All right. Welcome, everyone. My name is Gautam Chukka. I am a Biotech Analyst here at Chardan. For our next session, we have Adagene, and with me on stage is Mickael Chane-Du, Chief Strategy Officer.
Thanks for having me.
Mickael , yeah. Welcome. Maybe give us a quick overview of Adagene today, ADG126. What is going on with phase II, your neoadjuvant? Just walk us through the next [audio distortion] steps, go to ADM.
Sure. Adagene is a company focused on masking antibodies. Our lead program is called ADG126, or muzastotug, masked anti-CTLA-4, for which we have an ongoing randomized phase II trial for Project Optimus. You should expect data in the first half of next year for that. We are testing two relevant doses of ADG126 in combination with pembrolizumab. You mentioned also neoadjuvant. We have an ongoing IST from Singapore, evaluating a similar regimen, different dosing schedule in neoadjuvant CRC.
Perfect. CRC is a cold tumor, right? Tell us what is going on with CTLA-4 blocking. How are you going to turn it into hot tumor? More specifically, is it from clearing the Treg cells, or are you priming new T cells? Walk us through the biology there.
It's a little bit of both, but given the mechanism of action of ADG126, which ultimately leads to unmasking in the tumor microenvironment, we end up as a result, we believe, more Treg depletion, but it doesn't mean that there's no priming of the immune system. I'd say a bit more of a Treg depletion and then some priming as well.
The classical problem with CTLA-4 targeting drugs is the same, right? You're going to hit a wall. The efficacy rises, safety issues go up. What is your fix for that? Tell us about the SAFEbody and your masking approach, and what have you seen that led you to go into the clinic?
Sure. Thanks to our SAFEbody platform, we believe that we have this very, very high masking efficiency. We also need high expression of the target CTLA-4 to have activation of the molecule. We have those patients in combination with PD-1 at a dose level up to 20 mg/kg, which is really a tour de force in my opinion, when you keep in mind that the ipilimumab of the world are traditionally given between 1 and 3 MPK in combination with Nivo. Importantly, our discontinuation rate due to adverse event in the context of a phase I-B, is below 10%.
Historically, some of the masking approaches didn't do really well. BMS's last EP version showed no safety, and the other one, 288, produced no responses with [audio distortion] More importantly, how is 126 [ audio distortion] different than?
It's about the masking efficiency. Masking efficiency, by that I mean when the mask is present, you're not going to bind to the target, and when you have cleavage of the masking peptide, you don't prevent the binding to the target. We're very happy with that when we would compare ourselves versus the other masking technology. Number two, something that I just mentioned, we also need high concentration of the target CTLA-4, which is very, very highly expressed on Tregs, among others.
Do you want to touch upon how your mask is different [ audio distortion] ?
We need these two conditions to be activated. I will also mention that the binder itself, which is called ADG116, by the way, is differentiated in the sense that we bind to a different epitope compared to the Nivo or the, sorry, to the ipilimumab and tremelimumab of the world, which ultimately leads to this much stronger ADCC, 10x higher versus ipilimumab, which, by the way, is something that has been replicated by some pharma partners.
Okay, perfect. Let's move into the phase I-B/II experience with ADG126. You've seen some really good response rates, right? They climbed all the way from 0% to 25% to 36% as doses went up. These cohorts are enrolled one after the other, right? You don't have a pembro arm. What gives you confidence that the dose response?
Number one, keep in mind that PD-1 single agent doesn't really have activity in MSS CRC, be it in patients with or without liver metastasis, right? It's basically close to 0%. That's number one. Number two, we have looked extensively at the baseline characteristic of the patients across the different cohorts. There are some differences, but we believe that the main driver behind it is dose. That's really the most important in our opinion.
What's the best way to think about safety, right? Obviously, your safety events also went up with the dose, with the loading dose having approximately 50%. Should I frame it as masking pushes the safety or is it actually fully solving the safety and dose problems with CTLA-4?
Pushing the setting, I'd say.
Okay, perfect. What do you think is the benchmark? You have about 19.8 months or so, 48% alive at two years for the 10 mg/kg. If you look at the NLM patients of some of the competitor trials, they are almost like regorafenib, I think, showed about 12-something. Putting all this into context, what do you think is the right survival bar on OS?
It depends on the line of therapy that you consider. As a rule of thumb, you should think of median overall survival in the low teens. Because of the mechanism of action of these approaches, the regorafenib or fruquintinib, TAS-102 of the world, you are not going to see these typical plateau looking at the Weibull curve that you can see with PD-1/CTLA-4, not only in our data sets but also in other companies' data sets.
Okay. Next is my favorite topic, comparison of your drug versus other competitors. BOT/BAL, they had patients who previously received immunotherapy, and yours did not. How should investors compare the two data sets? Do you think you can show the same advantage that your high dose holds after you adjust for prior immunotherapy and peritoneal disease and all that?
Cross-trial comparison is always a challenging exercise. Probably people shouldn't do it, but we do it.
Right.
We have different cohorts. We have the 10 MPK cohort, which respectively have 10 and 30 patients, and then we have 14 and 12 patients. We deal with smaller sample sizes. Really hard to do the exercise. That being said, since you mentioned peritoneal metastases, I'll mention that in our phase I-B data set, 20 MPK Q6W of ADG126 with pembro did have responses in those two.
Perfect. For the upcoming phase II, your best phase I-B data was from the 20 mg/ kg loading dose arm, followed by the 10 mg/ kg Q3W. The phase II is not testing that. They're testing 20 mg / kg every six weeks, and then two doses, and then 15 mg/ kg. That's going up against the 10 mg/ kg arm. Why did you not carry the loading dose arm into phase II?
We like the loading dose. We didn't bring it into the metastatic setting, but this is a dosing schedule that we like, and we are now evaluating it in the context of neoadjuvant CRC. We do also like 20 MPK Q6W in the context of metastatic disease in combination with pembrolizumab. The AUC is slightly higher than with 10 MPK Q3W, but importantly, we have this initial bolus that we believe is very important in the context of patients with very rapidly progressive disease.
Okay. Let's talk about the bar, right? In the phase I-B, the two doses that are now in your phase II showed about 17% and 25% responses. What do you think is the bar for your phase II? Should we be in that range or?
I think it would be good that we replicate what we showed in the phase I-B.
Perfect. Then let's say if the phase II works, what would be the best case for phase III and overall survival, trial design? When do you think we can hear on that front?
After the phase II, we plan to meet with the FDA, and the phase II, the best case scenario should be a randomized phase III trial, using overall survival as the primary endpoint, and the control arm will be dictated by the lines of therapy of the patients. It could be, for example, if you assume later lines, you should think of the fruquintinib or regorafenib of the world. If you think of third line, think of TAS-102 Bev, and if you do a mix of the two, I guess you would think about a physician choice of therapy.
Okay, perfect. Let's talk about neoadjuvant setting, the most exciting part in this CRC development story. Agenus made the pivot to neoadjuvant setting, right?
Thanks for showing the way.
Yeah, exactly. They had about 60%-70% pathological response rates, right? What do you think your edge is? Where do you think you can add value? Are you going to top up those response rates, or what do you think the masking is going to achieve?
Keep in mind, when you look at the ROBBIN trial, which I think has very high odds of success, botensilimab is given for only one cycle at a dose of 1 mg/kg. As we speak, in our phase II IST in Singapore, we're testing ADG126 with a loading dose approach to the 20 followed by 10 MPK Q3W in combination with Keytruda. We believe that giving higher dose of CTLA-4, more cycles of CTLA-4 with an extended time to surgery should help our differentiation potentially, but we need to generate the data.
I do not know if you can talk about this, but what dosing strategy or how many doses are you testing in the neoadjuvant setting, the Singapore study? Is that something that you communicated to the street yet?
Undisclosed, but more than two.
Okay. Would that have a loading dose component and some sort of follow-up maintenance?
Yes, there is a loading dose component.
Okay. What is the time to surgery there? From the first dose to time to surgery?
At least eight weeks.
Okay. You think that's the right amount, or do you think you can stretch it further?
Cannot elaborate further, but time to surgery is important to capture responses.
Okay, perfect. When do you think we can hear more on when the data's going to come out?
2027.
All right, perfect. Maybe I think those are all the neoadjuvant questions that I have. Maybe you want to just quickly touch upon all the cool deals that we've done and cash runway and what to look forward to in terms of those deals.
Sure. Just for the sake of time, we are very excited about our trial collaboration with Incyte and their bispecific against PD-1/TIGIT data. Remember that data that we have generated so far have been in combination with pembro, which essentially is inefficacious in the context of MSS CRC. We are now combining with that bispecific, which has shown really encouraging, super encouraging data as monotherapy in the late line MSS CRC, and they're showing now data in the context of first line MSS CRC. We like the approach because there's a PD-1 component in that bispecific, but also because we could help Incyte to address an important mechanism of resistance in our progression of CTLA-4 Treg.
We are a potent CTLA-4 inhibitor. We are a Treg depleter. The hope is that we could further improve the outcomes on top of that bispecific. In terms of cash runway, the runway goes to the second half of 2028. We did the follow-on offering earlier this year in April which has been very helpful, again, for the balance sheet.
Okay, perfect. I think we are right on time. Thanks for joining, Mickael.
Cheers.