All right. Welcome, everyone, to Jefferies 2024 London Healthcare Conference. My name is Roger Song, one of the senior analysts covering SMID-cap biotech in the U.S. And then it's my pleasure to introduce our next company, BioAge Labs. And then we have our CEO, Kristen, here. Welcome, Kristen. Thanks, Roger. Great to be here. Awesome. Yeah, given BioAge just successfully launched the company in the public market a couple of months ago. So can you give us like a one-minute elevator pitch, and then we can go on the conversation? Yeah, for sure. Happy to give the brief intro to the company. At BioAge, we're focused on using, basically looking at disease through the lens of aging. We're working on aging targets that have the potential to really improve metabolic disease. The company has a lead program, azelaprag, which is an oral apelin receptor agonist currently in phase II trials with tirzepatide. This is unique in a few ways. It's a small molecule drug that when you combine it with an incretin, has the potential to do a few different things: increase weight loss, improve body composition, and to be well tolerated. It's very differentiated in this space. As I mentioned, we're doing a trial right now to see if when we combine it with Lilly's tirzepatide, we're able to increase weight loss as well as affect some other endpoints potentially. We'll be doing some other trials with IPO proceeds with azelaprag. We're also advancing another compound, our internally developed CNS penetrant, an NLRP3 inhibitor, which is also a target of emerging interest in metabolism. And that program will be filing IND in the second half of next year and going into a phase I SAD/MAD followed by an obesity cohort as well. And then behind these first two most advanced programs, we have a couple of earlier stage programs of the company too. We're working on a couple of additional targets that check the same boxes as apelin and also NLRP3 in the sense that they're linked to good outcomes in large human data sets, so positive functional outcomes over decades of aging. And they'll have applications and metabolic indications as well. Excellent. Great. I believe our conversation will mostly focus on your lead program, azelaprag, apelin agonist. So maybe start with the mechanism. So you already say you're in the phase II combined with tirzepatide, which is an incretin-based therapy. So how should we think about the mechanism different compared to the incretin-based mechanism for obesity? And then why do you think you can create some synergy with the incretin? And then we can go on to the other. Yeah, happy to go into all of that. So apelin is very distinct from the incretin drugs. Apelin in literature is described as an exerkine. It can basically mimic effects of peptide hormone that can mimic the effects of exercise. It's called an exerkine for two different reasons. One, if you go out and exercise, you go for a run or a bike ride, your body will make more apelin, and it'll have effects, downstream effects on your biology. And two, if you take an animal and you increase its apelin levels by some other way, not through exercise, but through a genetic intervention or just in injecting apelin peptide, for example, you do recapitulate several benefits of exercise, including improved body composition, metabolism, insulin resistance, et cetera. So the way that we think about the oral obesity landscape in particular, you can kind of divide it into two different categories, right? Because fundamentally, if you want to lose weight, there's really only two ways. You can eat less food or you can burn more calories, right? And when you think of the appetite suppressants, these are many of the molecules in later stage development right now: incretins, amylin, CB1, and NLRP3 as well, right? And in contrast, there's this set of emerging mechanisms that are more on the energy expenditure side. This is true of azelaprag, our APJ agonist. This is also true of some other mechanisms like AMPK, mitochondrial uncouplers, et cetera. And these are not competing with the incretins. They're potentially complementary. So you could envision, for example, like a fixed dose combo pill. This is really what's driven a lot of value for the company. You could envision a fixed dose combo pill of an oral GLP agonist together with azelaprag that could achieve better weight loss. Yeah, great. Yeah, we do see this kind of a different mechanism and potential kind of synergy between you and the incretin-based therapy. And then we start with the animal model. So we do see some interesting prevention of the weight gain at the monotherapy for the mouse model. And then we certainly see very profound weight loss if you combine with tirzepatide or any other incretin-based therapy. How should we interpret those two results and reconcile, say, okay, apelin is the right way to go to combine with the incretin? Yeah, great question. I mean, we think of this through the lens of what part of the weight loss regime is this drug most appropriate for, right? Because there's like the weight loss induction period where you want to have a lot of rapid weight loss. And then because most patients don't want to stay on that kind of regimen for years, I mean, the side effects are not great. What's the regimen that helps you keep the weight off? And as you mentioned, there's this very nice genetic evidence for apelin. Takeda published a paper where they built transgenic animals that overexpressed apelin. And those animals, interestingly, were protected from weight gain on a high-fat diet. And furthermore, the weight they did gain was higher quality, so a better ratio of muscle to fat. We've reproduced that data with azelaprag as well. So we're really excited about the potential to use this either alone or with a small dose of an incretin to prevent weight gain. But the near-term opportunity and what our clinical development is focused on now is really that initial weight loss. We do see a very profound synergy on top of an incretin background or other appetite suppressants like CB1, which we recently presented at Obesity Week, where you do get a profound additional weight loss in a model that translates well to the clinic. So that's what our first trials will be looking at. But we're excited about these other use cases as well. Got it. And then, given the data we have seen from the preclinical, and then you do have a phase Ib in the bed rest population, see some muscle change. So maybe start with the weight loss. What's your expectation as you combine with tirzepatide? Maybe how you design a phase II as a statistical power. And then what's your expectation really going to show in the phase II? Yeah, for sure. So our phase II trial, which is reading out in Q3, towards the end of Q3 next year, is powered to show an incremental 3.3% increase in weight loss over tirzepatide alone at six months. So I'll unpack exactly what that means. But in that trial, which is a six-month weight loss trial, we're using the low dose of tirzepatide. This is the five milligram dose. And the rationale for that decision is that five milligrams of tirzepatide gives you kind of the weight loss dynamics of an oral GLP, right? It gives you about 15% weight loss at one year. And that's where the company, that's where we really want to show additivity with azelaprag. So we basically want to show that you can take a 15% weight loss profile at one year and boost it to 20% or more for a couple of different reasons. Like that's the regulatory hurdle for approval. It's the most important reason. That's also interestingly the delta between oral and injectable performance, right? If you could get an oral combination that achieved 20% weight loss, it would be competitive with injectables. So working with Lilly, they helped us design the trial. The six-month version of that trial is basically looking for a 3.3% improved weight loss versus tirzepatide alone. So at six months, you get about 12% weight loss on tirzepatide alone. We're looking for 15% plus. And that should predict an incremental 5% weight loss at one year. So that's where we have power. And to your other question, this is conservative given the preclinical results. So we see a much more profound effect preclinically. This is just the conservative hurdle that corresponds to the regulatory bar. It would be a very exciting result to see in humans. Yeah, when we initiate the coverage and then we build the model for DIO versus the clinical. So if we use the DIO based on the historical study, your weight loss is way, way high. So what's the ceiling you expect to see? It doesn't make sense you can lose that much weight because your DIO model, those mouse basically become a lean mouse kind of again. Yeah, that's right. I mean, historically, and there have been review papers published on this, like there's a great Nature review paper, right? And if you take the weight loss in the mouse and you map it to the weight loss in the human, you can take about a haircut of a 50% on the effect size. And instead of three weeks, it usually takes a year, right? So it won't be as profound as in the mice where the combination fully restored the animals to a healthy weight. But yes, it should still be more than we powered the trial to see. Yeah. Yeah, got it. And then you did mention Lilly as the partner to design the phase II. And then how much involvement Lilly actually have in the phase II? Yeah, so they've been pretty involved, which has been a big help to us. This is the first time we've run an obesity trial. We announced our collaboration with them almost exactly a year ago, so last October. And as part of the collaboration on the phase II trial, they're supplying tirzepatide to us. At the time, it was really hard to get your hands on tirzepatide. So that's a very valuable contribution already. But we're also working very closely with the group formerly known as Chorus. It's Lilly Exploratory R&D now. It's partly like an internal CRO. So they helped us design the trial. They helped us even select the sites. So we're working with sites that have delivered quality data in Lilly trials in the past. So it's been great executional de-risking. There's also internal team members at Exploratory R&D who are some of the boots on the ground running the trial with us. Yeah. So they are your partner, but you, BioAge at the company, still the sponsor. And then you are running the trial. That's right. Correct. Yeah. Got it, and then after this phase II, given a lot of involvement from Lilly, and then what the rights they actually have, why they're trying to kind of help you supply the drug and then help you to design the study. Yeah, for sure. So in exchange for all this help, the drug supply, the clinical trial help, they're an investor in the company as well. They have a soft right of first negotiation. So what this means is that when our data read out, end of Q3 next year, we're a public company. So the top line data will be available to everybody immediately. But Lilly will basically be able to go into the data room first for some period of time ahead of other companies. So it's basically a head start on diligence. Got it. Okay, very good. And then so this is just weight loss at the top line. But given the mechanism we just discussed, you may be able to see additional benefit in terms of the body composition and et cetera. So how should we think about other endpoints potentially you're going to see at six months? This is still relatively early small study. How likely we're going to see some statistics or maybe some directional? Yeah, that's a great question, right? Like we got excited about this mechanism in the first place because it's linked to preserved physical function with age in large human populations. We have a clinical data set to support that, not in obesity, but in older patients at bedrest where we saw a significant rescue of metabolism and muscle as a monotherapy. So we are really excited about these other potential benefits of the drug. Those are all marked as exploratory in our phase II because for the most part, we don't really know how these change in populations. But we will be looking at muscle, fat, and bone with DEXA. We'll be looking at activity with wearables. We'll be looking at biomarkers. We really want to get as much information as we can out of this first look and use that to sort of better power future trials. Got it. And then what's next? So after this phase II, fast forwarding to sort of quarter next year, Lilly take a look, may or may not decide to step in, and then you're going to continue to push forward this program. But what will the next step look like? Because understanding you are also running another phase II/III for the semaglutide combination, which can qualify one of the pivotal studies. So tell us about your current working assumption about the pivotal program looking like for azelaprag. Yeah, that's right. We're initiating another study with azelaprag and semaglutide as a combination in the first half of next year. And the goal is related to sort of really our ultimate goals for this program. And there's really sort of two potential future paths for azelaprag. This mechanism really shines in combination with an appetite suppressant, right? And we don't have an incretin internally at the company. But there's actually a very valuable go-it-alone strategy, which is our base case that we're executing against, which is to pursue an incretin-agnostic label. There's a lot of precedent, for example, with drugs like PCSK9 against a variety of statins, right? So what we're doing right now is basically combining azelaprag together with those incretins approved for weight loss. That's tirzepatide and semaglutide today. As you mentioned, the semaglutide trial we're initiating in a few months is potentially pivotal in nature because it has that full year of weight loss dynamics. But the goal would be to pursue an incretin-agnostic label so that azelaprag could be used by patients in conjunction with any incretin, either injectable or oral, right? So that's sort of the company go-it-alone strategy. And of course, it could be interesting to someone with an incretin, with a small molecule incretin, to think about bringing in the product to build like a fixed dose combo pill. So that's the other potential way forward for the drug. Yeah, yeah, sure. And then in terms of this incretin-agnostic label potential, how big the safety database is going to look like given you are combined with different combos? So any preliminary discussion with the FDA in terms of the phase III program going to look like? We do have a lot of precedent from the incretin space, but not at the combination. Yeah, sure. No, so we haven't discussed the phase III design with the agency at this point, though we are working with several ex-FDA metabolic regulatory experts. And there's very clear guidance from FDA in terms of what you need for an approvable package in the obesity space. So the hurdle is a 5% incremental weight loss. That's why that's the primary endpoint in the trials we're running. And overall, you also need 3,000 patients exposed to the drug for a total of one year. So keep in mind too, like the sizing of our phase II trials to achieve that 90% power, it's 200- 300 patients, right? So if we're looking at three-ish incretin agents in phase III, that's a few hundred patients. And then there's other patient subsets. There's lots of room basically, right, in the approvable database you need to gather the information that we need. But as long as it's exposed to the azelaprag, it doesn't matter which combination you're going with. Correct, right? Or you could even look at rebound with some of them. Or there's a few different interesting experiments you could run. Got it. Got it. Okay, good. And then in terms of how azelaprag will fit into the future landscape, it's good. I cover a lot of these mid-cap obesity companies. You are not really their competitor because you potentially can be the add-on. But what's the use case there? So like you discussed earlier, as an induction combo, maybe later on become a maintenance, longer duration, longer interval. But how likely you will become a monotherapy at the maintenance? Because a lot of the GLP company also want to be the maintenance therapy at the monotherapy. So how should we think about that? And then another provocative question is, given the mechanism, how likely you're going to sequence the combination? Should you use apelin first or GLP first? And then what's the right way to combine? That's another layer of the question. Sure. So to your first point, like the first big opportunity is really in that initial induction regime. And this is pretty unique. Like a lot of companies are very actively interested in building the best performing weight loss pill, right? And we're in a fairly unique position in terms of what can you combine together with a small molecule incretin to amplify, improve its performance from a weight loss perspective, as well as potentially tolerability and body composition. So that's really our initial focus. And the reason for that is obvious too, right? Like there's very strong price pressure. It's very expensive to manufacture peptides, whether injectable or oral. These are very straightforward small molecules, right? There's a very strong cost of goods advantage, especially as you think that these are all long-term therapies, right? These are not one-and-done medicines for most people. And that sort of gets to your question about the maintenance phase. There's sort of less clarity on what that would look like from a trial design perspective, from a regulatory perspective. It's great to see that Lilly's doing some of those trials with orforglipron, right? So we think that, I mean, you've seen the real-world evidence, right? People don't like to stay on incretins for very long outside of a clinical setting because the AE profile where they see the most effectiveness is not great, right? So I think the maintenance regimen has to be very different. I think there's going to be a lot less sort of tolerance for some of these side effects. So we see ourselves as potentially playing a very important role there. Again, like probably in combination with like a smaller dose of an incretin, right? Because with incretins, it's very much dose-dependent tolerability, right? So if you could have a very low dose that is pretty mild in terms of its AE profile, that could still help potentiate the benefits of azelaprag. It's always interesting to imagine what's next. In the next five, 10 years, everyone going to be on incretin and then maybe adding on the apelin. So because you do have this preclinical model to support, you can prevent the weight gain post the incretin. That's the rationale. Got it. Okay, good. And then so another interesting question is, as far as I can know, I know not many apelin agonists in clinical development. So why is that? And then how did you get this drug? And then how differentiated compared to other apelin in the? Yeah, for sure. So it's a newer target, right? There's really only one other APJ agonist in the clinic that's earlier stage. And especially a newer target in obesity, I would say. And that's probably partly due to the fact that you don't see profound weight loss as a monotherapy, right? Like you really see this very potent effect in synergy. So I expect that to change. But there's still a pretty thin field of other molecules that are advanced at this point. And we're differentiated there too in the fact that this drug has been in over 260 people. It's very well tolerated as a monotherapy. That's an important point of differentiation versus other complementary mechanisms in this space. Very clean tolerability profile as a monotherapy. Yeah. How about on the molecular level? So understanding you are not biased towards or away from the beta-arrestin, why is that important? Any other molecular difference compared to other apelin programs? Sure. So our molecule is an unbiased agonist of APJ. So in that sense, it's recapitulating what natural apelin does. And there's a couple of reasons that we favor that approach. One is sort of that's where the evidence is, right? If you're looking at the genetic models, where they have upregulated apelin, you're looking at all the downstream effects of apelin, not only the sort of some biased subset. And what you brought up is beta-arrestin, right? So like there are some other molecules where they bias them away from some of apelin signaling, which is the beta-arrestin pathway. And there was a theoretical rationale to do that because people thought, oh, if we're activating beta-arrestin, there's a risk of receptor internalization, desensitization, a risk that hasn't borne out empirically. Amgen has done multi-month studies in animals, month-long studies in people with this drug, with no diminution of effect. And similarly, at BioAge, and you would see that happen over the course of a day. There's sort of no downside to activating beta-arrestin. And in contrast, there is metabolic upside. Just from the last few years, there's some very nice genetic work showing that activating beta-arrestin signaling specifically in obese animals has metabolic benefits. We think that's an important aspect of apelin signaling that you really want to capture everything that endogenous apelin is doing. Got it. Okay, very good. And then we all agree obesity is a massive population. Now also people try to target specific kind of subpopulation. How should we think about the apelin can fit into the future, maybe slice the pie of the overall population, some comorbidity, maybe some additional indication associated with obesity? Yeah, that's a great question. So apelin is linked, you know, it's not just a weight loss mechanism, right? There's actually a very large, there's a couple of different indications that are important obesity subpopulations where we think the mechanism has an extra chance to shine. And that's diabetes and also heart failure. So there's very extensive genetic evidence linking apelin to insulin signaling. The apelin knockout animals, for example, have lots of visceral fat, have worsened insulin resistance. And there's even a small clinical experience, a trial out of Inserm in France, where they infused apelin into overweight men and saw significant benefits in a glucose clamp design. So we think this is really interesting. Diabetic obesity has been harder to crack from a weight loss perspective. And taking azelaprag as a combination into that population, there should be the benefits from the additive weight loss, but also potentially separate mechanistic benefits from azelaprag itself. And that's why we're doing a POC study in that population as well next year. And the other one, of course, is around heart failure. So I don't think I gave the history, but this drug, azelaprag, was initially developed by Amgen. They took it as far as phase I only. Over 200 people, mostly healthy volunteers in a small cohort, two dozen people with a mixture of heart failure types that were followed out on drug for one month. They looked at biomarkers after that point, saw some small improvements. These data are published. And then sort of cut the program along with some other ones in the same division. There's actually very nice mechanistic and preclinical evidence linking it to benefits in heart failure. Obese HFpEF is also a really interesting subpopulation for the mechanism. Yeah, absolutely. Okay. As expected, we spend most of the time on the azelaprag, but you do have a pipeline in the discovery platform. Maybe spend the last couple of minutes about NLRP3. So where are you at that program and why this is exciting? Because we do see a lot of the activity out there. And also based on your discovery platform, what the additional pipeline upcoming in the coming years? For sure. So yeah, NLRP3 is an exciting target, emerging target in metabolism. And it looks like CNS penetrance is essential. And there too, this is the company's first internally discovered compound. We've been working on NLRP3 for several years because, again, of the link to positive functional outcomes in large human cohorts. That's what gives us confidence about a target. So the key things to know about our program, we've been given guidance that we're filing IND in the second half of next year. We have potential best-in-class potency. And we also have a novel binding site that we're expecting to publish for our collaborator over the next year. And following that, we'll go into a phase I SAD/MAD experience as well as a monotherapy obesity cohort. The other thing that is especially interesting for BioAge is that NLRP3 looks to be an appetite suppressant and azelaprag is additive with appetite suppressants. So it's early days yet, but we're excited to look at combination performance as well. Okay, noted. So it's a potential self-combination opportunity there. So the key differentiation is the novel binding site and. Better potency. Better potency. Got it. Okay. And then you do have this aging-based kind of biobank and then have the target discovery platform. So how should we think about how quickly you can turn the new target into the pipeline and then what we're going to see in the coming years? Yeah, definitely. So for those less familiar with the company, we've invested a lot in building some pretty unique human cohorts that have longitudinal samples collected over 50 years of aging from middle age onwards. And that means that we're able to go into those historical samples and say, what's different in those humans who live longer, are physically functional longer, mentally functional longer than the rest of us? What are those changes? And it's a way that we get conviction around the targets that we pursue in terms of their translatability and also their potential for sort of safe intervention. So that's NLRP3 and apelin, check that box. We have two additional earlier stage programs at the company that, again, are targets that emerged from the platform who are building novel molecules where they will have applications and metabolic indications, but they're earlier stage. So no specific guidance yet. Got it. Are they known target or it's completely new target? Pretty novel, yeah. Okay, got it. Thank you. I think that's it for today, and then thank you for being here and thank you everyone listening and attending. Thank you. Thank you.