If you have any questions, please reach out to your Morgan Stanley sales representative. Great, I would like to welcome, Peter Luo, CEO, and Raymond Tam, CFO of Adagene. Thank you very much for joining me today. And for those in the audience who are not familiar with Adagene, could you introduce your approach to developing antibody-based cancer immunotherapies, with a focus on your SAFEbody masking technology?
Sure, Max. Thanks for having us here. Our approach to antibody development is focused on two differentiated things. One is on the novel epitope, and second, develop a masking technology, so the first approach we show here for CTLA-4 will be able to generate a very unique antibody and a unique epitope of CTLA-4, which shows tenfold higher ADCC effect without any Fc engineering, and of course show low cross-species cross-reactivity, which enabling us to do really robust translational research from preclinical to clinic. The second thing is, well, develop a masking technology, which allow us to deliver the masked antibody to where the target are highly expressed, in this case, CTLA-4 in tumor tissues and T-regulatory cells.
So in this way, we'll be able to target the CTLA-4 on T-regulatory cells, in tumor tissues, and a unique epitope of CTLA-4.
Great. I think that's a great background, and allows us to now jump into your lead program, which is ADG126. If you can just give us some background on why you settled on CTLA-4, supporting clinical data or preclinical data, and then we can dive into the clinical data.
Great. I think the CTLA-4, to us, is a God-given opportunity in cancer therapy. Because if you look at the survival benefit of CTLA-4 in combination with PD-1, clinically, that's the best survival ever generated in any cancer therapies. And, of course, this are consistent with the fundamental biology. Jim Allison, who's a pioneer of cancer immunotherapy, would say, "The CTLA-4 biological hardwired in to the T cell immunities, get into the memory, and, don't do relapse, like a PD-1." So therefore, once those patients receive anti-CTLA-4, they can receive long-term benefit, and with a few recurrence.
Okay, that's helpful. So now we can dive into a bit of the clinical data. Your most advanced program, ADG-126, is being investigated in metastatic microsatellite stable colorectal cancer. Could you give us some background on how you arrived at this tumor type, and just set the stage?
Absolutely. Of course, we all know, CRC is a big indication, actually, the second largest one, if you consider men and women combined, right? And especially, like, globally in developed countries. Second, the MSS CRC, which are microsatellite stable, so far, the standard therapy are chemo, chemo plus Avastin, more chemos, right? So it's highly unmet medical needs for immunotherapy. No immunotherapy has been approved, except for the MSI-High, which only accounted for 5% in metastatic and 1% CRC patient populations. And the people who tried, for example, Nivo, Keytruda, other PD-1, they tried all kinds of PD-1 combinations with the last-line level, and all those essentially minimal response from those combinations, like, around the 5%, low single digits. So therefore, it's really important to find an approach which can get these cold tumors, you know, treatment to cancer therapy.
One of the reason why this tumor is so cold, because PD-1 has a low effect, that's the operational definition of cold tumors, yes, is because they have a high-risk Treg level in tumors, 40%. Also, its PD-L1 expression is among the elective expression, less than 1% to 82%. So this double effect makes it such a cold tumors and don't respond to PD-1 therapy alone. On the other hand, the CTLA-4 fundamental biology is Treg, which are hijacked by tumor to escape the T cell immunotherapy - immunities. So by depleting the CTLA-4 mediate, the Treg, which will make the tumor responding to the therapy.
By combining our anti-CTLA-4 plus PD-1, you can begin to see the tumor become warm, and the response, like, about 20%, and impressive PFS and also long-term benefit, we're gonna show in ESMO this year.
Okay, before diving into the initial data, talking about this specific tumor type, can you just discuss the prevalence, incidence rate, and the path for treatment right now?
Absolutely. So to start with, for immunodoublet, as we know, immunotherapy is very good for survival, but also immunotherapy is indirect. So therefore, the tumor response to immunotherapy are slow. Therefore, when you choose the indication, especially for this cold tumor in advanced stage, you have to choose a population we call the liver free metastasis, which progress less quickly. Therefore, it gives the immuno-doublet a chance to work on your immune system to react to the, to race with the tumor, to show that effect. So that's how we choose this patient population. It's about 30%, in this, you know, mCRC patient in the third lines. And others, like Agenus, also choose this population for that reason.
So you give your immunodoublet a chance to act on your immune system to slow down the tumor, show the response.
What's the incidence rate in, let's say, the United States? How many patients are being diagnosed with this specific subtype?
I think for this subtype, like MSS CRC, what I said, like globally, it's about 95% in the metastatic stage.
Okay.
It's pretty consistent, right? But if you specifically talk about the third line, in this population, like a liver metastasis free, is about 30%.
Okay.
of that.
That's helpful. So now moving on to your phase IB/II trial, could you discuss the trial design and what you are hoping to achieve with the part one part of the data?
Yes. So what we are trying to achieve here is, really the dose response. You know, so that's why we show you initially the dose escalation data from 6 mpk to 10 mpk, which is quite a high dose, as you know, for CTLA-4 therapies, right? And then we try that. We show, first of all, you know, about dose escalations. We show a strong dose-dependent disease control rate, and, of course, ORR and all this. We show only you go to the 10 mpk Q3W, you begin to show the ORR, like about 20%.
Mm-hmm
... for this population. But on the other hand, if you look at our data, the 10 mpk Q6W, you definitely show target lesion, significant tumor shrinkage, 60% or higher, but they do have a new lesion. Therefore, if you use the RECIST or iRECIST criteria, you don't call that a confirmed PR, but you definitely show activity here. But if you, on the other hand, if you look at 6 mpk Q3W, because you cannot control that disease progression initially, especially in that activation phase in the tumors, so disease progressed. Therefore, you really have a very little disease control rate.
So that's really gave us the first idea how this drug works inside the tumor: activation, active species concentration to reach the steady state, how long to reach that steady state, and therefore, how to drive the ORR and the PFS and all those data. Right? Once we have get that data, then we do cohort expansion at the 10 mpk Q6W and the Q3W. There, you begin to see quite interesting data. In that cohort, early this year, we released about the 10 patients for each dose cohort, and you can see with confirmed ORR and about 20% for the 10 mpk Q3W, but no confirmed ORR for the 10 mpk Q6W. Both show nice disease stabilization. Therefore, you can say, combine both data, we get a PFS data about seven months.
That's state of the art for this kind of immuno-doublet separate therapies. And of course, since then, we have accumulate the OS data at a different, you know, landmark, like a six-month line among that kind of data. We're going to be reporting ESMO. I'd like to invite you to look at that data, and because of those apply everywhere, immunodoublet is going to translate into OS benefit.
Great, that's very helpful, and we'll definitely touch on the ESMO presentation that's occurring, I believe, September thirteenth through the seventeenth. But first, could we just talk about your experience with the safety profile and your comfort at the dose that you're currently testing, which is the 10 mg/kg ?
Yes.
Overall, what do you feel about the safety signals that?
Yeah
... you've investigated? Is there anything you'd like to highlight in regards to the safety profile?
Exactly. I should say this is a dosage, 10 mpk, for example, Q 6 W, is tenfold higher than most of the dose approved by Ipi, right? 18 indication approved is at the 1 mpk Q 6 W, six weeks continuous dosing. And then also, there's tenfold higher the Agenus used for the anti-CTLA-4, 1 mpk Q 6 W. In fact, that's the dose from the FDA interaction. FDA allow them to do that, not 2 mpk, six weeks.
So this is underpinning the idea that your masking technology is potentially allowing you to increase the dose with a better, more manageable safety profile. Is that correct?
Absolutely. That's the sort of window we got, right? You are going to see our ESMO data. Not only we show the. We basically there, we have a very little grade three toxicity. Early this year, we report it, and also we're going to show the long-term, so-called late onset toxicity for this dosing dosing regimens at the six weeks in combination with pembro. And also we show at the 10 mpk Q 3 W. In this case, you definitely get a better efficacy. It's over driven ORR 20%. There, we do get about a 15% of grade three treatment-related toxicity, and we are also going to update that data with the lung cancer toxicity with this dose level, too. You are going to see what time goes by, how that toxicity goes, right?
Because I believe those are extremely important for this target, because late-onset toxicity has been a big issue for anti-CTLA-4. And therefore, you know, that's why FDA cares about this toxicity. That's why if you look at the Agenus FDA feedback, that restricts only to 1 mpk Q6W, and in fact, even on the heavy use of anti-TNF alpha in that case.
Okay, that's helpful. So, we can now talk about, I guess, ESMO setting expectations, the benchmark there. We're expected to see additional follow-up data from part one of the phase IB/II study. What else can we expect to see in regards to the ESMO presentation?
Exactly. So at the ASCO this year, we'll only release the part one data, and there's no ORR rate and all this. And, yeah, in the coming ESMO, because the second stage of data or Simon two-stage design already mature for PFS. So in this time, we are going to have the PFS data for 10 mpk Q3W, about the 20 patients, right, 24 patients. For that, PFS data, and, also the 10 mpk Q6W data. So we get separate this. And, ASCO this year, we combine them. And the second, we are going to have OS data rate, right, for both cohorts. And, you are going to see very interesting, OS rate for the, for this two, part one, because we get a 3-month or 9-month OS data now. Okay?
And so we'll be able to report that OS rate from six or nine months. You can benchmark with other data released, including Agenus, right. So I think we're pretty excited for that survival benefit data, and because you can also see those data compare very favorably with current standard of therapies, because that's all about immunotherapy for survival.
And in regards to the number of patients we should expect to see from part one and part two, is there a rough estimate you could provide?
Yes. I think that one more thing I should say is, in our part one, we only released the ORR data for about the ten patients. But in the coming ESMO, we double the patients done in 10 mpk Q3W. And then the question, could we double the responders in this case? I think I invite you to look at the ESMO data to see how reproducible this dosage in this patient population. Yeah.
So that's about 20 patients from part one?
10 patients from part one, another 12 patients of part two.
Part two.
Yeah.
There we go. That's how we get to it.
So that's why we double time, we call it. Yeah.
Helpful. Okay, great. And if we can just touch on the limitations in regards to this patient population, liver metastases, peritoneal metastases. Basically, you're excluding these patients. Your competitor is also excluding these patients. What are the implications of that?
Okay, yes. That's a really good question, actually, Max. Yeah. I think that the reason, as I just mentioned in the very beginning, why you use liver metastasis free or like a peritoneal free, is just because immunotherapy, even including immunodoublet, the response of cancer to this therapy is slow. So therefore, you'd like to choose the patients population with proper prognostic markers, which have a slow progression, not too aggressive. Therefore, they can receive multiple cycle of immunodoublet therapy to show that ORR, PFS, and the survival benefit, right? So that's the intrinsic reason for doing so. But if you look at a big scope of the entire patient population, liver metastasis patients, that's a big population. And we know current standard therapy are quite effective to control the disease progression for that entire population.
About the four to six months, the latest standard of care approved by FDA sounds like a Fruquintinib, and if you look at it in that perspective, you can use that standard treatment combined with your immunodoublet, then that will give you a nice window of four or whatever cycles for immunodoublet, then you will derive that OS benefit. You can build a much broader patient population. Of course, given the condition, your immunodoublet safety are still has a large safety margin to allow you to do that combination with standard therapy. Not just in the third line, the late line, because patient has more tolerable, because no choice. You are considering move to the early line, second and the first line. That's all the big pharma partner like to see.
With this kind of safety profile and the OS benefit, and we're opening the door to do that, so that's why we're very excited to talking about a potential for this immuno-doublet. That's OS benefit, and there's all this data with demo for this population, but once you combine with the standard therapy, this enable you to give a much broad patient population.
Is there any risk to enrolling patients, though, who have peritoneal metastases, and not knowing at that point, at when they're initially staged?
Yes, I think, absolutely. So when we enroll our patient, or you can say, we have peritoneal metastasis, right? Site and all this. In fact, the PI actually, also our PI at the City of Hope, Marwan Fakih , right? He's the first one really talking about site-specific metastasis impact on MS CRC patient populations, or you can say he classified liver metastasis, the most aggressive one, peritoneal, also very aggressive one, right? So that's why we sort of exclude those patients, even though we didn't realize early on those are the cases. But once you exclude that population, you see wonderful data, because simply patient can receive more cycles of therapy. In fact, you are going to see our data in ESMO release.
If you just look at the patients, you cut them by how many cycles of immunotherapy they can receive, without the worry about the peritoneal metastasis or not, you will see they can receive a benefit once, like, say, four cycles or more. Doesn't matter they have peritoneal metastasis or not. So that essentially tells you, those biomarker is not a convenient biomarker. As long as you can deliver the drug, the doublet, to your patient for more than four or more cycles, they will derive those OS benefit.
That's helpful. Great, so we have the ESMO update coming up, and if we can maybe talk about the implications of the data you've presented so far, and how that's led to additional trial initiations, a better understanding of the therapeutic index. What are the next studies that we should look forward to?
Absolutely, yes. So Max, we have been so far talking about therapeutic windows index. That's really the key words. For this therapy, you need that big window, which allows you to really dosing the patient at a wide range of dosing regimens. So that's exactly what we're doing. We're talking about 20 mpk loading dose strategies, and we're already talking about, we show that the safety is well-tolerated, so that's why we started the cohort expansion into 12 patients in this 20 mpk loading dose cohort. And we're going to show the data, our population PK data, to show how our population PK predictions for this loading dose approach, which allows you to activate the drug in the tumor site to reach that steady state in the four cycles. Then you can control that disease progression and drive the response.
We're going to release that, the safety data, and the efficacy data is still maturing, and we expect to release this late this year. This will basically complete the cycle of a story about how this wide therapeutic windows allow us to dose CTLA-4 in combination with PD-1, with such a robust dosing regimen. Also prepare us to talking to the regulatory agency, moving forward, what kind of dosing regimens we should use, because Project Optimus is quite important and meaningful for our clinical development.
That's great. And you also initiated a trial in China with an even higher dose. Can you give us some background on that?
Exactly. So yeah, Max. Yeah, because, you know, one interesting thing about targeting CTLA-4, people always ask, "Do you have the safeties?" They say, "Here we go, this is the safety." Then people say, "How's the efficacy? You know, it's so safe, are you, are you sure your molecule is efficacious by itself?" We say, "Okay, let's do that." So that's why we do the monotherapy at a 30 mg/ kg for our molecules. This is the highest dose ever used in humans, and we're doing that every three weeks and in China. And, you know, I can guarantee you, you will see, yes, you can see the, you know, the patient response to the drug. Yeah.
When can we expect initial data from this study?
I think we are still waiting for the, that data to mature, and because, you know, because this is quite a higher dose-
Mm-hmm.
or you can say, if you even look at our therapeutic index and the prediction following those population PK data, you will see we're really pushing the limits.
How is enrollment going?
I think the enrollments in general, and because it's a monotherapies, and the people somehow for this for CTLA-4, all the PI think you should use a combination with PD-1. So that enrollment is okay.
Mm-hmm.
Because we really want to demonstrate in select patient populations, could we have a monotherapy response? And as you know, so far for Ipi, only melanomas show response in monotherapies.
Yes.
Yeah, at a pretty low rate, 10%. Yeah.
Helpful. So let's just switch gears a bit, though, and talk about the competitive landscape.
Yeah.
There are other players in the field who are investigating anti-CTLA-4 molecules. Agenus is probably the closest player, and they recently announced a regulatory feedback from the FDA. Could you just give us some insight into your thoughts, how you're interpreting this signal from the FDA, and potentially the implications for your program?
Sure, definitely. I think we're pleased to say FDA allow them to get into this population, in MSS CRC liver metastatic patient population, and that means FDA believe this a meaningful therapy for this specific population patients, because given the high unmet medical needs and the human therapy, right? The second thing we are not quite surprised is FDA do pay a big attention to the safety profiles. So that's why even though they have tested extensively, if you look at the early release in a single arm trial, you know, 70 patients most of the time, and I believe 50 patients are dosing at the two milligram per kilogram, right? But the FDA only allow them to go to the lower one, 1 mg/kg every six weeks.
Mm-hmm.
Right?
And they also discourage them from filing for accelerated approval.
Yes.
Do you think it's a class effect or specific to Agenus?
I think, we, we'd like to hear more from FDA about that. But, you know, given 20% of a response rate, ORR, even compared to standard therapy, which the baseline is about 5%, is about the three or five, four, for the higher, right? So FDA, but I think the FDA's word is important. They said that there's no convincing evidence to show ORR PFS with OS rate. And, so indeed, if you look at the PFS, it's not that impressive. It's four months.
Mm-hmm.
We released about seven months, right? So we basically said, "You know, for this line of therapy, OS is not a curing, because the standard is about eleven months." All right? So what we really want to see, FDA's logic behind the OS rate, of course, that's a gold standard. We take that as a baseline.
Mm-hmm.
Could you, if your OS, if you show the correlation, your ORR, PFS, and OS, could the FDA might consider give you accelerated approval, if you can provide that data? That would be interesting topic I would like to talk to the FDA.
Very helpful. So rounding out our discussion on colorectal cancer, could you just, looking forward, give us an idea of when we can expect pivotal data and potential filing?
Okay, say that again, Max.
So in regards to-
Sure
... your program for ADG126, when looking forward, when potentially could we expect you to initiate a pivotal trial and ideas around filing?
Max!
I don't want to press you too hard, but an idea in regards to the future.
Yeah. That's definitely our aspiration, too, right? And, believe me, we're talking about discuss all the time with the senior officer, former FDA senior officer, was our consultants, right? And they're talking about this, right? Because the thing is always like, what's the patient population, right? And, could you consider that immunodoublet or combination, right? immunodoublet for this liver metastasis patient populations, or even including peritoneal metastasis populations, or you want to include the broad populations, right, with the combination with the standard therapies, right? So that's a big topic. And, second, and what kind of a dosing regimen you are going to bring about to do that, trials.
Because we have done extensive dose optimization and the dosing regimens. This former FDA officer said, "You guys have done more than most companies, including some pharmas, done in this dose, you know, optimization regimen exercise." So we definitely are very interested to bring all that data package and to prepare to talking to the agency about our trial designs and the combination arm and the patient population, how that control arm will be, how that patient limit will be, you know, based on that endpoint we are going to use for that designs. And, of course, if you look at the standard therapy approved by Fruquintinib and Sunlight, there like Fruquintinib, the treatment arm and the control arm is two to one, and which is quite important for small company like us if are giving moving forward.
And all those topics are in active preparations, and we want to get a package, a comprehensive package, to engage a conversation with the regulatory agencies.
Okay. Helpful. So with the time left, I'd like to touch on financials with-
Sure
... Raymond, but first, just in regards to any other programs you'd like to highlight in the pipeline. You have earlier stage programs, you have your, CD3 T-cell engagers. Anything you'd like to call out as to get on our radar?
Yep, Peter.
Yeah, Peter, anything in regard to-
Yeah, Peter
... earlier stage programs?
Yes, absolutely. We are very excited. Given the masking technology, showing for CTLA-4, which I call a beauty test for masking technology, because every masking technology testing on this target, while the most advanced one, and it shows how this actually works mechanistically and clinically, right? So while having a broad pipeline and about some very important targets using this masking technology, the most important one I'd like to get your attention is about T-cell engagers. And given the recent strong interest from pharmas and the biotech, look at T-cell engagers in autoimmune disease. We do have programs in very advanced stage, that CD20, CD3 T-cell engager with our masking technologies. We're extremely excited for that program. We released, by the way, that data ASH, three years ago in ASH.
Or you can say we show amazing safety data in a dosing regimen from 0.3 to 30 mg/ kg ever done for T-cell engagers. We still show a pretty amazing CRS profile for our molecules, and we also show how B cell get wiped out completely by our molecules in a dose-dependent fashion. And also a prolonged, you know, half-life for this molecule if you compare to other molecules, CD3, you know, CD20 or all this in the clinics, and even approved one. So we're really excited for this profile. Of course, we know in the tissue level, very interesting data about that, too. And this is going to make a big difference, right, in this therapy, in those indications. The safety are the most important thing, and then, of course, it also helps with other dosing regimens.
By the way, Max, I forgot to mention, our masked CTLA-4 has a minimal ADA, less than 10%, and even with those with ADA, has a minimal impact on the PK profile.
Helpful. Thank you, Peter. And Raymond, if you could talk about the financial position. You reported first half financials, $95.7 million in cash-
Mm-hmm
and cash equivalents. Could you talk a bit about the runway and capital allocation?
Sure, yeah. So, we have a cash runway, well into year two thousand and twenty-six, right? And, currently, we prioritize the development of ADG126, obviously, in combination with Keytruda. So, this is our focus, for the time being. Yeah. And, just to add on, on what Dr. Peter Luo said about the safety profile, and, we would like to highlight, as reported at ASCO GI, the safety profile of ADG126 in combination with pembro is comparable to the safety profile of pembro monotherapy. This is essentially why we have every potential for this IO doublet to go in combination with different modalities, with the standard of care, so as to expand the patient population and potentially move into the front-line setting.
Because of that, this is why, as Peter alluded to, this is for the company, exciting time for business development. We are having advanced dialogue with various global pharma companies for not only our CTLA-4 programs, but also T-cell engagers programs.
Great. Thank you very much. Well, I know we'll be looking out for ESMO updates, but thank you very much from both of you for coming in, and very productive conversation.
Thank you for your time, Max.
Thank you.
Thanks, Max.
Thanks.