Good morning, everyone, and welcome to H.C. Wainwright twenty-sixth Annual Global Investment Conference. My name is Arthur He, Senior Biotech Analyst with the firm. Thanks for joining us today to have a conversation with Dr. Peter Luo, the chairman, CEO, and co-founder of Adagene, and Mr. Raymond Tan, the Chief Financial Officer of the firm. Adagene is a clinical-stage biopharmaceutical company focused on developing next-generation antibody therapies for cancers based on its proprietary platform, including NEObody, SAFEbody, and POWERbody. The company currently has multiple drugs in clinical and preclinical development across different modalities. To discuss these programs and to learn about the company's development strategy in twenty twenty-four and beyond, I'd like to invite Peter and Ray to this fireside chat. Peter and Ray, welcome.
Thank you, Arthur. Thanks, Arthur, for having us here.
Peter, so I guess first, to help set the stage for the audience who are not so familiar with Adagene, could you give us an overview of the company's pipeline?
Sure. We have four clinical programs, and our most advanced clinical program is our masked anti-CTLA-4. We call it ADG126. And in combination with Keytruda, in phase 2 trials in MSS CRC. So we have other, you know, clinical programs ongoing, and you will notice most of our targets are very potent and toxic targets, and including some CD3-binding T-cell engagers, and we can touch upon later. And we think the reason we're targeting those pathways because we believe this key biological and clinical very fundamental pathway in cancer therapy, or actually on the other side of autoimmune, right? And because our technology capability allow us to make very potent and simultaneously safe molecules based on our, you know, three platforms you just mentioned.
So that's really the reason why we have those pipelines, and we put it into the clinics. Yeah.
So, as you mentioned, the ADG126 is your lead program. And, it's already generate encouraging phase 1 data, both as a monotherapy and in combo with pembro. Could you help highlight the data so far to our audience?
Sure. I think, yeah, if you look at the MSS CRC, especially second-line, there are two approval by FDA last year. One is called the Lonsurf. That was a TAS-102 plus Avastin or Beva. The other is fruquintinib, which was licensed by Takeda from HUTCHMED. Right, those are FDA-approved. And if you look at that therapy, they compare the previous one, they double the PFS from previous therapy, like from two months to four months, or four, or 5.6 months. And the OS, still marginal, is about 11 months. So as you can see, those are highly unmet medical needs. And by the way, MSS CRC, if you look at current therapy, there's no immunotherapy available, right? There's only small population patient called MSI-high.
The pembro and the PD-1 are quite effective, but not for MSS CRC, microsatellite stable. The immunologically cold, and they have very high T-regulatory expression profile in the tumor, 40%, and then the PD-L1 positive population accounted for more than 80%. As you can see, PD-1 therapy or PD-L1 is not effective at all, even considering a lot of combination studies by big pharmas in these indications.
Sure. So, I know the CTLA-4 has been a validated target, but the limitation is more on the safety side, like, so what do you think the ADG126 can help improve that cancer therapy to target a CTLA-4?
Yeah. I think the keyword is really the therapeutic index, right? If you look at the kind of anti-CTLA-4, they have very narrow therapeutic window, no more than three, two or three. You can see people are struggling between a dosage from one to three or one to two, given the recent FDA feedback for botensilimab, right? They are trying for two dosage, one milligram per kilogram, the other two milligram per kilogram, and the FDA only allow them to moving forward for one milligram per kilogram, effective two. Because even at that dosage level, the toxicity is already very significant. I mean, the safety is even worse than Ipi , which is used at a one milligram per kilogram every six weeks because the Fc engineering.
Mm-hmm. Yeah.
So as you can see, like, that's the biggest issues.
... So how the ADG126 can differentiate from the?
Absolutely. 126 will have a wide therapeutic windows. In fact, our asthma abstract just come out this morning. You can see we can dose it to 10 milligrams per kilogram. In fact, we'll report a 20 milligrams per kilogram in combination with Keytruda. That's 10- to 20-fold higher than what the current therapy can do. So with that kind of therapeutic index, what we want to achieve is two things: One, to make the previous therapy impossible, like MSCRC for immunotherapy, impossible become possible. Right? And then also to make those therapy, which are good, become so much better. If you look at the lung, small cell lung cancer, doing two dosing regimen approved in the first line, right? ADG 227.
Basically, one is EP plus level, and the EP is at a one milligram per kilogram every six weeks continuously, just because of the toxicity issues. But even with that kind of data, you can see the fat tails for long-term survivals, right? For the PD of an elective population, which Keytruda plus chemo cannot do, right? And if you look at that, the combination plus two cycle of chemo with standard therapy, they actually are doing quite well. Again, because the toxicity of that combination, they can do two cycle of chemo, unlike a Keytruda plus chemo, you can do many cycle of a chemo, right? Until intolerable.
So if you have a safety profile at the tenth of the higher dose for our anti-CTLA-4, or even higher, dosing it continuously, and then you have a safety profile, just like a Keytruda alone, like a combination, then you can combine with a standard therapy, like a chemo or any other ADC or whatever you can think about, and then dose it continuously. What kind of a wonder you can make for those indication already approved? Not to mention the MSCRC, which Keytruda or other anti-PD-1 can do very little about, right? We have a very impressive ORR, PFS, and OS data, right.
Speaking of the upcoming ESMO update for ADG126. What kind of data set can we expect?
Sure. Of course, I think, for people, familiar or not familiar with this program, early this year, in ASCO GI, we release, we call the, our first part of the, MSCRC data with our one, two, six, pembro combination with pembro. At the 10 milligram per kilogram, at the Q6 weeks, which we did that cohort expansion initially, and then we follow up with another cohort, 10 MPK, every three weeks, like another 12 patients. And then we show that data, and, you can see in the 10 MPK Q6, 6W, even though we don't have confirmed PR, but we do show very significant tumor reduction in target lesion, 60%. And, if you look at the stability of those patients remain on that treatment, the patient remain quite stable, right?
Therefore, but at that time, we don't have a long-term OS data, and in this ESMO, we are going to update that data at that dose level. At the six months, nine months, and the 12 months data for that OS survival, and I think you appreciate how the stability of the disease at this dosage can translate into the OS benefit at the time we're reporting this. Then if you look at the ADG126 Q3W, there we show confirmed PR, two confirmed PR, among 12 patients, right? And especially for that group without the peritoneal metastasis, 22% confirmed ORR. And the PFS at that time, because of both arms, we have to combine them, six weeks and the three weeks, three weeks one, showing a combined seven months PFS data.
But at this time, we can separate those two dosages reported about the six-week arm, and then also the three-week arm, because we do add the second part of that for another confirmed PR, right? So that data is getting mature now for the PFS, and I hope you can see very impressive PFS data for this immunotherapy, so for these populations, right? And for six week and the three weeks one. Also, you are going to see the OS benefit, right, at the nine months or six months, nine months, twelve months in combination, but we are going to report, continue to report that data for these two separate dosages this year, throughout the year.
... Yeah, sounds good. I'm looking forward to that data. So let's switch gears for a little bit. For your second program in the clinic, the ADG206, could you tell us what's the status of the program, and when could we expect the initial clinical data from this program for the 206?
Yes. I think the 206, as you know, is targeting 4-1BB, right? And we have an initial program targeting this unique epitope, which definitely shows there's no safety concern. We can dose it higher, unlike BMS Urelumab, right? That shows dose-dependent liver tox. And we found that we removed that tox concern, but the isotype we use, IgG4, is not potent enough. So this second-generation program, we put our favored masking technology on that binding site, and then add the Fc cross-linking for Fc gamma RIIb. And you can see we really pushed out the cross-linking efficacy data fourfold higher than Urelumab, which is the most potent 4-1BB agonist out there clinically. And so far, our dosing regimen reached 6 mg/kg. That's a really high dose, because Urelumab cannot go beyond 1 mg/kg. We still didn't reach DLT.
So I will continue that dosing, and we'll report that data when data become mature.
Sure. So I know you have forged multiple collaborations with different partners, including Sanofi and Roche, and et cetera, across different drug modalities. Could you help highlight the ongoing partnership to our audience?
Yes. We definitely have a very happy collaborations with our partners, and I think, you know, people say that, like, a collaboration like a dating, right? When you're only engaged for a period of time, more than six months or several years, then you begin to know each other, right? And you really know, and even, you know, no relationships ever been perfect. But as that relationship will be happily working for years, is really a testament for, you know, our capacity to deliver results to our partners, right? Not through our mouths, through our actions, right? And that relationship are deepening, as you can say, and you know, follow whatever happy collaboration we got. And you know, I think because of the partnership, I'm not allowed to say too much about this.
I should say, things are going smoothly, right? And we basically will need to continue that relationship and expand the relationship, right?
Yeah. In summary, this is a very exciting time for Adagene-
Mm-hmm
... in terms of business development. Peter mentioned about the best-in-class potential of our masked CTLA-4 antibody, ADG126. In summary, the safety profile of ADG126 plus pembro is comparable to that of pembro monotherapy, as we reported at ASCO GI earlier this year, and so as Peter said, this IO doublet has every potential to go in combination with other modalities, with standard of care, in due course, to address, bigger patient populations and potentially move into an earlier line of setting, and this is why, we are having advanced dialogue with various global pharma companies, so we will keep the markets posted in due course.
Sure.
Thank you.
Thanks, Ray. And let's take a little bit deeper in the pipeline. I know you guys also have a library of T-cell engager, as this space getting more and more attention there. So could you give our audience a brief overview for your T-cell engager candidates?
Absolutely, yeah. As you can see, you know, because we have this wonderful, you know, technology, we call SAFEbody, is not simply put your mask on the mice, on your mouse, right? It really allows you put on that and then breathe freely, right? And, so it makes wonders, actually. If you look up our masking technology around CTLA-4, this is the most advanced program in clinics, because early this year, BMS basically terminates the ten years collaboration with CytomX, right? There's a, you know, there's a lot of detail, get into that. But the bottom line is, will be able to leverage this platform to the T-cell engagers. We know CD3 is very potent targets. Look at all the approved drug in the T-cell engagers. The CRS still a big issues.
Even you can play tricks, like step dosing, pre-medication to suppress the immune system and all that, but still, that's borders, right? But when you come to the autoimmune, that has a really different safety profile requirement to the game, because there is a chronic disease. Safety requirement is so much higher than cancer therapy, right? So if you look at the data we've released two or three years ago in ASH, for our CD20, CD3 masked antibody. There we show with our masking on the CD3, you can dose the monkeys one hundredfold higher, from 0.3 to 3 to 30 milligram per kilogram. I'm going to challenge you to find any T-cell engager you have been able to dose in a monkey at this dose level. But no, I'm not talking about a flat dose, 90 milligram for the other curing program, market licensing.
90 milligrams divided by 70, that's less than 2 milligrams per kilogram. We're dosing it right, 30 milligrams per kilogram in the monkeys. You can see amazing PK profile, because it's much longer. We do compare this Xencor CD20, CD3 compounds are licensed originally by Novartis, then retained, and then licensed to Johnson & Johnson, retained by Johnson & Johnson, right? Because people try to play tricks, including step dosing, pre-medication, and sub-Q, and all this. There's a limit for you to play those games. We found a fundamental solution. That's how we show. If you look at the cytokine release, even at the highest dose, was still lower than people dosing at the 0.3 milligrams per kilogram, the cytokine release. Look at the way we've published the data.
Of course, given the recent interest in autoimmune, if you look at the B-cell depletion, it's very complete, right? Because our SAFEbody masked antibody, they have long circulation in the blood, so they can engage the target continuously. You can see complete B-cell depletion when you increase that dose, and they still maintain our safety. And that completion of a B-cell depletion, extremely important. If you look at the recent publication by Roche about CD20, CD3, because if you don't completely deplete that, they'll relapse, so we're very excited for that program, and now, because we do have tissue data, clean tissue data, we have not yet published this.
Sure, I'm looking for more data from your TCR engager programs. So for closing our conversation, Peter, could you remind us what's the major catalyst for Adagene in the next twelve months?
Yeah. I think that the, we are continuing, you know, enrolling patients, right? So we are going to show in our ESMO the 20 MPK loading those safeties. And because we work out something about drug exposures for the active species in the blood, because you can monitor in real time, right? Also, the efficacy and the safety profiles, and we come up that threshold, just monitoring active species in the blood. For that PK profile, you can have a very nice idea about the efficacy threshold and the safety threshold. So this allow us to push to 20 MPK loading dose. So we already enroll 12 patients in that dose cohort, so we are going to update that data and from there.
Of course, we're enrolling patients, expanding enrollment to China and Hong Kong, from U.S., South Korea, right, for our cohort expansions. We are also very excited, right, about giving this safety and the survival benefit and the data we got to combine with the standard therapy. This is really unique for this immunotherapy, the combination, because the safety profile we generate, just like Ray mentioned, compared to pembro alone, monotherapy. This allows us that kind of flexibility to cover broad patient population, including liver metastasis patients, which are big populations.
Mm.
Are also considering, together with our partner, to move it from late line to early line, second line, and third line, and other indications. Right.
Sure. Ray, what's the current cash position for the company, and?
Mm-hmm
... how about the runway for it?
Yep. We had $96 million as of June thirtieth this year, with runway well into 2026.
All right. Sounds good. Peter, Ray, thanks for coming down to talk to our audience. Thank you.
Thank you, Arthur.
Yeah.
Thank you.
Yeah. Thanks for your time.
Okay. Thank you.