's based on a zinc analogue at the 0.3 milligrams per kilogram. And we're quite excited for these molecules because, like you said, we believe this safety profile should allow us to have a better use in those autoimmune diseases and even cancer in community settings. Plus, the long half-life of this drug in circulation. It will make the usage of this drug easy to the community doctors, to the patients.
Yeah.
Okay.
Very good, Peter. Thank you for the time. Very interesting. Hope to catch up here at some point soon. Thank you.
Thanks, Steve, for having me here.