Hello, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the Botech Analyst here, and it's my pleasure to introduce the team from BioAge Labs. To my immediate left is BJ Sullivan. He's the Chief Strategy Officer. To his left is Dov Goldstein, the CFO. Just as a reminder, format for today is a fireside chat, but if anyone in the audience has a question, please raise your hand and we can try and address it in our discussion. Before we get started, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, BJ and Dov, thanks for sharing your time with us today. Maybe to kick things off, I'll just hand it over to BJ who can make some introductory comments, and then we can get into the Q&A. Sounds great. Thank you for having us. Just to introduce the company briefly, BioAge is a platform biotech company. We apply the biology of human aging to identify targets for cardiometabolic disease. Our lead program is BGE-102. It's a potential best-in-class NLRP3 inhibitor. We shared data earlier this year from an extended phase I that we ran, where we were thrilled with the profile that emerged across several key dimensions. One was the magnitude of biomarker reductions that we saw in obese, inflamed individuals. Two was the dosing paradigm, with 60 mg able to achieve 24 hours of IC90 coverage, and at 120 mg achieving essentially complete target inhibition at trough, 98%. The safety tolerability profile that we observed, really we thought it was exceptional. Lastly, one of the key differentiators of this molecule is its tissue distribution and ability to access protected compartments like the CSF as well as the retina, and so that certainly informed our indication strategy that we'll get into in a little bit. So that's our lead program. We have two phase IIs that are ongoing with BGE-102. One is QUELL-CV, which is a dose-ranging trial in obese individuals with elevated inflammation. There, we're going to be looking at cardiometabolic biomarkers, inflammatory biomarkers, teasing out a dose response, and building the safety database over an extended treatment duration, so over three months. We'll have that top-line data at the end of this year. We also recently dosed the first patient in our QUELL-DME trial. This is a trial looking at BGE-102 in diabetic macular edema, and it is similarly three months of treatment across three arms, so looking at BGE-102 as a monotherapy as well as in combination with VEGF. There, we recently actually announced that we had increased the size and the scope of the trial to power for best-corrected visual acuity. This is now, we are now looking at that as a primary endpoint, visual acuity, with 90% power to show a four-letter improvement. That trial is now enrolling, and we are expecting data by the end of next year. Yeah. Right. So that is our BGE-102 program. We also, behind that, are developing a family of APJ agonists. This is, APJ is a target that was derived from our platform. It is one of the most strongly correlated with both longevity as well as preservation of physical function. We showed with a prior molecule very, very nice preservation of muscle integrity in bed rest. Pre-clinically, with APJ agonism, we see a doubling of weight loss on top of a GLP-1 and complete restoration of lean body composition. We are developing both an oral small molecule as well as a parenteral APJ agonist with the goal of addressing both segments of the GLP-1 market. Yeah. Great. Thanks for that introduction. A lot to sort of dig into there, but maybe just start at a high level, maybe talk a little bit more about your platform, how it works. Also maybe touch on your collaborations, too. Mm-hmm. Yeah, so our platform is sort of the central thesis of the company. I think everyone is familiar with biobanking as a concept. It has taken off in recent decades. I think we are very focused on human aging, and the key variable there is time. We partnered with some of the world's leading biobanks that have been following patients for decades, starting from healthy middle age through, in many cases, death, and then charting, doing sort of detailed phenotyping along the way, physical function, cognitive function, and then doing serial sampling as well. So we can now go and follow those samples, apply modern omics technology, and ask the question, what is the biology that is predictive of good outcomes and vice versa, right? That really informed a lot of our therapeutic hypotheses. Yeah. And maybe just to touch on the collaboration. Sure. On the platform side, we have a collaboration with Novartis. This is really around target discovery, where we're looking at the intersection of human sort of healthy aging, and that's our contribution to the collaboration, and they have some very rich exercise intervention datasets. We are trying to identify targets at the intersection of those two things. Yeah. We also have a collaboration with Eli Lilly, and this is a molecule discovery collaboration. We are looking for, we are building molecules against novel targets that have emerged out of our platform. Yep. I want to dig into BGE-102, but maybe just a follow-up question just on the platform and targets. I do not know if you can talk about pipeline or other maybe targets you are considering looking at sometime in the future or how you think about that. Yeah, we haven't disclosed the more novel targets. Yeah. I mean, those are. I think as those programs mature, we'll sort of share more information. Yep. Makes sense. Now if we just shift to BGE-102, as you mentioned, your lead asset, maybe just give us a quick background there and maybe focus on sort of the mechanism of action and how it works. Yep. NLRP3 is an inflammasome, and so this is really the key mediator of sterile inflammation in the body, and so you can think of that as in the absence of a pathogen. In the context of, for example, metabolic stress or nutrient abundance, hyperglycemia in the case of DME, these all activate the NLRP3 inflammasome, and that triggers an inflammatory cascade that results in sort of maturation of IL-1β and further downstream IL-6. It also importantly controls an inflammatory cell death process called pyroptosis. This is a target with broad utility in a range of diseases that are driven by inflammation. Folks have been trying to drug this target for 20 years at this point, starting with MCC950, the Pfizer compound, and we really feel like we are able to reach escape velocity now with this probably fourth generation approach that we have. I think if you think about the evolution of this space, there was the original molecule, there were subsequent generations of compounds trying to remove the alerting structures and improve the safety profile, then entirely new chemistry going after the same binding site. What we did was we actually did a DNA-encoded library screen and blocked the existing binding site to find totally new binding sort of domains in NLRP3. That is the origin of BGE-102. This is a homegrown program. We have a differentiated mechanism of action in that it is able to inhibit both the active and inactive inflammasome, that that binding site is available in all of its conformations. Importantly, too, we have a very broad IP estate around this molecule as well as the chemistry broadly, and actually have issued IP for ligands that broadly interact with this binding site. So we think it is a really differentiated mechanism, and we feel very strongly about our sort of IP position around it. Yeah, great. Just given the mechanism of action and kind of the inflammation piece, can you talk about the opportunities and where you can go with that and sort of how you came to deciding your current pathways and kind of where you are focused on today? Mm-hmm. Right. So, a lot of what we are doing is looking for at least sort of preliminary de-risking signals from the cytokine experience and sort of cytokine neutralization strategies. So where have IL-1β or IL-1, generally speaking, strategies been efficacious, or IL-6 inhibition? Then where do we think that those cytokines are primarily attributed to NLRP3 activation in that disease context? Then, where do we think we can provide differential value, whether it is through a more attractive route of administration, a safe and well-tolerated daily oral, or actually providing differentiated biology and going upstream and being able to capture not just the best described canonical IL-1β, IL-6 axis, but also IL-18 and this pyroptotic cell death. Right? So we think we can differentiate on both of those fronts. I am sure we will talk about ZEUS and ASCVD. Yep. That was sort of a shock to the system, I think, for everyone, and certainly the cardiovascular community, and very disappointing for patients, truly. We can talk about the implications of that, but I think beyond that, we are looking at diabetic macular edema and ophthalmology indications where there has been success with cytokines. Again, we think we can provide incremental value, and I think the biology, for example, in DME, the inciting event is hyperglycemia, and that is sort of a canonical activator of NLRP3, so we think the biology harmonizes very nicely. We are certainly exploring a variety of other indications where this could be sort of a valuable approach and thinking about, again, the sort of the framework we are applying is, where has there been de-risking cytokine experience? Where do we think that that experience is downstream of NLRP3? Where do we feel that the development opportunity and feasibility and then the commercial opportunity, the risk benefit makes sense for sort of a company of our profile? Yeah. No, makes a lot of sense. Maybe we can dig into the ASCVD, the phase I-B data you shared earlier this year. You touched on it already, but maybe just what were the key findings there, and how does that sort of translate into your thoughts moving forward? Yeah. So the phase I data that we shared earlier this year, there was a sort of a standard SAD/MAD component, and then we also did two cohorts of obese individuals with elevated inflammation. We treated those individuals for 14- 21 days, and there we saw rapid reductions in hsCRP, a sort of a systemic inflammatory marker, 86% in actually both cohorts, and sort of concordant reductions in IL-6 and fibrinogen. Importantly, we saw at the 60 mg dose, you get 24 hours of IC90 coverage. So really nice target inhibition. At the 120 mg dose in phase I, which actually corresponds on an exposure basis to the 90 milligram dose we are testing in this longer duration trial, you get essentially 98% target inhibition at trough. If we need to completely inhibit the target, we feel that we can do that, and we can do that with a very tractable once daily dose, and a dose that then in phase I was exquisitely well tolerated. Yeah. Right? I think we see really nice alignment across all of those dimensions coming out of the phase I. We also did lumbars on those patients and saw exposures at the 120 mg dose that were 3X the IC90. So we are able to really potently inhibit the target across compartments and do that in a way that is very well tolerated. Yep. Makes sense. You are going to be sharing, I think, updated phase II data from QUELL-CV later this year. Maybe just talk about what is the key goal of that study and what you are hoping to learn there. Yep. There are several goals. QUELL-CV is our dose ranging trial, for peripheral inflammation. It is a similar patient to the phase I, obese, inflamed individuals, where we are testing three doses of BGE-102, so 30 mg, 60 mg, and 90 mg. 90 mg at steady state is going to give us, we expect, 98% target inhibition at trough, so complete pathway shutdown. By contrast, the 30 mg dose we think will give us sort of a suboptimal biomarker response. So we are really trying to tease out the dose response in terms of the expected panel of inflammatory and metabolic markers. We will be adding additional assessments compared to the phase I. For example, we will be doing MRI imaging of the liver and looking for the inflammation CT-1 signal, for example, where ventyx showed a benefit, that was as monotherapy and additive to GLP-1. We'll be looking at A1C and just a variety of inflammatory and metabolic markers there. Importantly, also looking at safety and tolerability over this three-month treatment duration, right? We're really hoping to extend the findings that we observed in phase I and that profile over a longer treatment period. Understood. You mentioned earlier ZEUS and maybe talk about your thoughts on what happened there and then how that impacts how you think about your program. Yeah. I think importantly, we do think NLRP3 is a very distinct target from IL-6, and it would've been fabulous had the For context, there was the IL-1β experience in the CANTOS trial with canakinumab. There was a 15% MACE benefit as the headline number, in patients who achieved CRP reductions through IL-1β. Below a sort of a normalization threshold, there was a 25% benefit. So we know that intervening in inflammation, targeting inflammation can work. It's a matter of what is the right target. Potentially, which are the right patients. ZEUS, obviously this was the Novo IL-6 agent in CKD patients with ASCVD, had a hazard ratio of 0.99, so essentially no treatment effect on MACE. There were some questions going into the trial. Is it the right target? Yeah. IL-6 is downstream of IL-1β. If you think about the context, NLRP3 is activated in a plaque, induces a local IL-1β signal, and that translates into a systemic IL-6 signal. Is the relevant biology at the plaque level and not at the systemic level? That's a question. Within the trial itself, there were questions of, are these patients too severe, essentially, to have a benefit? Is the risk not modifiable at that stage? These are patients with, in some cases, very severe CKD, and so at that point, has the train left the station, so to speak? By targeting inflammation, it's just not modifiable at that point. That question remains, and we may know more when we anticipate ZEUS will be presented at AHA. The other question was, between CANTOS 10 years ago and now, there's been an introduction of GLP-1s and SGLT2s, and would the drop-ins reduce the residual risk? Without having seen the data, Novo did include in their press release with the trial, that that wasn't the case and that didn't impact the result. I think that there's certainly more that we'll learn from the full ZEUS readout, hopefully later this year. Novo terminated the two half trials that they were running, one outcomes trial, one functional trial. ATHENA and HERMES were those two trials. The DSMB thought that it was unlikely it was going to achieve a different outcome to ZEUS. There is another trial ongoing, which is the acute post MI trial. This is ARTEMIS. That one, they reiterated guidance that we're going to get that data in the first half of next year, and that's a very different patient population from ZEUS. I think it'll give us a window in helping us understand, was it not the right patients or is it not the right target? More on the horizon, although, it's interesting, the strategic posture, even Novo in the immediate aftermath of that news was proactively touting NLRP3 as potentially a better target for the reason that it is capturing the upstream biology that IL-6 may be missing. Yep. Right. I think that there are questions to be answered in the coming months— Yep. —on that front. What does it mean for us? We were preparing for a phase III outcomes trial initiation in the second half of next year. Given this news, we have put that on pause for now. We are looking at additional different indications that, again, have been de-risked by cytokine neutralization experience that we think are predominantly downstream of NLRP3 and have an attractive risk-benefit profile. That is our focus now, and we have indicated we intend to share at least one additional indication by year-end. All of that preparedness is, we can turn that back on should there be a de-risking signal, and we get more confidence and clarity on the go forward in ASCVD. The net of it is, we actually think that in a way, the negative result very much supports the upstream biology. Yeah. We will know more with the full ZEUS data and then ARTEMIS data in the first half of next year. Got you. Great. Maybe we can shift now just to ophthalmology. You talked a bit about it earlier, but maybe to start, just the rationale for going into DME, the unmet need. The advantages of your approach there. Yeah. I think that there's one aspect that I want to highlight, which is just that we have the molecule that can address this indication. As I mentioned, we have really nice tissue distribution, and we've shown that in a range of preclinical species. We've sort of validated the CSF exposure in our phase I. Going after ophthalmology generally is our way of taking advantage of that distribution profile and the ability to address these indications in these protected compartments. I think that that was important for us as we think about the development plan for BGE-102. In thinking about DME specifically, it's initiated by hyperglycemia. It's diabetic macular edema. Hyperglycemia and metabolic stress in the retina actually activate the NLRP3. That's sort of a canonical stimulus for NLRP3. Not only induce a cytokine cascade that culminates in IL-6 in the retina, but also controls this inflammatory cell death process. What we've observed in preclinical species is that when you induce hyperglycemia in a mouse, you sort of recapitulate the DME phenotype. When you treat with oral NLRP3 inhibitor, an analog of BGE-102, you get complete rescue of retinal vascular permeability, so just sort of fluid leakage into the retina, as well as total rescue of the integrity of the microvasculature and endothelial cell tight junctions, and the integrity which is compromised by hyperglycemia. We think that, again, we were motivated by the IL-6 experience in DME. Targeting inflammation corresponds with benefits in visual acuity. We think that there's value and there's incremental biology to targeting NLRP3 and going upstream in addition to being an oral. There's data with canakinumab, there's data with mouse genetics suggesting that NLRP3 inhibition or targeting this pathway can improve glucose control, actually. It's not just a convenient way of getting to the eye, but it may actually benefit the key risk factor for DME as well. We think that there's really a nice alignment there with our approach. Our trial now, QUELL-DME, it's a three-month trial, and we're looking at both BGE-102 monotherapy as well as on top of VEGF. This is really informed by the IL-6 experience in DME. We're powered now at 90% for a four-letter improvement in BCVA, and we think about that is clinically meaningful and would support advancement in DME, especially if you think about delivering that benefit in a safe and well-tolerated oral. The DME landscape is one where half the patients are sort of in a watch and wait category, where they have edema, but they don't have sufficiently compromised visual function that they want to go and get monthly or quarterly intravitreal injections. These are often working age people, and it's a huge patient burden. Yeah. Even patients who've initiated intravitreal therapy are often non-compliant with the dosing schedule, so the real world treatment outcomes differ substantially from what you see in a trial. There, I think, a really exciting opportunity would be for those early patients, can you delay initiation of intravitreal therapy? Then on the other end of the patient journey, for patients who are on an intravitreal therapy but don't have sufficient disease control, can you add this mechanism to give you better sort of correction of visual acuity. Yeah. Right. We think about QUELL-DME specifically as a proof of concept in this indication, but also more broadly as a sort of a beachhead into ophthalmology generally. We're looking for BCVA improvements, but we're also doing a variety of exploratory endpoints, OCT imaging. We're looking at intraocular biomarkers, so we want to demonstrate more broadly a clear pharmacodynamic effect in the eye, because there are indications like geographic atrophy where NLRP3, we think, has a very important role. This'll inform DME specifically, but also the broader ophthalmology strategy more generally. Yep. Great. I guess, assuming you get positive results in DME, what would be the next steps there? Like a full phase III, or how would you? Yeah. No, absolutely, as well as sort of expansion into other indications— Yeah. —in ophthalmology, and I think it's attractive because we feel that we can develop through NDA here and potentially commercialize as well. We think it's a therapeutic area that lends itself well to a company of our scale. Yep. Yeah. That's something you would consider sort of commercializing on your own, or you think a partnership is the way, or? Yeah, I think all options are on the table. Yeah. But I think, a go it alone is certainly feasible from our perspective. Yep. Makes sense. Maybe we can shift now to just the APJ agonist. You gave us a little bit of it in your prepared remarks, but I guess, what's different this time maybe? Let's start there, and what are the next steps? Yep. So as a reminder, APJ, it's the receptor for an exerkine called apelin, and so it's secreted by the muscle during exercise. This peptide is, again, one of the strongest signals in our cohort for longevity and preservation of physical function. We had licensed an APJ agonist from Amgen, and they're demonstrated very profound muscle preservation at bed rest. We did a trial in obesity and there was idiosyncratic DILI related from all expert feedback we got to the compound. So we have very high conviction in the target, and so right now we're pursuing both an oral small molecule as well as a parenteral approach to APJ agonism. The oral small molecule is a totally distinct chemotype. We're targeting the same biology with a totally different chemistry in a low oral dose. With the parenteral, we've disclosed a collaboration with JiKang Therapeutics in APJ agonist nanobody. We think what we're trying to accomplish here is improving with the GLP-1, both the quantity and quality of weight loss, and in our preclinical data, again, you get a doubling of weight loss with the GLP-1 and you get complete restoration of lean body composition. In looking at where the market stands now with GLP-1 and the unmet needs there in the oral small molecule space, I think that there's certainly orforglipron disappointed, I think, in terms of the headline weight loss number not really being in line. It's a compromise in terms of weight loss. There having incremental weight loss is probably value proposition number one, and body composition is value proposition number two. I think on the parenteral side, it's the opposite now that we've achieved bariatric surgery-like weight loss. The body composition element, I think remains an unmet need. Importantly here, too, our prior experience suggested that there's no tolerability issues associated with APJ agonism. If you think about that in combination with GLP-1, I think that's really important. In looking at some of the more anabolic mechanisms that have tolerability profiles that are more similar to GLP-1 as monotherapies, the prospect of combining may be a lot to ask of a patient. Our experience certainly supports really no tolerability issues of any kind and certainly not any GI issues. We think the complementarity of these mechanisms is very high. Yeah. Very interesting. Maybe in the last couple of minutes here, we can just fire off some of our survey questions we've been asking all our biotech companies. These questions are in key theme areas. I guess the first one is just China, what's your thought on innovation coming out of China? Or how does it impact your R&D approach or BD playbook? Yeah. From a BD perspective, we have a global view. As we've talked about, we have a collaboration with JiKang Therapeutics out of China, and we're certainly, again, we have a global view. In terms of competition, at least on the BGE-102 side, I think one of the key advantages of this program is, again, because it was a totally novel chemistry, a novel binding site, and we have a really broad IP estate around that. We have issued IP for broadly covering ligands, sort of interacting with the binding site, and we feel like we're really well-positioned from a competitive perspective there as well. Yep. Great. The second question is in an area that keeps getting more interest by the day. It's just AI, implementing AI, and where you've used it and where you might use it in the future. Yeah. No, this is a definite question of great personal interest. AI for the company has been part of our DNA since our inception. I think on the data science side and the platform side, Yep. it's always been there, right? I think this is not novel. I think the LLMs and this has been a huge area of focus for us. For us, it's not that any process or activity, there's not going to be sort of a magic bullet, but it's more about how do we incorporate this and incentivize this as part of our ways of working. It's a change management thing more. Yeah. question as much as it is a technical question. How do we encourage aptitude here and incorporate this again into our ways of working? I think we have made great strides here, so really across the company. It is not just the platform, it is every function now. We are encouraging and certainly promoting use of a variety of AI tools. Great. Then maybe the last one here is just which policy variable, whether it is FDA, Medicare negotiation, MFN, tariffs, or global pricing sort of matters most to you? I think it depends week to week. Yeah. Okay, great. We are just about out of time, so why do not we end it there?