Hi, welcome to HCV and RISE's 27th annual global conference. Today, we are very pleased to have with us HH Kim, CEO of MetaVia ., a biotech company focused on finding a cure for metabolic diseases and obesity. HH, welcome to the conference. We're very pleased to have you here.
Thank you for having me, Ananda. It's always a pleasure to join the HCW conference.
Sure, thank you. Maybe we can start with our first question. The DA-1726 and DA-1241 are tackling probably two of the biggest challenges in cardiometabolic diseases: obesity and NASH. If you don't mind, can you walk us through the scientific rationale for pursuing these specific mechanisms and the unmet needs you are trying to address in each indication?
Let's start with the DA-1726 obesity drug. It's a GLP-1/glucagon dual agonist. It's a once-weekly injectable peptide. I think everyone knows GLP-1s these days, and I don't have to go really too deep into it. It is, to me, a true dual agonist because we have the glucagon. That's the biggest difference. Yes, there are companies ahead of us in the later stage of clinical trials with this similar mechanism of action. Our biggest difference is how do you balance the GLP-1 and the glucagon? For example, GLP-1, what does it do? It decreases appetite, and this and that, everyone knows about it now. One of the most important aspects of GLP-1 is that it controls glucose. Glucagon, on the other side, provides energy burn and breaking down the white adipose tissues. Plus, it has a direct effect in the liver.
A negative side of it is that it actually increases blood glucose. How do you balance these two great mechanisms of action and try to get the best result? Our approach is a three-to-one approach. Unlike the other drugs that are in the more later stage of clinical trials, in our Phase I, up to 32 mg that we have had the top-line results out during April this year, actually showed great glucose control. That's very different than the other drugs out there with similar mechanisms of action. Obese patients, a lot of them, more than 50%, have type 2 or pre-type 2. Able to tackle that patient pool and provide additional benefits is the key here. When you think about GLP-1, GIP, what does GIP do? It kind of helps out with lowering the GI side effects, more on the tolerability side. You have AMLIN. What does it do?
It only decreases appetite. GLP-1/glucagon is a true dual agonist that has a very distinct mechanism of action from the two. The best part of, in order for this type of drug to succeed, it will have to control the glucose level. I believe that we are seeing early signals that our drug can do that while we have the glucagon really shedding a lot of fat out of the waist area. That's the scientific background on DA-1726. DA-1241, it's a small molecule, once daily, orally available pill. We did a Phase IIA. The most easiest way to explain the mechanism of action is that it increases production of natural GLP-1s in the gut. The GPR-119 agonist, they have receptors in the liver as well. We have direct hepatic effects.
We ran a Phase 2A, 16 weeks, over 100 patients, and we actually showed very good, compelling data with that drug in presumed NASH patients.
Got it. Great. Maybe we'll try to deep dive into the DA-1726 program first and then go to DA-1241. You talked about GLP-1/glucagon ratio, the importance of those aspects with respect to developing the product. How does DA-1726's unique GLP-1/glucagon ratio and PK differentiate it from its competitors, like pemvidutide or retatrutide, particularly in terms of tolerability and patient outcomes?
That's a great example, Ananda. Let's look at pemvidutide. They're perfectly balanced one-to-one ratio, and because of that, GLP-1 is trying to lower the glucose levels while glucagon is increasing. If you have a perfect balance, it crosses out that effect. That's why pemvidutide in early stages, they already said that they won't be able to use the drug on type 2 diabetes obese patients because they don't have glucose control. Now, the triple G is a little different, right? Because it has a GIP. When you look at retatrutide, the Eli Lilly drug, so retatrutide, they said it's about eight to one balance. During their Phase I study, early stage study, in their research paper, they said that they have not seen any glucose control within that six-week period. It's weak. It's weaker, but it's interesting, isn't it? One to one cross out. Everyone gets that, 8:1 .
Why? It's very different. Just because you have more GLP-1, it doesn't work that way. There has to be a balance. We believe three to one balance in the inhuman has more chances of showing and highlighting both aspects of the drug.
Got it. Sorry.
With that, GLP-1, as everyone knows, we have GI side effects. Glucagon also has similar side effects. That's why pemvidutide, retatrutide, triple G, everyone has about 20% or more discontinuations in their clinical trials because of heightened AE issues. For us, although it's very early, when we did, we go up to 32 mg dose level. We had two vomiting issues after the first dosing. We had a bit of nausea, but everything cleared out after the second, third, and fourth. There was a vomiting incident after the third, but that was only one case. 32 mg with that excellent AE profile and safety profile, we still lost more than 4% of weight in just four weeks of treatment. We believe that is coming from that balance as well. We are currently running a 48 mg cohort in Phase I.
Originally planned it for four weeks, similar to the rest of the cohorts. After seeing how the patients were reacting and the subsequent reactions, we decided to add on another four weeks to this. We're hoping to have that data released within this year. I can't give you all the details, but it is unfortunate that when these patients signed up for the four weeks, they signed up for four. When you tried to ask them to extend another four weeks, there are issues, right? They have personal jobs, and they have other arrangements. We won't be able to see the full picture, the full subjects going into the additional four, but I do believe it will be enough to see an early signal on how this drug will do over four weeks.
Interesting. With the ongoing 48 mg MAT cohort for DA-1726, what specific safety and efficacy benchmarks are you targeting to determine the MTD? Depending on the results you are expecting, how will this influence your broader obesity program?
Thirty-two milligrams became forty-eight. That's about a 50% increase in the dose level. Because of that rapid increase, there could be some of the AE, GI AEs that come out. I'll have to be honest with you, Ananda. I'd rather have a more potent drug than something that doesn't work, right? What we're trying to do in eight weeks, we would like to see how the safety works. We're not doing titration again. We'd like to see how that no titration 48 mg goes up to eight weeks. We'd like to see an AE profile where there could be some of the GI AEs coming up in the front end, but most of it gone in the back end. That's our target. On the efficacy signals, it's an eight-week study. I do know that recently there were Viking release on oral, Eli Lilly's oral 4 release.
There were a couple of early stage AMLIN drugs that had data released this year. Some of them actually reached around 7% in about 5-6 weeks.
Right.
Our goal is a dual agonist. People shouldn't compare apples to apples with AMLIN because AMLIN doesn't really have this much benefit to the patients.
True.
In eight weeks, I believe our goal will be somewhere around 7% or over.
Got it.
I think that will be potent enough to move forward. After this, we'll probably focus on a Phase II, try to seek a longer study with more patients. We're looking closely into the HbA1c because now we're looking at eight weeks. We may be able to see HbA1c levels change, not just the glucose level. We're doing DEXA scans and FibroScans. Why is that important? DEXA scan will somewhat show us how the fat loss, lean mass loss, how that compares to each other. Plus, FibroScan, of course, MRI PEF, but it will show us, does this drug have some effect in the size of the liver? It's going to be important because glucagon as a dual agonist, we should be able to tackle the type 2 diabetes obese patient pool, and we should be able to tackle the NASH patients as well.
Right.
This way, we can differentiate from the two approved drugs because they're more into curing or tackling NASH by losing weight. They don't have direct hepatic effect. Our drug with glucagon, we will be able to tackle NASH with direct hepatic effect. That early stage FibroScan maybe could show us it's working or not. It will be an early signal, but still, we're looking at a lot of different aspects compared to what we have done in the past with the 32 mg and the earlier cohorts. With the eight-week study, we'll be able to have much more knowledge of how this drug works in subjects.
Got it. Yeah, that makes sense. Quite a lot has been packed into that eight-week study. Given the competitive landscape, it looks like the HbA1c, the NASH aspect of it will be important from the competitive landscape. Probably the next question is, obviously, as you are thinking of going to the Phase II or in a bigger program, how are you thinking about potential partners or accurates or what's the strategy? What will be the strategy going forward with DA-1726 if the drug kind of shows the best-in-class potential according to the way, according to your benchmarks?
It's everyone's dream in biotech that we'll be able to develop it to the end and commercialize it. It's just way too big of a market to bring it by ourselves. I do believe partnering or collaborating will be very important to maximize the potential of the drug. We'll be open to discussions with everyone, especially the big pharmacies who haven't gone into the OBC space yet. I do know they are looking for a flagship in clinical stage drug, but they want something different. They want something very different so that they can put it as a flagship. I believe if we have tolerability, now we can show DEXA, FibroScan, HbA1c levels. We'll have somewhat of an early stage complete package so that we can sit down and discuss.
Got it. Makes sense. Maybe we can switch gears right now to look at that, you know, the DA-1241 program. You know, for those who are less familiar with GPR-119 agonists, can you just explain what's the MOA of DA-1241?
Basically, to put it easily, GPR-119 will promote production of natural GLP-1s. Plus, there are receptors in the liver, which the drug will be able to deliver over to the inflammation side of the NASH patients. You promote GLP-1s and have direct interaction with some of the receptors in the liver. Easily put, or else it gets very complicated.
Got it. You know, and so coming to, so recently, you had presented at the ADA 2025 the preclinical data showing the additive hepatoprotective effects of DA-1241 in combination with FGF21 analogues. How do you envision the combination strategy evolving in clinical trials, and what are the next steps in order for you to validate these findings in humans?
To me, what I know in the market and all the players in the NASH right now is looking for a combo. Yeah, because one drug will not be able to cure this very, very complex liver disease. Now, FGF21, it can tackle F3 and F4 up to cirrhosis, which is just quite an amazing drug. Because of its strength, it won't be able to treat F2 and F1 patients. Rasmatrium, the approved drug, going into F2 and F3 stage. They are doing a clinical trial on later F3 and F4, not proven yet. Semaglutide, GLP-1s. GLP-1s without the glucagon, they'll be able to treat NASH to a point where just by losing weight, naturally, it will lose the fattiness. More into the F1 and F2 and early F3 maybe. It could be a little weaker. Everyone is everywhere in this F1 to F4 stages of NASH.
Our drug probably will be in F2 and F3. It doesn't lose weight. We have direct hepatic effects that provide inflammation, anti-inflammatory effects, and a little bit of scar resolution. For us, oral, once daily, it makes perfect sense for us to look for a combination partner. We have been doing a lot of animal studies on it. We did an EASL poster last year with semaglutide combination, which showed much better results compared to semaglutide standalone. FGF21, the poster at the ADA showed it will enhance FGF21's coverage of the whole NASH patients. Plus, it showed better results than standalone FGF21s. We're doing other studies with Rasmatrium and other candidates so that we understand in the animal models what we're looking for and what we can benefit by adding DA-1241. That will be our strategy going forward.
Got it. That was helpful. Maybe following the promising Phase IIA results of DA-1241 in NASH, what are the key priorities in terms of upcoming end of Phase II FDA meeting, and how are you preparing for the potential Phase III?
Right now, we're just focused on finding that combo. With GLP-1s, FGF21, we have GLP-1 plus glucagon and retatrutide, as I mentioned, from Eli Lilly in late stage Phase III in NASH. It's going to be a very, very crowded field out there, market. Just as a single standalone drug, we don't believe there will be that much of a need in the market. That's why we're very much focused on finding this combination potential. As you know, like Novo Nordisk, they acquired the oral GLP-1 as well from a Chinese partner. Why are they doing it? Because they want to expand their label. They want to have this combination in their hands as well. That's the strategy that everyone's taking. It's our strategy in going forward as well.
Got it. You mentioned about FGF21. Given the synergistic potential of DA-1241 with FGF21 analogues, are you exploring partnerships with companies developing complementary assets? What, according to you, would be an ideal collaboration?
We are looking at companies and talking to companies on potential collaborations. The biggest thing would be, to me, it feels like we would like to have somebody who is closer to approval than early development. It would benefit DA-1241 going forward. Plus, the biggest part of this combo is that, as Modrigo showed, Resmetirom is oral, and they got the oral GLP-1. Plus, we're oral too. FGF21 analogues are injectables. We are looking into all aspects and trying to figure out what is the best, but who knows?
Got it. Very helpful. As a company, I think that kind of brings us to the last part of this discussion, which is, you know, as a company focused on transforming cardiometabolic diseases, how do you see MetaVia's portfolio kind of evolving in the next three to five years? What role do you envision for AI-driven collaborations like the one with Syntekabio in kind of shaping your pipeline?
Now, the DA-1241, 16 weeks, Phase IIA, the safety profile was amazing. You can't even compare it to any other NASH drugs out there. Because of that, we're looking for a combo. Because of that, a great safety profile, we figured that if there are any other indications we can expand based on the safety, it would be great. As you know, traditionally, when you try to find another indication, it takes years. With the AI-driven research, we found out that we may be able to do it in two or three months. That's why we're working with Syntekabio with the AI platform, trying to figure out if there are any other indications that we can use this drug for. We have DA-1241. We're focused on that side. Now, DA-1726, we actually have a collaboration with another company called Immunoforge.
We're actively looking to find a lead candidate for a long-acting DA-1726.
That will be a monthly injectable. We're hoping to get that result and share it with our investors and our shareholders soon. Plus that, I think the next will be us looking for a maintenance drug. Now, my strategy for DA-1726 is very simple. Looking at the insurance landscape in the U.S., looking at how the actual patients on GLP-1s react, it doesn't make sense to think people will be on GLP-1s forever. Typically, like recent data show, like 70% dropout in one year. When you look back, six months of that was dose escalation, finding the right dose, the titration. My long-term goal will be to use DA-1726 because of its great tolerability. You start at day one with no titration. You get to where you want to be in six months. I don't believe everyone needs to lose 20% of your weight.
The sweet spot, I believe, will be 10 %- 15%, somewhere around there. Use it for six months. You lose that much weight. Then you have the ability to go back to your normal life and try to stay out of that obesity level of the BMIs and try to live a healthier life. I don't believe people should be on these drugs forever unless you're type 2 or NASH. That's a little bit different. Just healthy obese people, if they can lower their weight and get off the drug and still control it, that would be the best scenario for everyone, for the insurance, for the patients. I think that should be the goal. Maintenance drug, we're starting to look for some candidates. What is a maintenance drug? I think the definition hasn't been set yet. Everyone has different ideas.
To me, it feels like a maintenance drug shouldn't be giving people GI issues. If you're having GI issues, why do you call it a maintenance drug? It should be just a weight loss drug. Control GI issues and just give people a little bit of a push in the back so that they can still maintain and get a healthier lifestyle after the drug. That's our goal on a long-term basis. I'm hoping to find that maintenance drug and get a definition of that.
Very nice. That was very helpful, HH. Thanks for taking time out to talk about MetaVia. I think the discussion was very helpful in terms of investors getting updated about your recent pipeline programs and the futuristic outlook of the company. Thanks very much.
Thank you for having me, Ananda.
I hope everyone enjoys the conference.
Thank you.