Welcome, everyone, to Jefferies Lending Healthcare Conference 2025. My name is Roger Song, one of the senior analysts covering BioAge Labs in the U.S. It's my pleasure to have the fireside chat with our next company, BioAge. Welcome, Kristen and Paul. Thank you. Thanks, Roger. Awesome. Alrighty, so we have a lot to cover today, and then very interesting development in the field. Before that, maybe Kristen, if you can give us one or two minutes and an elevator pitch for BioAge because you are recently IPO, and not that recent, but it's kind of a new IPO company. What BioAge is developed to address the main need for the healthcare. Thank you. Yeah, for sure. Is this? Yeah, that works good. Thanks for having us, Roger. Yeah, in broad strokes, BioAge is really focused on advancing multiple mechanisms that are relevant to metabolic aging. We've invested a lot in human cohort data that gives us conviction in which mechanisms of human aging will translate to the clinic and have relevance to specifically metabolic aging. Our most advanced program is NLRP3, currently in phase one, and I think most of what we'll be talking about today. We also have APJ agonists, where the goal is to file IND next year, and a couple of earlier stage collaborations with Novartis and Lilly, bringing forward other targets from our platform that have similar applications. Yeah, excellent. Yes, you do have a platform. I do not want people to lose sight of that because that was one of the key reasons that can fuel the whole kind of pipeline development. Also, investors also focus on the lead program and then the pipeline, the clinical pipeline. Maybe, yes, we are going to spend most of the time today for the NLRP3. You have your NLRP3 in clinical right now. You will have the data readout in the coming months. Before that, very interesting, recently we heard from your competitor or the field about the NLRP3, the first kind of clinical data showing something relatively surprising, but also very exciting data. Give us your take on that data, particularly more metabolic cardiovascular benefits than the weight loss versus compared to the initial kind of expectation. Yeah, for sure. As many of you may be aware, Ventyx had a readout recently. They also, like us, have a brain-penetrant NLRP3 inhibitor that's really potent, good dose, etc. We were really excited to see that data set come out. As Roger mentioned, there were some surprising features, right? Like these are really, we were thinking of them as obesity drugs. There was zero weight loss in the Ventyx trial. What there was was very profound and sustained reductions in CRP of around 80% or so and rapid, right? Like Like really quite rapid. That's really what drove the market response to Ventyx, to our drug as well. I think a lot of analysts are speaking about these as potential oral IL-6 drugs, right? Like really driven by the Tourmaline acquisition by Novartis this summer. These are drugs that really have profound impacts on CRP and a host of other cardiovascular risk factors that could play a really important role there. Beyond the CRP itself, which I think is the real headliner, they saw very nice reductions in LPA, in liver inflammation, which is really interesting and something we plan to follow up on as well. Of course, they also showed that these drugs that inhibit NLRP3 pretty profoundly and also get into the brain can be safe over an extended duration as well. Very nice safety profile. Excellent. Yes. For disclosure, I did cover Tourmaline before and then before the acquisition, all the way to the acquisition. It is a quarterly IL-6. That is why Novartis is really excited. Now we seem to may have the oral IL-6. You go beyond that, right? You have the lipids and then beyond the HSCRP. That's right. Yes. I think the level of the reduction for HSCRP, 80%-90%, we have done some analysis, seems to correlate with the potential kind of cardiovascular benefit. For MACE outcomes. Yes. And then based on the human genetic data, but also we're going to see the cardio outcome study result from Novo maybe in the coming months. That's right. That's what they. Yeah, we're looking forward to that readout. That will be the huge news for the field. Definitely. One of the major ones. Okay, so that's good. I think Ventyx is the first one to report the NLRP3 in the metabolic obesity population. We have a couple of NLRP3, including BioAge. You do have the preclinical data. Can you just compare across the preclinical model, see where BioAge stands and then where's the Ventyx and how are we going to potentially translate to the human? You mean in the context of obesity specifically? Yeah, obesity, maybe metabolic, if anything you have. Yeah, for sure. I mean, there's first of all, I guess there's some general features of the molecule, right? Like we think we have potential best-in-class potency as well as brain penetration. These are just general characteristics of the molecule. In our preclinical development, like those of many others with brain-penetrant NLRP3, we really focused on obesity, which, as I mentioned, is most likely not going to translate. From an obesity perspective, we had very profound weight losses among a therapy, additivity with the incretins. This has been seen in the hands of other companies too. So, Nemoura, [Ten V], not there as well. Yeah. There's some other characteristics of the molecule that are unique as well if you want to add to that, Paul. Yeah, yeah, sure. First of all, the majority of the compounds that are right now being developed are derivatives of MCC950, which has a specific binding site and actually had some issues with it that precluded development. We discovered our molecule completely independently of MCC950. Structurally, it's unique. Any of the potential liabilities that might be associated with that should not happen with our molecule as a result of its structure and its non-mechanistically based potential toxicity. That is one difference. What we've determined using crystallography is that we have a completely unique binding site and that every other molecule binds to the ATPase pocket to inhibit NLRP3. Now, ATPase is ubiquitous and there are multiple mechanisms throughout the body in addition to NLRP3 that require ATPase to be active. To have off-target toxicity related to that also is not a liability of our compound. That is two potential differences. As a result of its unique binding site, there actually is a possibility that in addition to blocking inactivated NLRP3, this is in a pocket that is unique that might have the ability to block activated NLRP3 as well. That is also a potential advantage for our compound. We have, as Kristen mentioned, really nice brain penetration where at least in animals, it is at parity with what is in the circulation. We are optimistic that we should get significant CNS effect. When we look at our preclinical tox, we have a really nice margin of safety that gives us incredible flexibility on how high we want to go if that is required for therapeutic benefit. It is a really nice compound to date. It is performing well from a pharmacodynamic perspective in animal models. From a safety perspective, it looks really good. Kinetics, it should clearly be a once-a-day molecule that has a relatively low daily dose. All the things you hope for in early phases, we'd seem to check all those boxes right now. Just to briefly highlight on the different sides too, we did put out a couple of papers this summer. We published the crystal structure with Matthias Geyer, who's an expert on NLRP3 structural biology. We also published a paper with Dr. Rebecca Cole showing some of the, so you know that basically there's some CAPS variants that are not inhibited by MCC950 and for the first generation of NLRP3 inhibitors that are inhibited by ours that might be due to the unique binding site. Okay, got it. How much preclinical data so far you have seen in terms of differences? I know that how the molecule design seems to be a bit different and then maybe even more potent and then different profile, but how the preclinical model has shown the difference and then how you think this potentially can translate to. It seemed, yeah, there's a bit of difference. The magnitude of effect, both as a monotherapy and in combination with GLPs, of all the things that have been publicly released, we seem to have the best effect from a dynamic perspective in terms of weight loss. Weight loss. That's obviously another thing that we've seen in our studies, in addition to this pretty profound magnitude of effect, is that some of the other compounds, despite continued therapy, start to rebound in terms of weight. We showed no rebound. We went to our maximum effect and continued therapy and it stayed at that plateau. It never rebounded. Yeah, got it. Obviously, NLRP3 field, at least in the obesity or the metabolic space, it's still early, right? Seems the compound, we do see some variation across different compounds. So that's. It's always the case, sure. Okay. Obviously the question is, since Ventyx did not show weight loss, right, but they do show profound metabolic benefit. How do you think about the BioAge? You are still targeting to, you want to set the expectation for weight loss or you want to take a step back, say, okay, maybe we will see. Yeah, I mean, we view that as a lot less likely now, right? I mean, it's probably most likely a failure of translation. Anytime you're taking a new mechanism from mice to humans, it's a gamble. So we think that's still exciting upside and the trial design that we're going to pursue next year will still be able to be fully powered to capture that if that's happening. Given what Ventyx saw, given that they got very nice brain exposure with a potent compound and saw zero weight loss, we think that's not very likely at this point. Okay. I mean, as Paul mentioned, there are still reasons why it could be different, right? I think there are five preclinical data sets with NLRP3 inhibitors, brain-penetrant ones, and obesity. Ventyx had the smallest sort of effect and also had a rebound. That could be a difference, but given the clinical data to date, we do view that as unlikely. Obviously, there's a number of reasons something could fail. The first is the mechanism isn't correct. That's probably what's going on. In retrospect, this isn't an active mechanism. It also could be the molecule, the distribution, the potency, the brain penetration, and the patient population. There's all other things that we could look at, but I think the risk of success has been dramatically altered by Ventyx's data. Yeah. It's about the expectation, right? So you don't want to say, okay, this is our base case. We're still going to see the weight loss given all the data. Where are they seen, right? Kristen said. We're still looking to see that? Yes. This would be very welcome upside if it does happen. Yeah, I mean, human data is king, right? And what we did see with the Ventyx compound was some really exciting, profound, rapid CRP reductions, some other changes in the liver, etc. So we're very much going to be remaking our trial around it seems to be those. Maybe that's a fair segue is what you want to see in the SAD/MAD healthy volunteer before you move into the phase II, right? I know initially phase II is obesity, but maybe let's see what kind of profile you want to see for the phase I SAD/MAD. Definitely. Go from there. Our SAD/MAD, which is ongoing right now, was always really designed to support any indication, right? That is still true. It is healthy volunteers, multiple doses. We are going to learn a few different things, right? The most important thing is sort of picking a dose to go forward. We are going to be able to see a dose where you get 90% IL-1 beta inhibition peripherally and in the brain, right? That is the number one most important thing coming out of that study. Really, the goals are to show safety, to show that this is a nice once-a-day drug with a low daily dose, and to show that we really can achieve that degree of target inhibition in the brain and body. Those are the goals coming out of the SAD/MAD. That is fairly unique, right? It's very nice with this target that you have this very nice PD readout that lets you select that dose to carry forward. That would be the one that we would then take forward into a three-month longer look, similar to the Ventyx trial that just read out, looking at these cardiovascular risk factors. We'll have that data in hand by the end of 2026. Yeah, this particular mechanism is fortunate in that there is a good readout of effect in that after dosing, you can draw blood and stimulate it. The stimulation produces IL-1 beta, so you can actually look at an ex vivo ability of the drug to inhibit the actual target as opposed to just taking an in vitro measurement and then say, well, our plasma concentrations are above a calculated in vitro IC90. We could actually prove that inhibition in an ex vivo model in humans. That I think is much more translatable. Yeah, that's a pretty neat for the ex vivo IL-1. So outside of IL-1, any other PD marker you will be reporting or you will be watchful? Yeah, I mean, these are healthy volunteers, so not really in the SAD/MAD, but there's a host of interesting things we'll look at in the obese cohort after. Yeah, obviously we can look at CRP, although these subjects aren't in their baseline inflammation. Although even if you look across a normal population, there are certain individuals that will have elevated CRP. We will be able to get at least a measurement of whether or not this is affecting CRP even out of our phase one. That is another objective to look at this. IL-6 is harder to get in normal volunteers because it is not a function of the stimulated blood. It is what is available at baseline. We do not expect to see anything until we go to a population that is more inflamed. I see. So IL-6 is not, you cannot do the ex vivo assay? You can't do the ex vivo assay, no, because there's enough circulating IL-6. Because IL-1 beta you can look at as a stimulated outcome because it's very quickly cleared. You can view what's stimulated and measure it. With IL-6, there's a baseline level that has nothing to do with stimulation that you can't affect. Got it. it. Okay, good. Yes, we look forward to that data readout. It will be very, very important to see the PD marker. Let's say you get pretty profound IL-1 reduction and then safe and then all the dose PK supporting the QD. What will be the next kind of strategy? I understand if you do not treat the obesity or the weight loss as the base case, maybe you should pivot the phase two into more cardiovascular trial versus the obesity trial because initially I think you are doing the obesity trial. You'll try to do it. Yeah, the initial design really was to go into obese patients with elevated CRP, right? Within sort of, which is half of all obese patients, right? These are the people, it's a very large segment of that population that is at increased cardiovascular risk, etc., right? Even post the Ventyx data, that's still a very strong interest, I would say, from pharma. It's still something you could combine together with an incretinic drug to improve cardiovascular outcomes, to improve potentially liver outcomes as well. The trial really is mostly we're layering on additional readouts that we think we'll be able to learn from. Of course, it's going to be oriented around CRP now as opposed to oriented around weight loss. We're going to be looking at inflamed individuals at risk. Yeah, Paul, do you want to speak to some of that? Yeah, that's right. I mean, obesity is still a great cohort because they're a hyper-inflamed population. It's a great cohort to look at the ability of these drugs to affect these inflammatory mediators. Where the weight loss part of it sort of goes along for the ride, it's a great model of how well these drugs can perform in terms of blocking the relevant inflammatory markers. That's essentially how we're focusing on it. We will get that out of it. There's also, within an obese population, there are neuroinflammatory markers that you can measure. An obese population, for example, has elevated CSF NFL. We'll be able to look at that and see if there's an effect on more of a relevant CNS marker, which these drugs were initially developed to look at neurocognitive function. We'll get a sense if there's a relevant effect on those also. We will measure IL-6 as part of it because the obese population does have an elevation in baseline IL-6 as well. We'll get a sense of if it's working there in addition to IL-1 beta and CRP. Yeah, I agree. Obesity is still a very relevant population with the baseline kind of. Yeah, all the comorbidities associated with cardiovascular outcomes are accentuated in an obese population. Yeah. Would you still have the BMI cutoff like a typical obesity trial, but also enriched for the. Yeah. That is one of the things that the Ventyx data kind of taught us, that we should enhance the probability of seeing effects on that. We are going to look at a slightly more obese population. We'll use things like baseline CRP as an entry criteria to make sure they're a little more inflamed than just the general population, I think, in looking at it. Yeah, but higher BMI usually means more inflamed, and we'll have separate criteria for both BMI. Yeah, it's directly correlated. You can look at data that the higher the baseline BMI, the higher the baseline CRP. Yeah, but it's a great learning set, right? You can run a quick experiment and see these changes in an inflamed but otherwise healthier population. Exactly. You can learn from. Yeah, that's right. You have some time to design the phase II, right? Yes, we do. The only good thing about them being first is that we can learn from your experience. I don't know where's the Ventyx. We talk a lot about here. Another thing is, I understand the initial trial you want to definitely see the monotherapy kind of activity. Given may or may not see the weight loss, if that's possible, you can accelerate the incretin combination to show this obesity, maybe see both sides of the story. Just like I think Ventyx, they also have the combination. We did. We were not planning on doing a combination. It is very hard actually to have power to see a combination weight loss effect in a three-month trial. You would need a much larger sample size. If we do not see weight loss as a monotherapy, I would not expect to see it as a combination. I mean, it's been shown that GLPs can have an effect on liver inflammation as well. So looking at this as a combination, we could also see if it accentuates the ability of modulating the effect on the liver. Yeah, I think the purpose of doing the combination may not necessarily you want to see an incremental weight loss. Rather, you may see sustained kind of benefit on the cardiovascular or the lipids. And then because a lot of people, the population, a lot of people will be on incretin and then see how NLRP3 can be used on top of that. Yeah, and a lot of populations that's relevant. Obviously for the incretins, they're looking at other potential indications beyond just obesity. That's where this might be beneficial in combination as well. Right. Is that part of the phase II, initial phase II, or it will be a little bit later? That's not part of the current plan. Yeah. Yeah. Obviously, we'll look at markers of inflammation. And we'll look at markers of liver function as well as part of it, including MRI of the liver. Yeah, to be clear, like an incretin combo is not part of the plan, but we certainly will look at liver inflammation, right? Yeah. It should have an independent contribution from this mechanism. Yeah. Got it. Okay. Makes sense. All right, so that's the phase II. Maybe we'll still kind of fast forward your phase I and now you give us data and then we talk about phase II. What will be the next step for the? That is a subject of intense debate at the company. I mean, this has a lot of promise in these cardiovascular indications in MASH. There are a few different options on the table. This would be a study, this phase two we discussed, that is going to read out end of 2026, right? This would be a study initiating in 2027. I think there are a lot of different directions. We certainly want to add on another indication. We think that we have a very differentiated drug. Again, one of the features of this drug is it gets really well into the eye and the brain. We are thinking about other indications to layer on there, but nothing to disclose at this point. Sure. Sure. I know you have the partnership with Multiple Launch Pharma. Do you think this program all the way to phase II, obviously, BioAge is fully funded to do that? What do you think about the next stage? You think you want to have a partner to accelerate this and fund this, or you may want to see a little bit more signal before you? Yeah, I mean, we very much want to go with a loan strategy as well. Certainly, we're not going to be running our own MACE trials. That's not the plan. There are a lot of other indications where it has potential, right? We want to generate that data set, but we think there are a lot of other ones where we as a small company can generate really valuable data as well, not only next year, but over the coming years. Yeah, we see the MASH space and it seems SMIP BioTech can all the way to very late stage and before you have to. That's an interesting one that we're, yeah. Absolutely. Okay, so maybe just the last couple of minutes and then we should talk a little bit about the apelin because that was the target I really got excited about when you went public. I think it's still a very valid target. How do you think about where you are now for the apelin and then why you think the current candidate can be different from previous ones? Also, what's the plan for that? Yeah, for sure. We're still very excited about apelin biology. This is an exercise mimetic mechanism that has the potential to increase weight loss when combined with an incretin drug and also preserve relative muscle mass, which is important especially in an older population. Here we really have two different strategies, both an oral and an injectable strategy. What we communicated a few months ago is that we're on track to file IND for these programs next year. Our oral program, we've already filed our first patents, novel small molecules, super potent, chemically distinct from azelaprag. Our injectable program, we partnered with a Chinese company called Jiqing Therapeutics, founded by Dr. Fei Xu, who first published the crystal structure of the APJ receptor. She's an expert on that biology, and she built a really potent nanobody agonist. We're really advancing both of these programs in parallel because we think they're addressing different segments of the obesity market, the sort of once-a-day oral and the more longer-acting injectables. Yeah, we think it's reasonable in that, as Kristen alluded to, the fact that these are chemically completely distinct from azelaprag. Our investigation suggests that the issues we saw with liver enzymes are not related to mechanism, but were related to the structure. To have a completely independent structure minimizes the possibility of seeing that again. Yeah, yeah. I think that what we saw from the azelaprag is a surprise, right? It is not necessarily target related. It is more. We don't believe it's mechanism related. Yeah, that's correct. Okay. Maybe just the clinical plan. What's the timeline look like? And then how should we think about the whole program? Yeah, so filing IND next year, right? We're here to get back into the clinic as soon as possible. Then similar to azelaprag, like after phase one, we would want to go into combination studies with incretin drugs. I mean, orforglipron should be available then, right? Because again, the real potential of this here, like an oral combo. Yeah, we're still very much excited about that prospect with our next-gen compound. Is Lilly still part of the partnership? Or I think you used to have the azelaprag as the supply agreement. Yeah, we had Lilly, a specific collaboration with Lilly on that trial, on that azelaprag trial. They're partnered, so that's over. They're partnered with us on other earlier stage programs at the company, right? We have a partnership where we've selected a couple of promising targets from our platform where they're helping. Yeah, these are independent. This is separate though. Not apelin. They're different targets. That's a clarification. Okay. Got it. Yeah, since we're just last 30 seconds, the early pipeline and how much you can tell us? I know we started the conversation by saying you have a platform, so how much kind of early pipeline you can tell us now? Yeah, for sure. I can't name targets, right? As I mentioned, at an earlier stage in NLRP3 and APJ, we have a couple of targets we're working on with Lilly. At an earlier stage, we also have a larger scale target discovery platform with Novartis. They're really excited to find novel targets at the intersection of aging biology and exercise biology. They have great human exercise omics data. They want to find other targets that are really like apelin. Here it's more, it'll take a few years, right? The goal is to find targets that nobody else is working on and develop drugs against them. Some of these will be developed by Novartis, other ones by us at BioAge, and we'll sort of owe milestones and royalties either direction. Got it. Okay. Great. I think thumbs up. I am really happy to have this chat with you. It's great. Thank you. Thank you, Roger. Appreciate it. Thanks so much. Appreciate it. Thanks so much.