Great. Good afternoon, everybody, thanks for joining us for the next session. I'm Matthew Harrison, one of the biotech analysts here at Morgan Stanley. Very pleased to have Adagene with us for the next session. Before we get started, I need to read a quick disclosure statement. Please note that all important disclosures, including personal holdings disclosures and Morgan Stanley disclosures, appear on the Morgan Stanley public website at morganstanley.com/researchdisclosures. With that, pleased to introduce Peter Luo, the CEO of Adagene. Peter, I know you want to make some opening comments, so I'll turn it over to you for that, then we can get into Q&A.
Thanks, Matthew. Thanks everyone for your time. Today I'd like to take this opportunity to walk you through a few highlights about Adagene. Here are the investment highlights. I'd like to walk you through the opportunities Adagene presents. First of all, we're a platform company, and we have three platforms around antibody engineering. With these three platforms, we have created three global clinical assets. The NEObody clinical assets, which is the agonist, 4-1BB agonist, ADG106 and the CTLA-4 antibodies against a unique epitope. We also have our first SAFEbody in the clinics. We call it ADG126 against CTLA-4 targets. There are more coming around those SAFEbody coming from this platform. Finally, we do have this POWERbody pipelines coming from the POWERbody platform.
We recently announced we have five IND enabling programs, and some of them are already well into the IND enabling process. Also we show some partnership, and right now many around our platform with global partners and domestic Chinese partners. We also continue building our leadership teams. Those are the highlights. I like to also introduce the platform here with a little bit of details. Our NEObody platform is a technology allows us to target some very unique epitope, and in this case, an epitope conserved between mouse, monkey, and humans. This unique epitope not only gave us a broad species cross-reactivity, it also brings some very unique biology about those targets. For example, the CTLA-4 and the 4-1BB targets allow us to balance the safety and efficacy. With our SAFEbody platform, we'll be able to only activate the antibody in tumor microenvironments.
This will widen the therapeutic index for target like a CTLA-4. With our POWERbody platform, we take advantage of the SAFEbody give us to those modalities only allow those either Fc- enhanced or the T-cell engagers or ADCs, the kind of a modality only activate those powerful modality in tumor microenvironments. Those are the core technology we're going to use and help our partners and ourselves to create highly differentiated products. These are the collaborations we have done so far. As you can see, the SAFEbody platform allow us to create a lot of partnership, especially in ADC modality with our global partner, from the Japanese partner, Pola Pharma, ADC Therapeutics in Switzerland, and Exelixis in the U.S. We'll continue this partnership and with some big global partners.
With our NEObody technology, we work with NIH, Celgene, and GSK to create very unique molecules against those tricky targets and those unique epitopes. We've also out-licensed some pipelines to domestic Chinese partners. The two programs to the Sanjin Group , one is about known target of PD-L1 and the novel target about the other targets and enter into the clinics. We also work with Hengrui. Our three clinical programs, our ADG116, which we've shown here in these pictures, compare with ipilimumab in the purple-colored one crystal structure. Our green-colored antibody in crystal structure here, a small change in the epitope with a big change in its biology and mechanism of actions. We'd like to share with you some of that excitement in our clinical developments.
Also the SAFEbody, which with the masked binding site against the CTLA-4 target, push that therapeutic window even much larger than typically can be achieved for these targets. Of course, our 4-1BB agonist, we've shown here in the crystal structure in the green colored one compared to the BMS molecule on the top and the Pfizer molecule in the bottom. Here again, we show this new epitope can bring the safety and efficacy in this challenging targets. With the three clinical collaboration with Merck, we recently announced, and in combination with KEYTRUDA, and we're excited for this opportunity. Of course, the endorsement by Merck for the differentiation we're bringing for the CTLA-4 targets, even though they have an in-house program, and also the clinical program in combination with ipilimumab.
With our 4-1BB agonist, again, with KEYTRUDA, as you can see, we will be able to benefit from more extensive experience in combination with KEYTRUDA in the field. We're looking into those indications which are still challenging for PD-1 therapies. Those combination will be exciting. As you can see, we put it here. Right. The 4-1BB NEObody 116, we put it here. I think this still was the only target other than PD-1, PD-L1, shows monotherapy efficacy and multiple indication in combination with PD-1. Was the only IO target so far clinical proven for its efficacy by itself and also multiple combinations. There are still a lot of challenging with the safety for the kind of approved therapy. In fact, there's only one approved modality so far for this target.
The challenge is really coming from the safety of the current molecule against CTLA-4. By hitting this unique epitope, we'll be able to come up with much more potent molecule, fivefold higher than the ipilimumab in a head-to-head comparison, and threefold safety over GLP tox studies. This both improvement in safety and efficacy because of targeting this unique epitope to give us a benefit in terms of how to block this target and how to come up with very strong Treg depletion. This unique epitope really allow us to come up with very robust pre-clinical and clinical program. We have announced we have dosed in the patients right now at a 10 mg/kg. Perhaps the highest dose and so far same for the ipilimumab. We clean up the DLT at a 6 MPK dose level.
So far, for 22 patients we dosed use our drug. There's no drug treatment-related toxicity for grade 3 or grade 4. We only observe two grade 2 treatment-related tox. If you look at the historical data for ipilimumab at a 3 MPK, the grade 3 and the 4 toxicity rate is about 30%. With the dose escalation so far at the three patients at a 3, another three at a 6, and one patient at a 10, we didn't observe any grade 3 tox so far. We think this safety profile definitely compare favorably with the historical data, and we'll be able to report the top-line data this year for the dose escalation and also the cohort expansion data at a 6 MPK this year. The next program is I basically just walk you through this very quickly, how we compare with ipilimumab head-to-head, right?
At the dose level, we are basically five times more potent than the ipi here. The mechanism is really the Treg depletion in the tumor microenvironment, and the low difference in the PBMC and the kidney. There's very strong ADCC effect compared to the ipi and the soft ligand blocking compared to the ipi in the green color that we showed here, the green color molecules. Our SAFEbody program, and with this masking, and so far we have dosing about 10 patients, and we are dosing patient now at a 3 MPK. We'll continue reporting this dose escalation data about this SAFEbody program and other things. I have to say, those clinical progress are very exciting for us for this targets have been known for years.
This SAFEbody, again, we've shown not only are safe, they are also active against the tumor models shown here. When they combine with PD-1, they really shows a nice combination with PD-1, like our NEObody. Also the safety profile in that combination is also very robust in our pre-clinical models. Again, it's the Treg depletions. Those are the GLP tox data we published, and I refer to you to look at this data and the compared data published by BMS last year in the ASCO. You can see, we'll be able to dose in the monkeys at a 30 mg/kg without a serious damage to the monkeys and a 200 mg/kg our safe masked antibody. Those data compare very favorably with ipilimumab and the ipilimumab Probody ADCC-enhanced ipilimumab Probodies. Our 4-1BB agonist.
We have published extensively about our dose escalation data and include some dose cohort expansion data. We show this epitope here can make a difference in balanced safety and efficacy. We have been able to dose cohort expansion at a 3 MPK and a 5 MPK, much higher than other reported. With this, one of the high-risk stable disease rate at the 56% for monotherapy, some partial response from our drugs. We think we are making some breakthrough in this agonist antibody against the challenging targets. Again, we have published extensively for the PD markers we show for NK cell, soluble CD137 and the correlations with the clinical response and the predictive biomarker relate to the tumor shrinkage with this proprietary biomarkers.
Finally, our exciting pipelines about our differentiated CD47 in terms of efficacy and the safeties and the issues related to other modality around this target and our bispecific T-cell engagers. I basically will end my talk here and put some major catalyst event here for your reference. I'm open for some Q&A sessions. Thank you for attention.
All right. Thank you, Peter Luo. Appreciate those introductory comments. Why don't we go through a couple items? Maybe the first thing that started is with the NEObody CTLA-4. I think one of the things that you've highlighted in the past is about ADCC and that improving efficacy. Maybe you could just comment on why you think that's different and why you think no one else has done that in a target like this before.
Okay. Yeah. Matthew Harrison, it's great. I think that this really relates to our platforms because as we show you here, you have our NEObody platform where we are able to come up with very novel design for antibodies, and we basically leverage what we call the AI-powered antibody design platform. This really allows us to come up with design with the same sequence, but with a conformational diversity in the CDR regions. What this allows us to do is this dynamic expanding pockets allow us to engage target like a CTLA-4 in a very novel way. This adaptivity not only creates the cross-activity, which are very challenging in general for antibody engineering. We show here the epitope we created here, right? We created this epitope.
This come in to blocking the ligand binding between CTLA-4 and the CD80 and 86, very different from the ipilimumab. Not only that, the same isotype IgG1, we show a huge difference between the ADCC effect from our antibody compared to the ipilimumab.
Okay. That's helpful. I guess, you highlighted sort of the dose levels that you're through and especially those dose levels compared to ipilimumab. Maybe just remind people about how many additional dose levels and where you think you can get to. I think maybe more importantly, what that potentially gives you from a combination standpoint. Obviously the combination here is what everybody's interested in.
Absolutely, yes. Currently, what dose in the patient at 10 MPK, this is our original highest dose we intend to do. Given the robust safety profile we have seen, we revised the protocol to go up to 20.
Okay.
Yeah. Of course, in combination measures, just like you mentioned, and in the field what the people do is usually do one dose level lower than the dose you have a DLT occurrence. Currently, we already clean up the dose. DLT cleanup is a 6 MPK. We can do dose escalation at a 3 MPK. Because we have dosed the patient right now at 10 MPK, if we clean up the DLT at 10 MPK, that means we should be able to do the combination dose at a 6 MPK.
Okay.
Yeah.
Okay. Got it. I guess the follow-up to that is obviously you have both the NEObody and the SAFEbody against the same target. Is there a reason that you take both of these forward or would you expect the SAFEbody to have the same kind of efficacy as the NEObody, but potentially, because of the conditional activation , be able to even dose higher?
Okay. Yeah. Absolutely. We know our SAFEbody has a very good safety profile. This therapeutic window is so much larger, right? We show you this GLP tox data here. At the 200 MPK, the monkey are perfectly happy. If you look at the efficacy, our SAFEbody is not as potent as the NEObody because the way we're masking it and activate it. What we found is interesting is given this much therapeutic windows, we can dose in the animal at a higher dose. For example, we can achieve the same efficacy just like our NEObody if we increase the dose a little higher in monotherapy. What's interesting is if you look at the combination, the same dose level, our SAFEbody not as potent as the NEObody, but when they combine with the PD-1, no difference in the efficacy in the combinations.
We will also have beginning to show there's no actual safety signal added to that combinations. Basically, just like you said, Matthews, we have the flexibility to dose in the patient higher because with this added safeties. We also have this flexibilities to combine with PD-1 with a better safety in these combinations and allow us to adjust the dose and the flexibility, again, in that combination too.
The end point is we don't want to leave any efficacy on the tables, which has been an issue I've seen in a lot of PD level combination because of the safety concern, even though we know the 3 MPK is a better combination with, say, PD-1 because of the safety concern and people have to settle with a lower dose, for example, 1 MPK even longer duration, for example, in lung cancer, six weeks instead of three weeks.
Right. Okay. You're going to do combinations with both the SAFEbody and the NEObody with pembrolizumab next year. I guess it sounds like you want to see if there's any differentiation between those combinations before you decide on which one may be the better concept.
You're right.
Okay. Good. Maybe can we talk about 4-1BB and then maybe we'll have a minute or two for CD47. 4-1BB, look, I guess the top question here is you've clearly demonstrated activity previously in your data set, but you've also talked about a biomarker approach to enrich the population. Maybe just give people about a sense of the path forward here and what sort of data we should be expecting to get from the monotherapy studies.
Okay. Yeah. For the monotherapy data, and we struggle with in total, we have a dosing patient of 98 patients from both U.S. and Chinese patients. We do have a lot of PK and also other biomarker data not yet published. We will be able to fit both population from the U.S. and the Chinese patients, and we see no difference. Those population PK simulations also tell us the recommended dose for monotherapies and of course, the dosage which is used for combinations. Those are data we plan to release in some major clinical conference about details about those data. Also I should say right now we're doing combination with the PD-1 in China and in those escalations, we have seen very strong T-cell activation through that combinations.
Of course, under this PK data and the PD data, also we have seen some very interesting observation from that mono come to the combos and for those PD marker changes and dose-dependent manners and of course the PKs goes with that. We like to publish some of those data, again, in the major clinical conference. I should say one of the excitement is about the biomarkers, because those biomarker were shown from basically the patient samples from both U.S. and China, and some of the tumor type can reach extremely high expression levels up to, say, 40%-50%. It turns out those indications are more sensitive to PD-1 therapies. Those are exciting combination studies we're looking into and, of course, monotherapy studies in combination with PD-1.
Those excitement we're pursuing ourself and together with our partner like Merck because those indications are highly unmet medical needs.
Okay, good. That's helpful, Peter. I guess maybe could you also just comment on the competitive profile here, right? You've got 4-1BB, PD-1, PD-L1 bispecifics out there. There are people looking at 4-1BB, IL-12, IL-15 agonists, right? There's all kinds of competition out there. Maybe just how do you think about the landscape?
Yeah. Again, that's a very interesting area. We do notice some of the PD-1 or PD-L1 bispecific, we find that those are interesting because we are doing the combination in that space. I think that matches. I sort of will say we need to come back to the fundamental biology of the 4-1BB. I think if people should go to the bispecific space, really based on the biology reasons why they use those bispecific. This inevitably has to answer the fundamental biology about the 4-1BB. What we've shown here in our studies and some of the things we've already published, our antibody target this unique epitope is blocking the ligand, natural ligand binding on this epitope completely. Not a Pfizer molecule, not a BMS molecule, if you look at the crystal structure published by them.
We know having a competitive ligand blocking competitive agonist to this target, we'll be able to activate this target in a native ligand-like fashion. It's a kind of a safe and efficacious in that way. Of course, there's a cross-linking effect, which unusual from, say, PD-1 and other kind of targets. That cross-linking also an important effect that people should consider. With our antibody, we're trying to balance out those things. We show, in fact, in monotherapy, agonist is safe, unlike some people worry about agonist may not be safe. We show it's safe. It can be through core expansion at the dose level, like 3 mg/kg and 5 mg/kg, no issues. Right.
In terms of those bispecific combinations, we found the Genmab data are interesting, especially when they show some response data in indications and so each indication we already know, and the indication people don't yet quite know. We pay a lot of attention to those indications because those things could correlate with the biomarkers we found in our antibodies. We do find some interesting correlation in those observations. Of course, we like to see if our combination data also shows consistent with those bispecific constructs. We have bispecific construct, but at least in our hand, we didn't see any synergy from the bispecific construct compared to the combinations.
Okay. Okay, good. Well, Peter, thank you for those comments. Maybe just in the last minute or two, we can touch on CD47. Just I think for everybody's benefit, just talk about the differentiating properties versus the leading CD47 that Gilead has, as well as Pfizer's efforts.
Exactly. Definitely, we found the Gilead and also recent Pfizer data are very exciting in the space and together with others. I basically want to think about several points. The first point I should say, if you look at the recent Pfizer deals compared to other CD47 modalities, I think one major difference is the recent Pfizer deal, they do show monotherapeutic effect with a respectable response rate. Monotherapy. While if you look at the most of the antibodies, they have marginal monotherapy effect, mostly through combinations. We think it's important in the checkpoint space to demonstrate other monotherapy effect. Okay, that's the first comment. The second comment is about the safety. I think we do notice this safety profile has something to do with the epitope.
If you look at the CD47s and also others, they have shown a different epitope, making a safety profile different from CD47s molecules. With how they say the priming effects. In our antibody, we show this novel epitope we identify shows very different safety profile in terms of hemagglutination and all those effect, we show that nice dose dependence. Of course, with our SAFEbody, we'll be able to come in to address those safety issues in a even more powerful ways. Also we show a very, very favorable PK/PD in our molecules in the monkey studies. We basically say, not only you want to address those safety issues, you also have to make sure your molecule still has this efficacy you want to show. With our SAFEbody technologies, we definitely can address those different Fc functional site. Right.
This allows us really come up a molecule with the potency we want to see and still with the safety profile so much higher than we have observed compared to other things. We've also addressed other antigen sink in a very robust way. The robust PK and PD profiles.
Okay. Well, good. Well, great. Peter, thank you for being here. Thank you for your comments. Very nice to see you.
Thank you, Matthew. Thanks to everyone.