Good afternoon, thank you for joining us today for BioAge Labs R&D Day. I'm Chris Patil, VP Media at BioAge. Before we begin, I would like to remind everyone that during this call, we will be making forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are based on our current beliefs, plans, expectations, and assumptions as of today, and are subject to risks, uncertainties, and other factors that could cause actual results to differ materially from those expressed or implied by such statements. These risks and other factors can be found in our most recent annual report on Form 10-K, quarterly reports on Form 10-Q, and other filings we have made with the Securities and Exchange Commission. We encourage you to review these filings, as well as the full forward-looking statements disclaimer on the next slide for a more complete understanding of the risks associated with our business. We undertake no obligation to update or revise any forward-looking statement, whether as a result of new information, future events, or otherwise, except as required by law. A copy of the presentation materials for today's call are available on the investor relations section of our website at ir.bioagelabs.com. Welcome to BioAge Labs R&D Day. Today, we'll be presenting an update on our lead program, BGE-102, our oral brain-penetrant NLRP3 inhibitor, including our Phase I clinical results and our development strategy across cardiovascular and retinal disease. We're joined today by members of the BioAge management team and by four leading external experts who will share independent perspectives on the science and clinical opportunity. Joining from BioAge are Dr. Kristen Fortney, our Chief Executive Officer, Dr. Paul Rubin, our Chief Medical Officer and EVP of Research, and Dr. Dov Goldstein, our Chief Financial Officer. We are also joined by four distinguished guest presenters, Professor Matthias Geyer, Director of the Institute of Structural Biology at the University of Bonn, Dr. Michael Davidson, Professor and Director of the Lipid Clinic at the University of Chicago Pritzker School of Medicine, and CEO of New Amsterdam Pharma, Dr. Brian Hafler, Associate Professor of Ophthalmology and Visual Science at Yale School of Medicine, and Dr. David Boyer, Senior Partner at Retina-Vitreous Associates Medical Group. Here is how today's presentation will flow. Kristen will open with a brief introduction to BioAge and our lead program. Professor Geyer will then share structural biology insights into BGE-102's unique mechanism. Paul will walk through our Phase I clinical results in detail, followed by our cardiovascular development strategy. Dr. Davidson will speak to the role of inflammation in atherosclerotic cardiovascular disease. Paul will then introduce our ophthalmology program, and Dr. Brian Hafler and Dr. David Boyer will provide their perspectives on NLRP3 and retinal disease and on the DME and GA treatment landscape. Kristen will close with our pipeline and near-term catalysts, after which we'll take questions from the analyst community. With that, I'd like to turn the call over to Dr. Kristen Fortney, our Co-Founder and CEO. Kristen? Thank you, Chris, and thanks everybody for joining today for our R&D day, where we'll do a deep dive on our lead NLRP3 program, our science, and the indications we're pursuing. At BioAge Next slide. At BioAge, we're harnessing the biology of human aging to develop new therapies for cardiometabolic diseases. We built BioAge in one of the world's largest longitudinal human aging datasets. That platform, validated through ongoing partnerships with Novartis and Lilly, has produced a pipeline led by BGE-102. BGE-102 is our oral brain-penetrant NLRP3 inhibitor. A potential pipeline-in-a-pill targeting efficacy in line with injectable anti-inflammatories across multiple indications. On the cardiovascular risk front, we've already demonstrated potential best-in-class profile for CRP reduction. We've seen basically an 86% reduction in CRP in obese subjects, and 87%-93% of subjects achieved normalized CRP below 2 mg/L. This is the critical threshold that we believe will correspond to cardiovascular benefits. On the ophthalmology side, therapeutic retinal exposure of our drug enables oral treatment of diseases including diabetic macular edema, where intravitreal anti-IL-6 has shown benefit. We have a very catalyst-rich year. Our cardiovascular risk trial is starting soon and will read out by end of year, and we're also starting middle of this year our DME trial. Beyond NLRP3, we're also working on APJ agonists. This is an exercise in medic for obesity that has the potential to increase weight loss and help improve body composition, and we're on track for IND submission by end of this year. Next slide. Chronic NLRP3 activity drives disease and predicts pure human longevity. NLRP3 is known as a master switch to innate immunity, when it's chronically activated by metabolic stress, it can drive sustained inflammation that's directly linked to cardiometabolic disease and shortened lifespan. We see this strong signal in our human cohorts, as you can see here on the top right, where individuals with elevated NLRP3 are predicted to live shorter lives. There's a very nice human genetic signal, where Mendelian randomization analysis links NLRP3 expression to heart failure. Next slide. Our lead program, BGE-102, is well-positioned to address diseases driven by inflammation in both the CNS and the periphery. BGE-102 is a potent, structurally novel oral brain-penetrant NLRP3 inhibitor, our Phase I data shows it has the attributes needed to address inflammation-driven disease across multiple organ systems. Just to walk you through a few of the highlights here, we have potential best-in-class potency, as demonstrated by our 1 nM IC90 in the human ex vivo whole blood stimulation assay. We've shown 24-hour IC90 coverage at the 60 mg once-a-day dose. And as I already mentioned, we've seen really profound potential best-in-class CRP reductions, with 87%-93% of subjects showing normalized CRP reduction after two to three weeks of treatments in line with anti-injectable anti-IL-6 drugs. To date, we have a very attractive safety and tolerability profile from our safe Phase I study. All AEs to date mild to moderate, self-limited, and no dose dependency. We have large safety margins coming out of our three-month GLP tox study. We also have potential best-in-class CNS penetration with a 0.7 Kp,uu,CSF and a very strong IP position for our novel chemistry. Next slide. One of the unique features of our molecules is our novel binding site. As you can see on the left here, this binding site indicated in purple is where many of the other NLRP3 inhibitors bind, including MCC950. In contrast, BioAge has a novel binding site which leads to potential advantages. We can bind to both inactive as well as active NLRP3. On the bottom right of this slide are three papers that we put out over the past couple of years about our novel chemistry, novel biology, and also novel binding site. I'm gonna hand it over now to Dr. Matthias Geyer, our structural biology collaborator, to take you into more depth on our novel binding site. Thank you very much for the invitation and for having me here. What I would like to show you in the next couple of minutes, is a new way to inhibit the NLRP3 inflammasome. There are three ways that makes the BGE-102 compound different from any other compound that is in the clinic. At first here, this is human NLRP3. It consists of three domains. You see the regulatory NACHT domain, you see the sensory LRR domain here at the bottom, and an ADP binding site. What we discovered as biochemists and structural biologists is the BGE-102 binding site, which you see here at the top, it's close to a regulatory helix, which is required for membrane attachment, and that's where the compound is binding to. You see here in the hinge between these two domains, the MCC950 binding site, which is already targeted by the Pfizer and sulfonylurea analogs that exists since 20 years. We determined the structure, the cryo-EM structure of BGE binding to NLRP3, and that's shown here in green. You see nicely at the top how this compound glues the regulatory helix at the bottom in order to fix it and inhibit its rotation. The MCC950 binding site is shown here in the hinge. The site is less accessible in between these two domains. Looking at these binding sites, the NLRP3 protein exists in at least three different conformations. What you see here to the left is NLRP3 bound to ADP. That's the inactive state. Upon a priming step, which can, for instance, be a phosphorylation, the activation occurs. This requires a 90-degree rotation that you see in the middle, and then ATP is being bound by this AAA ATPase. This is the active state. Only then is the point of no return. When this active state, when 10 proteins come together and form this disc assembly, which is shown here to the right, this is the NLRP3 ATP inflammasome, and that's the signaling competence state that lead to inflammation. Interestingly and importantly, the BGE-102 binding site is accessible in all three states. This means that not only the inactive state can be targeted or the active state, but even the signaling competent state, for instance, for providing degradation. That's a unique pharmacology approach because it's able even to target hyperactive mutations of these proteins. The third feature is that BGE is selective for NLRP3 specifically. There's not just one NOD-like receptor NLRP3, but 22 in humans. There are 14 NLRPs and another eight NLR, like NLRC. Within this family, already the closest homologue to NLRP3, which is NLRP12, has in the 26 residues that makes the binding site for BGE-102, already eight residues are different to NLRP3. You see this for NLRP10, NLRP6, and NLRP1, that they have 13, 15, 16 residues different. That's shown in this cartoon here to the right, that these different amino acids lead to clashes with the compound, meaning that basically the compound is not able to target any of these other family-like NOD-like receptors. This provides a lot of specificity for BGE-102 for specifically targeting NLRP3. To summarize this, there are three structural features that set BGE-102 apart from any other compound that is in the clinic against NLRP3, and that's the binding site here at the top is unique from every other inhibitor. The binding site is accessible both in the resting state as well as in the active disc-like conformation. Thirdly, the BGE-102 binding site is selective for NLRP3 and within the inflammasome family. With that, I'd like to thank you and thank for the attention. Dr. Paul Rubin will now walk us through BGE-102's Phase I clinical results. Thank you. Our Phase I program was a comprehensive dose escalation study in healthy volunteers as well as in obese participants. It was designed to show pharmacokinetics, pharmacodynamics, and to measure key inflammatory biomarkers, including hs-CRP. The obese cohort was particularly interesting in that patients that do have obesity are representative of patients that might be later studied in cardiovascular disease, is that they have both risk factors and have increase in inflammation. The study consisted of three components, the single ascending dose study, which consists of 36 subjects, as well as nine obese subjects. We looked at doses between 10 to 120 mg, and the 60 mg dose we looked at both fed and fasted. The multi-ascending dose cohort was healthy volunteers that included 18 subjects at 60 mg and 120 mg for 14 days, and a multiple ascending dose cohort which consisted of obese subjects where CRPs at baseline were greater than three. This was 41 subjects where we looked at 60 mg for 21 days and 120 mg for 14 days. As I mentioned, the obese MAD cohorts are particularly relevant in that they are representative of populations that we will study in the future, including cardiovascular subjects. This particular group in our Phase I was designed to mirror our Phase II eligibility criteria in subsequent trials. Next slide. Fortunately, the study met all our key trial objectives. The drug was safe. It was well-tolerated. The PK was dose proportional, which clearly supported once-daily dosing. We showed potent suppression of IL-1β, which is kind of the main marker for the activity in an NLRP3 inhibitor. We showed up to 86% CRP reductions in obese subjects, which was very robust. In general, the safety, from a safety perspective, all adverse events that were recorded were mild to moderate, self-limited, and there were no dose-limiting toxicities seen. The pharmacokinetics were dose proportional, and the half-life of this drug clearly supports a once-a-day dosing schedule. The pharmacodynamics revealed that we can achieve greater than 90% IL-1β suppression after a single dose for 24 hours at both the 60 and 120 milligram doses. Interestingly, when we measured CSF levels via lumbar puncture, we showed that at these doses, we exceeded the IC90. In obese subjects, 86% CRP reduction at both the 60 mg and 120 mg was seen, and 87% of the subjects at 60% and 93% at 120 mg showed CRP reductions that were below 2, which is considered very clinically relevant. Next slide. Across the full program, BGE-102 was very well tolerated with an adverse event profile was very similar to placebo. We only saw mild to moderate treatment emergent adverse events. They were all self-limited. They clearly were not dose dependent. There were no serious adverse events, and no subjects were discontinued because of adverse events. The adverse event rates were comparable to placebo, and as you can see, it was 61% versus 59%, which is also typical of a Phase I study. There were no clinically meaningful changes in vital signs, in laboratory analysis, or electrocardiograms. Next slide. Before going through the actual biomarker data, I'd like to orient you as to the baseline characteristics of the obese cohort. These participants had BMIs in the mid-thirties and meaningfully elevated CRPs, again, similar to the population we plan to enroll in subsequent trials in Phase II. There were two active cohorts plus placebo, 60 mg, where there were 19 subjects, 120 mg, which showed 14 subjects and placebo with eight subjects. The median baseline CRP varied between 4.85 and 6.3, which is well above the 3 mg/L high CV risk threshold. It was a clearly diverse population; this included 31.6% African American representation in the 60 mg cohort. Next slide. The obese MAD cohort safety and tolerability was also as represented here, was quite clean. We saw no signals that would cause any concern. There was a very low rate of related treatment emergent adverse events, and all of these were mild to moderate. There were no discontinuations due to drug. There were no serious adverse events or severe treatment emergent adverse events. We did not see any neutropenias, thrombocytopenia, or infections in this particular trial. Next slide. I'd now like to walk you through the pharmacokinetic and pharmacodynamic data from our healthy volunteer cohorts, which established a foundational PK/PD profile for BGE-102. Next slide. In our single ascending dose cohorts, 102 showed dose proportional PK across the 10 to 120 mg range, this is very, very good for creating a foundation as to how we want to select our dose. There was also dose proportional exposure between the 10 to 120 mg range. Next slide. With repeat dosing, both the 60 mg and 120 mg doses showed accumulation approaching steady-state trough concentrations above the IC90 for IL-1β, confirming full 24-hour target coverage with once daily dosing. Both doses maintain trough above the human ex vivo IL-1β IC90, that's at near steady state by day 14, both clear the IC90 threshold and could explain this comparable downstream biomarker effect. Next slide. An important differentiator is the fact that BGE-102 crosses the blood-brain barrier and shows CSF concentrations at the 120 mg level well above the IC90 by day 14. The 60 mg was also above the IC90 at this day 14 level. In fact, the Kp,uu,CSF of 0.7 is the best that we've seen reported. The fact that this drug does get into the brain allows us to potentially explore CNS-related chronic inflammatory conditions. The same molecule can also address retinal disease. It establishes this possibility for us having this pipeline in a pill concept. Next slide. Moving forward from kinetics to target engagement, we demonstrated 90% IL-1β suppression at the 60 mg trough and 98% at a 120 mg, which is essentially completely shutting down the target. We believe that this inhibition, which does relate to also IL-6 inhibition, and that they are clearly sequential, provides the pharmacodynamic basis for downstream decreases in both CRP and IL-6. Next slide. We looked at IL-1β suppression over a 24-hour period after a single dose, after a dose at day eight, and then again after single dose on day 14. What you can see here on day 1 is that you do see, corresponding to the Cmax, a relatively robust inhibition of IL-1β at 10 hours, but it reverses as the drug levels decrease. It suggests that this effect is indeed reversible. By day eight, where you're getting kind of approaching steady state levels, you're seeing very significant inhibition across the full 24 hours, and that's even more profound by day 14. We believe that we can achieve, and this is measured, complete inhibition of IL-1β throughout a full 24-hour period. Interestingly, when you look at the PK at day eight of the 120 mg dose, we know that if we gave 90 mg, we modeled this, you will achieve the same levels at 90 mg at steady state. We could essentially achieve the same level of inhibition using a dose as low as 90 mg. Next slide. I'd like to move on to the obese MAD cohorts. As we mentioned, we believe these are particularly relevant because they have both cardiac risk factors as well as a hyperinflamed state as indicated by increases in CRP. Next slide. As mentioned, our Phase I included two obese MAD cohorts, and we looked at a 60 mg dose and a 120 mg dose. This was specifically designed to evaluate exploratory marker endpoints in the population we do intend to treat in Phase II. As you can see, the obese population had a baseline BMI between 32 and 42, a baseline CRP greater than three. They were not allowed to be on incretins. We looked at the 60 mg dose for 21 days, the 120 mg dose for 14 days. We believe that data from these cohorts directly influence our ability to choose appropriate doses for our Phase II A study. Next slide. Interestingly, both the 60 and the 120 mg dose showed an 86% median decrease in CRP relative to placebo. This again, is the best that we've seen reported and provides us with a possibility of having a best-in-class performance. It's also comparable to injectable IL-6 antibodies. We believe that the comparability of 60 mg and 120 mg at or near the ceiling of the hs-CRP dose response curve allows us to explore both potential doses, or at least the exposures related to both of these doses. Next slide. When we look at absolute CRP levels over time, we see that both doses drive median CRP from elevated baselines down to approximately one by day seven. This is well below the 2 threshold that we believe cardiovascular benefit begins to kick in, as demonstrated by the CANTOS trial. When you look at it, in both cases, independent of the dose, you're seeing by day seven that the CRP levels are driven down to approximately one. They both perform the same way, even despite the fact that the baselines were slightly different, with the 60 being higher than the 120. This is maintained throughout the full observation period. Next slide. As mentioned, getting CRP below 2 has been shown to be clinically relevant in terms of decreasing outcomes significantly. This is an important level. When we look at the numbers of subjects that reach that threshold, we're quite struck by the consistency of the drug. We can see that 87% of those patients at 60 mg and 93% of those at 120 mg reached this level. Interestingly, we got 60%-71% were actually below 1. The belief is that where two is clinically relevant, the lower the better, where you can get continued benefit by driving this even lower. This links our data to the outcomes in the CANTOS trial. Remember, when in the CANTOS trial, those subjects that had a CRP below 2 showed a 25% reduction in MACE. Next slide. Looking at IL-6, you can see that both the 60 mg and 120 mg had significant decreases in measured IL-6 levels, ranging between 55% and 78% at 60 mg and 58% to 69% at 120 mg, and was clearly different than placebo. Again, this confirms the fact that our drug is hitting its predicted targets, that reducing IL-1β resulting in IL-6 decrease, ultimately reducing CRP. Next slide. Now, where we didn't have elevations in IL-6 as an entry criterion in the CSF for this particular trial, we did find that two subjects, when we explored these, did have elevations in IL-6. In both cases, the drug drove IL-6 levels down by day 14. We believe this is related to CSF production and reduction, and that when you compare the CSF levels to the plasma IL-6 levels, you see the CSF levels were significantly higher, suggesting that this is not just a simple case of diffusing from the plasma into the brain, and this drug is actually having an effect on decreases IL-6 in the CSF. Again, it's underscoring the fact that we can look at this drug as a potential therapy for chronic inflammatory conditions in the brain. Next slide. We also saw that both the 60 mg and 120 mg doses resulted in comparable decreases in the levels of fibrinogen, another important risk factor, ranging between 23% and 30%. In fact, taken with the CRP and the IL-6 levels, BGE-102 suppresses a broad spectrum of the inflammatory cascade, which theoretically can address multiple risk factors with a single oral molecule. Next slide. With the Phase I data as the foundation, I'd like to turn to our clinical development strategy, essentially how we plan to advance 102 into proof-of-concept studies across multiple indications. We're going to focus on our cardiovascular plans as we've recently increased the size of our planned Phase II-A study as part of our prioritization of enabling a Phase III start by the end of next year. Next slide. BGE-102 penetrates both the brain as well as the retina, and therefore, we believe we can address inflammation-driven diseases across multiple organ systems, including both the eye and the brain, as mentioned before. Cardiovascular and metabolic in the periphery is also possible, plus other diseases where you're seeing a chronic inflammatory component that is in some ways causative for these particular diseases. We can consider things like insulin resistance; we can consider MASH. All have been shown to have a link to upregulation of the NLRP3 inflammasome. Right now, as mentioned, our lead indication is cardiovascular risk, but we're also gonna be exploring ophthalmological indications as the second therapeutic area. Next slide. The cardiovascular opportunity for an oral anti-inflammatory is substantial. Inflammation is known to be an independent risk factor that's on par with cholesterol. The addressable population in the U.S. is approximately 15 million patients, and the channel dynamics strongly favor oral versus other modes of therapy. Elevated CRP increases cardiovascular risk across LDL strata. It's additive to LDL as a risk factor and not redundant with lipid lowering. 60% of the 25 million ASCVD patients have elevated CRPs. We believe that we can pursue not only the secondary prevention which has been looked at before, but potentially high-risk primary prevention, especially because oral administration allows us to do this. Like statins, which started at secondary prevention and expanded to the much larger primary prevention population, we believe we can achieve this with this mechanism. We believe that over 80% of statins are prescribed by PCPs, and that's also because of the oral highly preferable way that this is administered. We believe that this can emulate that particular lesson which has been taught by these drugs. We can look at the fact that this is oral, allows us to add these to statin regimens or combined in fixed-dose oral combinations in the future. This, we believe, will open the full primary care channel, an opportunity that we don't believe is achievable with injectable compounds. Next slide. We've designed our Phase II-A proof of concept to characterize the full dose response of CRP with arms specifically chosen to support optimal dose selection for later development. In this study, we'll have four arms, which includes placebo, 30 mg, 60 mg, and 90 mg once daily, 40 per cohort in with a 12-week treatment period. Our eligibility for this study is very similar to our obese MAD cohort, where we'll see BMIs of 32-42, CRPs greater than three, and having one additional CV risk factor in addition to obesity. The primary endpoint in this study is percent change in CRP, but a key secondary endpoint will be normalization rates. That is the number of subjects that we can reduce CRP to below 2 mg/L and below 1 mg/L. Exploratory endpoints will include Lp(a), fibrinogen, IL-6, MRI, which will look at both liver and body composition, and other metabolic parameters. We'll also get a chance to look at body weight as a function of time on this drug. We believe the 90 mg high dose is rational because, as I mentioned before, 90 mg at steady state will provide exposures that are comparable to the 120 mg dose at one week. If you recall that one week 120 mg dose provided maximal or optimal inhibition of IL-1β. We believe we can achieve that with the 90 mg dose at steady state. The other doses, along with the 90 mg, will allow us to characterize the full dose response curve. We anticipate data from this trial in the second half of 2026. We'll now turn to Dr. Michael Davidson, Professor and Director of the Lipid Clinic at the University of Chicago Pritzker School of Medicine and CEO of New Amsterdam Pharma. Thank you. I'm excited to talk to you today about a topic that I'm very passionate about, that is the anti-inflammatory strategies for atherosclerotic cardiovascular disease. Let's start with the next slide. The debate about inflammation and heart disease actually goes back more than 150 years, and we had this concern whether inflammation was associated with heart disease or inflammation was causal for heart disease. In fact, I always found myself on the other side of the debate with Paul Ridker arguing that it was just an association and not causal. Of course, over time, you know, based on data, especially the CANTOS trial, I had to change my opinion, and now I'm firmly in the camp that inflammation is causal for heart disease, and now we have exciting approaches to modify that risk. Next slide. When we discuss inflammation and heart disease, it's important to point out the concept of residual inflammatory risk. When we consider a patient in the, in your clinic or that you're evaluating for risk, you think about different types of of residual risk. It turns out that inflammatory risk is actually one of the most common residual risk factors that needs to be modified to further reduce risk. Roughly half the patients that we see have some form of inflammatory risk that puts them at greater risk for cardiovascular disease in the future. Next slide. What's the magnitude of that risk when you think about it? We can look at it in different ways, the CRP being the broader way to think about it, and then IL-6, which is the actual cytokine that induces CRP production. Both of them predict major adverse cardiac events, CV death, and total death across multiple trials. This is from the STABILITY trial, which had a very large data set to consider both CRP and IL-6 for predicting cardiovascular events over three years. Next slide. What is this residual risk as it compares to other residual risk factors like elevated LDL or elevated Lp(a)? Of course, both LDL and Lp(a) are very important targets of therapy. LDL has been our mainstay of preventing cardiovascular disease. Lp(a) is an exciting novel target that has important data reading out probably this year. When we think about the risk associated with each of these modifiable targets, you can see that actually high inflammatory risk, as designated by elevated CRP, has by far the greatest relative risk reduction. Not only is residual inflammatory risk very common, but from an associated hazard ratio, it's actually the most potent of all the residual risk factors. Next slide. When you think about a patient that is before you with high LDL, you put them on a statin, and the LDLs come down, and the LDL levels are improved but still not low enough. We still talk about lower is better for LDL levels, and now the new guidelines have endorsed, you know, below 70 or even below 55 for high-risk patients. When it comes to relative residual inflammatory risk, the statin only brings that CRP level down, you know, very modestly, so that CRP remains elevated as a marker of that residual inflammatory risk. The question is, what can we do about that residual inflammatory risk? Now we have evidence of benefit for modifying that risk through the cytokine pathways. Next slide. Here's an illustration of the targets for reducing inflammatory risk. When you look at the very upstream of NLRP3 inflammasome, that's what stimulates the different cytokine release. We can target IL-1β upstream or IL-6 downstream when we think about how to improve that risk associated with cardiovascular disease. It's multiple targets to consider. I'm gonna focus right now on the IL-1β first and then talk about IL-6 next. Let's go to the next slide. This is the breakthrough for improving residual inflammatory risk, and that was the CANTOS trial. Up until this point, again, I was not in the camp that inflammation causes cardiovascular disease. It was just a risk marker. The CANTOS study changed all that. We had three different doses of canakinumab, an IL-1β inhibitor, and placebo. That was compared in a high-risk population with cardiovascular disease. The next slide shows the actual data. What we see is that the major adverse cardiac events was reduced by 15%. If you look at the typical MACE 4, MACE 3, which is CHD death, non-fatal MI and stroke, now we add in revascularization, there's a 0.83 hazard ratio of 17% reduction of cardiovascular events. The point though is that when we look at the responder analysis, which is very important for how we think about future anti-inflammatory therapies. Next slide. We see that when you look at on-treatment CRP levels or on-treatment IL-6 levels, the magnitude of the benefit is even greater and up to a 50% reduction in mortality if the IL-6 levels or CRP levels are lower, achieve lower levels during the trial on treatment levels. Next slide shows it in a little bit different way. When we think about the magnitude of that benefit across the other known treatments that we use all the time for LDL lowering, for example, we see that we see somewhere between a 14%-20% reduction with LDL lowering therapies. GLP-1 is about 20% reduction. When we think about anti-inflammatory therapies from CANTOS on treatment achieving a CRP below 2 and IL-6 below the lowest tertile, we see a 30% and 35% relative risk reduction. If we're able to achieve these very prominent benefits on CRP, we can therefore see a very prominent benefit on reducing cardiovascular events. Next slide. Now I want to move on to, you know, my own development of ziltivekimab. Again, we started the development of ziltivekimab before the CANTOS trial. When the CANTOS trial came out, you know, we pivoted away from another indication to ASCVD, and we deliberately chose a dose of an IL-6 inhibitor that we thought would be the sweet spot for reducing CRP effectively, but not having the adverse effects associated with IL-6 inhibition. We see that a very prominent dose effect, even a very low dose, of ziltivekimab, a IL-6 ligand inhibitor, resulted in very prominent, you know, CRP reduction. Next slide. We look at on-treatment responder analysis. You know, all three doses achieved a very prominent benefit on getting CRPs below 2, which was the threshold in which the CANTOS trial showed this tremendous morbidity and mortality benefit. Next slide. However, it's also important to point out that anti-cytokine therapy, you know, affecting the inflammasome, we see a benefits across the board on multiple biomarkers that are associated with atherosclerotic cardiovascular disease. I point out these three because these three are linked to the causal pathway for heart disease. Fibrinogen being a very important effect on thrombosis, SAA having a direct toxic effect on the vasculature, as does haptoglobin. We see these very prominent benefits of an IL-6 inhibitor across the board affecting what we think are causal factors for atherosclerotic cardiovascular disease. Now, with ziltivekimab acquired by Novo Nordisk after the RESCUE Phase II trial, I'm very gratified to see that, you know, this approach has been taken by Novo Nordisk and then other companies as well are now evaluating this for many major adverse cardiac event reduction type trials. The most prominent, of course, being the ZEUS trial, which focused on a population of those with chronic kidney disease and high CRP with atherosclerotic cardiovascular disease. This ZEUS trial is important because it, you know, will be the first IL-6 inhibitor to be going into this population that the CANTOS trial showed a very prominent benefit. In the subset of patients in CANTOS that had ASCVD and CKD, there was a very profound absolute benefit. What's important about that is because when you have CKD, chronic kidney disease, and inflammation, LDL lowering therapies are not nearly as effective. This is a population where LDL lowering does not seem to be the main driver of reducing cardiovascular events. That's also being looked at across the board in acute coronary syndromes or in heart failure. There are others that are now looking at the same approach, reducing major adverse cardiac events in other CVOTs as well. Next slide. Now moving on, I want to talk about NLRP3 inhibitors and how they are potential for being an oral IL-6 with comparable reductions in hs-CRP, which is important because it's upstream. Now we have, as you'll see, you know, data coming, we have the ability to lower CRP as well as an IL-6 inhibitor, but also by being upstream may be affecting other cytokines that also play a role in atherosclerotic cardiovascular risk. Next slide. Here is the potential that if we go upstream with NLRP3 inhibitors, oral inhibitors, we also block IL-18 as also as pyroptosis as well. You look at the effects of IL-18 as well from the CANTOS trial. That also is a contributor in that residual risk. The lower the IL-18 level, also the lower cardiovascular risk. By the benefit here of having an upstream inhibitor does provide that additional cytokine protection that you don't get from IL-6 inhibition alone. I'm excited about, you know, where we are with, you know, both IL-6 inhibition and now the oral approaches with NLRP3 and how we can utilize those therapies to further reduce risk in our patients. Thank you very much. I'd now like to turn to BGE-102's second therapeutic area, that of ophthalmology. I'll walk you through the disease biology, our preclinical data, and the design of our planned proof of concept study in diabetic macular edema. Next slide. Beyond cardiovascular risk, BGE-102's brain and retinal penetration opens a second therapeutic area in ophthalmology, and we believe an oral anti-inflammatory has the potential to be transformative for retinal disease. This will be a new mechanism in a space previously dominated by single MOA therapies. Diabetic macular edema has been looked at being treated with both anti-VEGFs as well as geographic atrophy has been shown to be treated with successfully treated with complement inhibitors. They're both heavily saturated around single mechanisms. Our drug would have a lower treatment burden, where it's oral versus intraocular injection, which can be up to monthly. It drives real-world adherence. Current outcomes lag clinical trials due to non-compliance. This oral, the ability to give it oral, can enhance compliance and possibly increase efficacy rates. This also allows simultaneous treatment of bilateral disease. For example, you don't need to inject two eyes with an oral drug. It also addresses systemic risk factors in our case, including hyperglycemia and systemic inflammation. BGE-102 has demonstrated therapeutic retinal exposure across multiple preclinical species, including primates. Next slide. NLRP3 sits at the nexus of disease biology in both diabetic macular edema as well as geographic atrophy. The upstream triggers are different. Both pathways converge on inflammasome activation and downstream pathology that BGE-102 is designed to suppress. In diabetic macular edema, hyperglycemia plus oxidative stress leads to NLRP3 stimulation, causing release of IL-1β, IL-6, and VEGF, resulting in vascular leakage and vision loss. Pyroptosis in endothelial cells, another effect of the NLRP3 inflammasome, contributes to the disease process. Blocking NLRP3 can also, by decreasing pyroptosis, add additional benefit. In geographic atrophy, cellular debris such as drusen and lipofuscin then stimulates NLRP3 activation, leading to pyroptosis, RPE atrophy, and photoreceptor loss. IL-6 inhibition has begun to validate the anti-inflammatory approach in DME, but IL-6 is only one downstream arm. NLRP3 inhibition addresses the full cascade, including IL-1β and pyroptosis that we mentioned previously. Monotherapeutic antibodies do not address these multiple downstream factors. Next slide. We've done multiple preclinical models that kind of confirmed that this particular mechanism does have potential benefit. For example, in a streptozotocin mouse model, as demonstrated here, this is of diabetic retinopathy. Orally administered 102 monotherapy restored retinal vascular integrity in a dose-dependent fashion. A clean preclinical readout that BGE-102 reaches the retina at therapeutic exposures and modifies diseases. This was, I think, a very interesting and relevant outcome. In this study, fluorescein angiography showed a reversal of retinal vascular leakage back toward health controls at both 20 and 50 milligrams per kilogram. Claudin-5, which is a measurement of vascular integrity, showed that tight junction integrity was preserved at the microvascular level. This was shown with monotherapy. There was no anti-VEGF combination needed to demonstrate this vascular protection. BGE-102 also addresses the systemic risk factors driving diabetic macular edema. In a diet-induced obesity model, oral BGE-102 improved insulin sensitivity at a level comparable to semaglutide, and the effect recapitulates the NLRP3 knockout phenotype, which has been shown by other investigators. We can improve not only directly effects on the retina, but also those factors that can contribute to onset and potentiation of the disease as well. In this study, we showed that HOMA-IR was improved at day 26 with oral BGE-102 therapy. The effect size was in line with what was seen with semaglutide subcutaneously administered. It also recapitulates, as I mentioned, this NLRP3 knockout mouse phenotype, confirming on-target mechanism for the metabolic benefit. In summary, this single oral therapeutic can not only affect ocular inflammation, but the underlying drivers of this particular disease. Next slide. On the geographic atrophy side, oral delivery of BGE-102, an analog of BGE-102, prevented age-related lipofuscin accumulation in a natural occurring AMD mouse model. This directly addresses one of the canonical inflammasome triggers in geographic atrophy. We did this study in HET3 mice, which are mice that are more comparable to normal healthy animals as they age. We compared this to age-matched controls. Interestingly, these animals with age develop lipofuscin punctae, which are very similar to what's seen in geographic atrophy, and we're able to study the ability to reduce the accumulation of these lipofuscin punctae versus age-matched controls. We showed a significant benefit. The translation implication here is that an oral inflammasome inhibitor reaching the retina can address an upstream driver of this particular disease. Next slide. We've designed our DME proof of concept study to answer a key translational question, that is whether or not oral BGE-102 can reach the eye and suppress intraocular IL-6 levels, the same target that intravitreal anti-IL-6 antibodies have validated in diabetic macular edema. This particular study is a 3-arm trial with 30 patients per arm. We'll have an anti-VEGF plus oral placebo arm, an anti-VEGF plus BGE-102 arm, and a sham plus BGE-102 arm. We'll look at this drug as a monotherapy as well as in combination with anti-VEGFs. The primary endpoint in this case will be the% change in intraocular IL-6. This is a PD study designed to demonstrate target engagement in the eye and not necessarily visual acuity outcomes. However, we will look at these as exploratory endpoints, including additional intraocular biomarkers, plasma biomarkers, best-corrected visual acuity, CST, both structural and as we're seeing both structural and functional signals. The treatment will be through eight weeks with follow-up after that eight-week period. We'll now turn to Dr. Brian Hafler, Associate Professor of Ophthalmology and Visual Science at Yale School of Medicine. Good afternoon, thank you for giving me the opportunity to present today. Today I want to walk you through the scientific and clinical rationale for targeting NLRP3 inflammasome in retinal disease with a primary focus on diabetic macular edema. Then share how this same biology may extend into dry macular degeneration and geographic atrophy. The core idea is that diabetic macular edema remains a high-burden disease despite effective anti-VEGF therapy, and human biomarker data suggests that a substantial component of the disease is inflammation rich, not purely VEGF driven. This creates an opportunity for an oral therapy that acts upstream of multiple inflammatory mediators. In this context, oral inhibition of the NLRP3 inflammasome with the potential to reduce inflammatory cytokines, reduce vascular leakage, and either complement existing anti-VEGF therapy or in selected patients potentially provide an alternative approach. In diabetic macular edema, the initiating stress is metabolic. Chronic hyperglycemia leads to oxidative stress, which activates the innate immune pathways in the retina, including microglial activation and microglia cell dysfunction. That inflammatory environment can then activate the NLRP3 inflammasome. Once NLRP3 is activated, we see downstream production of inflammatory cytokines, including IL-1β, IL-6, and TNF-alpha. These cytokines can contribute to blood retinal barrier disruption, vascular leakage, and ultimately macular edema. In diabetic macular edema, NLRP3 acts as an upstream inflammatory amplifier that sits above several mediators relevant to leakage and retinal thickening. In geographic atrophy, the biology is different at the initiating step, but the inflammatory logic is similar. The initiating stress is driven in part by drusen accumulation. Drusen can activate innate immune pathways, including microglial activation. That again converges on NLRP3 inflammasome activation. In macular degeneration, NLRP3 activation leads to inflammatory signaling, including IL-1β, and contributes to retinal injury and degeneration. Over time, that can cause geographic atrophy, where we see loss of the RPE and photoreceptors. Diabetic macular edema is one of the major causes of vision loss in patients with diabetes. We have effective therapies, especially intravitreal anti-VEGF agents, the real-world burden remains high. In pivotal and real-world settings, patients often require repeated intravitreal injections, in the first year of treatment intensity can be substantial. In Protocol T, a median of nine intravitreal injections were given in year one across treatment arms, this matters for several reasons. First, the treatment burden is high for patients. These are often working-age individuals, many with systemic diabetes complications, who need frequent visits, imaging, monitoring, and injections. Second, not all patients respond completely. Even with anti-VEGF therapy, some patients have persistent edema, retinal thickening, and incomplete visual recovery. While anti-VEGF therapy has changed the standard of care, there remains room for differentiated mechanisms, and that's when oral therapy becomes especially interesting. An effective oral treatment for patients could reduce procedure burden, expand treatment options, and address disease biology that is not fully captured by VEGF inhibition alone. I want to move from the clinical burden to the human biology. Because the rationale for targeting NLRP3 is not simply that oral dosing is convenient. The rationale is that human diabetic macular edema has an inflammatory component, and this component is measurable. One of the most important pieces of the rationale comes from human aqueous humor studies. In the 124 patient study, eyes with diabetic macular edema showed higher levels of multiple inflammatory and angiogenic mediators compared with diabetic eyes without macular edema, and these included IL-1β, IL-6, IL-8, VEGF. What's important is not simply that these markers were elevated, the key point is that inflammatory markers correlated with anatomic measures of disease, including macular thickness, macular volume, and disease severity. That really tells us that diabetic macular edema is not just a VEGF disease, it's also an inflammation-rich disease, and that's an important distinction. Anti-VEGF therapy addresses the central downstream mediator vascular permeability, but it might not fully address the upstream inflammatory program that contributes to edema, vascular dysfunction, and tissue stress. That's why aqueous IL-6 is a particularly useful pharmacodynamic marker. It sits in the inflammatory pathway, it's measurable, and from a clinical development standpoint, it's a clear translational bridge. If targeting NLRP3 is engaging the relevant biology, we would expect to see also targeting IL-6. The important question will be whether modulation of inflammasome-related biology shows any clinical signal in diabetic macular edema related to visual acuity. In this randomized Phase II clinical trial, patients receiving vemurafenib, which blocks IL-6 in combination with ranibizumab every four weeks, demonstrated a trend towards a consistently greater improvement in vision compared to ranibizumab alone. Taken together, these data suggest that blocking IL-6, in addition to standard anti-VEGF therapy, may provide incremental visual benefit beyond blocking VEGF alone. Lamivudine is an oral nucleoside analog reverse transcriptase inhibitor developed as an antiviral drug that suppresses inflammasome activation indirectly, including through NLRP3 link signaling. In exploratory clinical data for a randomized trial evaluating lamivudine, at week four, the lamivudine group showed a 9.8 letter best-corrected visual acuity signal compared with -1.8 letters in the control group. This really suggests that modulating inflammasome-linked biology may have clinical relevance in diabetic macular edema. The reason this matter is that we're not starting from a purely theoretical mechanism, but we have human inflammatory biomarker data and exploratory clinical evidence suggesting this pathway may be relevant to visual outcomes. BGE-102 is an oral inhibitor of the NLRP3 inflammasome. This is important because NLRP3 sits upstream of several inflammatory mediators relevant for retinal vascular disease, including IL-1β, IL-6, and TNF-alpha. In diabetic macular edema, the disease involves several overlapping processes: metabolic stress, vascular dysfunction, inflammatory activation, breakdown of the blood retinal barrier, and ultimately fluid accumulation in the macula. An anti-VEGF therapy targets one of the most important downstream drivers of vascular leakage, but NLRP3 inhibition is a potential attack earlier in the cascade by reducing inflammatory signaling that can contribute to leakage and retinal injury. Because it's oral, it's differentiated from current injection-based therapies, and that oral profile is not a minor feature. In retinal disease, route of administration is central to the patient experience. This is a cartoon showing the mechanism of NLRP3 activation in microglial cells leading to cytokine release from a review I recently published in Seminars in Immunopathology. These data are from a paper I published in Nature Communications showing that IL-1β, a downstream effector of NLRP3, drives VEGF-A expression and retinal vascular leakage. IL-1β is one of the key downstream cytokines produced after NLRP3 inflammasome activation. The top row shows intraocular injection of PBS in the mouse eye, with the photoreceptors on the bottom and the ganglia cell layers on the top. The control has relatively limited VEGF-A expression. The bottom row, after intraocular injection of IL-1β, we see increased VEGF-A signal in the retina, as shown by yellow colocalization on the right. This matters because it shows that VEGF may in part be downstream of inflammatory signaling. Mechanistically, if we inhibit NLRP3 upstream, we may reduce IL-1β signaling, and if we reduce IL-1β signaling, we may also reduce VEGF-A-linked vascular leakage. I'll now shift to the second part of the presentation, the role of the NLRP3 inflammasome in dry macular degeneration, because NLRP3 may have broader relevance beyond retinal diseases like diabetic macular edema to also geographic atrophy. This is a review recently published showing the left panel a healthy eye with the optic nerve and the macula in its center. In both juvenile macular degeneration and age-related macular degeneration at center, there are yellowish drusen deposits in the macula. The right panel shows an area of macular atrophy from RPE and photoreceptor loss. Drusen contain inflammatory signals in the outer retina that can activate the NLRP3 inflammasome. This provides an important mechanistic bridge between AMD pathology and inflammasome activation. In dry macular degeneration, geographic atrophy, inflammatory activation are thought to contribute to progressive degeneration of the RPE and photoreceptors. Drusen components in yellow can activate NLRP3, which can contribute to cell death. NLRP3 inhibition becomes a rational strategy to explore in geographic atrophy. This is a cartoon of a healthy retina on the left from a review recently published, and the right panel shows the retina with dry macular degeneration. Drusen contain both oxidized lipids and amyloid beta, which is a pro-inflammatory component relevant to geographic atrophy. In the mouse model of macular degeneration on the right, subretinal amyloid beta causes RP degeneration, shown by the lack of healthy RPE. In the NLRP3 knockout mouse, the RP is protected and the healthy RPE% returns to normal. Thus, NLRP3 is not just associated with retinal degeneration in this model, it appears to be functionally involved, and these data support the idea that inflammasome inhibition may be relevant in geographic atrophy. The next question is whether inflammasome inhibition is showing a signal in human geographic atrophy. In an early clinical data from an intravitreal inflammasome inhibitor implant, K8 in geographic atrophy. In the low-dose cohort, there is a 53% reduction in GA lesion growth at month three compared to untreated eyes. This is directly interesting and consistent with the broader hypothesis that inflammasome biology may be therapeutically relevant in geographic atrophy. For context, pegcetacoplan, a C3 complement inhibitor, showed a 17% reduction in lesion growth at 12 months in the OAKS and DERBY Phase III trials. These data are useful as a human signal because the inflammasome inhibition can be explored clinically in geographic atrophy. Fluoxetine, which is a weak inhibitor of the NLRP3 pathway, is retrospective evidence of decreased macular degeneration incidence. Taken together, the macular degeneration data suggests that NLRP3 inhibition may be relevant beyond diabetic macular edema to also dry macular degeneration geographic atrophy. Thank you. We now turn to Dr. David Boyer, Senior Partner at Retina-Vitreous Associates Medical Group. Hello, my name is David Boyer. I have the privilege today of talking to you about diabetic macular edema and geographic atrophy, the treatment landscape. Let's talk about diabetic macular edema first. Diabetic macular edema is the leading cause of vision loss in working age adults. There are about 27 million patients globally. About 25% of all patients will develop diabetic macular edema within 10 years of diagnosis, the average age is about 60. Some of these people are still working at the time of diagnosis. What are the reasons? Elevated HbA1c is the largest risk factor for diabetic macular edema progression. That is a long-term test indicating three months of the average glucose, it indicates the higher the number, the worse control they have. This is characterized now by central vision loss with distortion. You can see on the right what normal vision would be, on the further right, you can see the effects of having diabetic macular edema. The treatment, standard of care today is still anti-VEGF therapy. Anti-VEGF therapy does have some problems. First of all, it's an intravitreal injection that has to be given frequently. Even with intravitreal injections, not all patients will do well. Diabetic macular edema progresses secondary to hyperglycemia-driven vascular fluid leakage that causes central vision loss. The cartoon on the left shows hyperglycemia breaking down the retinal blood barrier, showing some edema, some thickening of the retina, fluid eventually accumulates in the macula, which is visible on the OCT, which is a area down below. Eventually, with persistent fluid, the photoreceptors are damaged, leading to permanent central vision loss. 45% of diagnosed patients are treated with anti-VEGF. That still leaves you about 55% that are observed, probably because of the need for intravitreal injections, either the patient doesn't want to do it. It's a time-consuming, and it's not one injection and done. They have to be given on a continued basis. Certainly, 55% of the patients that are observed may have mild vision impairment, again, over a long period of time, this can progress to structural damage on the OCT. Anti-VEGFs initiated become the center for center involving vision loss. First line, again, as I said, was anti-VEGF, the second line would be intraocular steroids, which carry with it the risk of cataract formation and intraocular hypertension. Compliance is a very big challenge for all of us that treat these patients. We know from clinical studies that if we treat the patients on a constant basis every eight weeks and continue that treatment, we can maintain their vision. In the real world, this doesn't occur. The number of injections that are given in the real world are much less than are given in clinical trials. We see a marked reduction in the number of injections that are given over the period of time, possibly because the patients get tired of coming in, possibly because the drugs don't work as well. Less injections are given, and this unfortunately correlates extremely well with poorer vision than one would expect from clinical trials. Here you can see the real world with 4.2 gain of vision, where in the clinical trials we had anywhere between 10.7 and 13.3 letters of improvement. Here in the real world, only 4.2 letters of improvement, indicating that we're not following the criteria, mainly because they're not coming in, they get sick, they can't come in for the injections, so that causes them to, well, lose vision on a chronic basis. Even with strong compliance, even when the patients come in, 50% of the patients in the clinical trials continued to have persistent fluid, even when they used aflibercept, bevacizumab, or ranibizumab. You can see here from the columns, the number of patients with persistent fluid at four weeks, up to 24 weeks is still rather large in these trials. An effective oral agent could benefit not only the patient's current treatment, but it could allow for a treatment at a much earlier stage. Basically, you can see here, the patients that are observed with no visual impairment, mild visual impairments still are being observed, even though they may have some edema, and the treated patients that are inadequately controlled about 25% or well-controlled about 20%. If an oral agent was present, treatment could be administered in the observed phase and hopefully prevent any progression to patients developing significant macular edema. What about geographic atrophy? Geographic atrophy is one of the leading cause of blindness in the elderly, characterized by irreversible central vision loss. We know dry macular degeneration is overall the leading cause of blindness, and geographic atrophy is a form of dry macular degeneration. It is the most severe form, estimated about 18 million patients by the year 2040 and rapidly growing as this occurs in patients as we get older. The average age is 75, but as you get into the 80s and 90s, which many of the patients now are living to, the incidence of geographic atrophy increases. It is characterized by loss of central vision, poor low light acuity, meaning that the patients need more light to be able to read, see a menu, and even drive at night. It causes blurred or distorted vision. In five years, time to legal blindness is seen. In 10 years, it's virtually total legal blindness. There are several approved therapies, but no therapy up to this point has shown benefit to date in keeping or preserving vision or improving vision. Geographic atrophy is really characterized by a continuous neurodegenerative decline. Drusen build up and initial RPE begins to dysfunction, the RPE cells lead to photoreceptor degeneration, as the photoreceptors are the ones that convert light into visual signals. The patients lose the photoreceptors, they lose areas of vision. They eventually get to atrophy, at which time they have areas, what we call scotoma, where in those areas the patients cannot actually see. The effect of geographic atrophy on quality of life is devastating and eventually can make it impossible for independent living. You can see that it impacts driving, reading, traveling as much. It also impacts work, whether they're volunteering, self-confidence, finances, mental health, and even relationships with significant other friends and family members, as they can't see well enough. People will wave to them, and they're afraid that they don't want to wave back. They don't know who they are. The approved complement inhibitors in the first year will reduce growth by 15%-20%. Again, the visual acuity continues, unfortunately, to diminish. You can see here at, on the bottom part of the left slide where the visual acuity diminishes, whether they're receiving monthly, every other month or sham, the visual acuity continues to worsen. The lesion growth, however, is impacted in a positive manner. We have two studies, the OAKS and DERBY trial here. You can see that the progression or the size of the lesion, the size of the scotoma will increase in the sham group as compared to the actively treated group. Still no improvement of visual acuity in any of the treatments that we have available. Complement inhibitors are really only prescribed by 10% of patients, mainly because of the fact that it does not affect the vision per se. It does reduce the scotoma. It does cause the patients to preserve more aspects of their vision. The central vision is unfortunately impacted. There's a very high treatment burden. The treatment's given every 4, 6, or 8 weeks. The office visits for the caregiver and the patient are burdensome. The injection sites, you know, given injections every 4, 6, or 8 weeks to the elderly patient is not easy. An effective oral therapy could rebalance the efficacy and treatment burden. We can treat earlier. We can treat as patients get very small lesions where we right now will observe them because we don't want to put them through the problem of giving injections on a frequent basis. This is an area that the oral agents can really make a big difference. It can be used at an earlier stage of dry macular degeneration. What happens is you have drusen dry macular degeneration with pigment alterations early, and about approximately 20% of patients with dry will go on to developing geographic atrophy. We only treat the ones with geographic atrophy right now. There's no injectable treatment for dry macular degeneration, which is very, very common, except for taking the AREDS supplements, and asking patients to eat a Mediterranean diet. There's a number of approvable endpoints. One of the problems that we have when we treat patients with good vision is how do we know that we're really impacting the quality of life or we're really helping the patient? One of them is the EZ layer that's being evaluated in several trials. It's a photoreceptor rich band observed on the OCT. It's a crucial biomarker for assessing the RPE and photoreceptor health, and it's correlated very well with vision loss. The FDA has said that reduction and EZ attenuation loss precedes the GA and is a strong predictor of visual function, and recognizes it as an approvable endpoint. Stealth, which is a subcutaneous injection, has gotten FDA approval for the EZ attenuation as a endpoint. Rapidly, we're expanding new horizons for finding the benefits of these treatments early, and hopefully, we will be able to employ oral agents at a much earlier stage to preserve photoreceptors and reduce vision loss. I want to thank you very much for your attention. I'd now like to turn the call back to Kristen for our pipeline summary and to open the line for questions. Thank you, Chris, and thanks to all our speakers today. I'll close with a brief overview of our pipeline and our near-term catalysts. BGE-102 is advancing in 2 therapeutic areas. Our APJ agonist is moving toward IND, and our platform partnerships continue to generate additional programs. As you can see on the slide, we have a important catalyst coming up this year for BGE-102. Our cardiovascular risk study is starting soon, and we'll read out by the end of the year. Our DME study is starting mid of this year and reading out mid of next year, and we're on track to submit an IND for our APJ agonist by the end of year. Our collaborations are progressing well, and we have a very strong cash position. Next slide. With that, we're happy to take your questions. With the placebo variation in CRP, it's very rare to see people go below that threshold of 2. Next, we have a question from Sam Semenkow from Citi. On the magnitude of CNS penetrance, how translatable is surpassing the IC90 in CSF to penetrating brain tissue? Do we know what potency is being achieved across brain regions? Paul? I mean, we haven't looked at specific brain regions, in general. We have done some experiments proving that this drug is centrally active, and you can get, with systemic administration, you can get decreases in IL-1β within the brain. We've proven that that's the case. We've spoken to a number of experts specifically in this regard, and what our understanding is the levels in the CSF correlate very highly with levels in the intra cerebral ISF, in the interstitial space within the brain. We believe that, yes, the IC90 and the CSF should be very correlative to what's actually active in the brain going on. Next up, Michael Ulz from Morgan Stanley. Seeing as there are multiple doses that show significant reductions in CRP and favorable safety, can you talk about the strategic advantages 102 could offer with potential dosing flexibility as you think about development in different patient populations? Yeah. Right now, it's unknown how much inhibition is required for clinical efficacy. What we have with our drug is the ability to go from mid-range to complete inhibition at safe doses. I think that does provide an advantage. That if it requires 90% plus, we can do that, at least, you know, we showed safety in our Phase I trials. If you need lower, that's EZ just by reducing the dose. I think it absolutely does offer a flexibility in the way that we select doses, depending on what's required for each individual disease that we pursue. Whether it gets into the brain or not as well. Yeah. Right. Next up, Andy Hsieh from William Blair. Given the rapid onset of BGE-102, did you gather patient-reported outcomes in these Phase I studies? If so, what are some initial patient feedback on BGE-102? That's an interesting question because these, you know, massive inflammation changes happen super-fast. I don't think we were really looking at this. Yeah. Paul? We didn't. Yeah. It's actually a great suggestion. In retrospect, maybe we wish we did because we did see these rapid. We didn't have any specific patient-reported outcome instruments, you know, looking at quality of life or overall well-being. We didn't have anything regarding that. Yeah. Another question from Andy. Is there a biological difference among ASCVD patients presenting with elevated CRP and those who don't? Michael, you wanna take that one? Sure. I think that the key thing is that there's a subset of patients that have high CRP that are different from those that don't have high CRP. They tend to be those that have insulin resistance, cardiometabolic risks, central obesity, chronic kidney disease. Turns out they also have very high morbidity and mortality in general. Those are the key ones that we think about when we consider who has that residual inflammatory risk that we can address very well with one-oh-two. It's if you understand the type of patient that you can see in a clinic, they do stand out in those regards. There are other factors, like for example, they could have inflammatory diseases, RA, inflammatory bowel disease. It also would put them in that high residual inflammatory risk. It is a kind of a mixture of different types of patients, but the bottom line is they all have very high cardiovascular risk, and they could benefit from a therapy like this. Next is Amanda Vera, Oppenheimer. Top of mind for most of us is HS data from a downstream agent shared this week. How do you think about exploring additional indications beyond CV and DME? When could we see pursuit of other indications materialize? Broadly here, I mean, that was a, you know, interesting data set that came out, additional validation that IL-1β is involved in that disease. As you know, there's many indications where NLRP3 is implicated and where there's additionally some validating data from IL-1β or IL-6. We're really evaluating many different potential indications, looking for de-risking human data, and there is the potential for us to add those over time if they meet our bar, if they meet our hurdle. Next up, a question from Yasmeen Rahimi from Piper Sandler. What does ZEUS need to show to establish inflammation as a key cardiovascular marker? How do we connect the dots between IL-6 and NLRP3? Do you think ZEUS is the right population and has run long enough to establish CRP as a key risk marker? Michael, that's for you. Sure. I think just to step back, I mean, ZEUS was designed, you know, based on CANTOS, and we picked, within the CANTOS population, you know, those that would most likely benefit from an anti-inflammatory therapy. Those that got their CRP below 2, which is almost 100% of patients on ziltivekimab in the Phase II-B trial, those that had chronic kidney disease, and of course, preexisting cardiovascular disease. It should work robustly on absolute risk reduction. This is very high risk, and I mean, I can't speak to, you know, exactly what the duration and patient numbers are. We know what I've heard is that the event rates were very high as predicted, and in the powering of the study, you achieve a, you know, a 20% relative risk reduction is likely to be achieved if the CANTOS read-through with zilte does actually materialize. I think how that relates here is that we likely will see it, so that'll validate, you know, IL-6 inhibition directly as a benefit. However, I think one of the key findings, two things could happen that really would help I think provide a good avenue for 102 as an oral therapy, of course, you know, instead of an injectable. Also that, if there's still high risk even on treatment, that implicates maybe IL-18 as an additional target that can further reduce that inflammatory risk, which would be a very positive finding. That, that one may not happen right off the initial data read out. The other, of course, any related IL-6 safety issues, or injection site reactions or things like that could be push people to an oral. I think the advantage of having an oral therapy that can achieve the same degree of CRP reduction, which is linked to IL-6 reduction, I think would be a very appealing therapy for clinicians once this ZEUS validates the benefits here in a prospective trial. Thanks. Another question from Sam. How do you think about triaging the list of indications that could be addressable by 102? Specifically, what is your appetite for evaluating 102 in HS? What capacity do you have on your cash runway to expand into additional indications beyond ASCVD and ophthalmology? We've commented a bit on our sort of appetite to go beyond these indications. We're really looking for, again, there's like a large menu of potential indications to pursue. We have a pretty high bar in terms of where we think the opportunity is and also where we think our molecule has unique attributes, like for example, our really excellent eye penetration. I'll let Dov speak to our cash runway and how that, what capacity that gives us. Yeah. We put out Q1 results this morning where we disclosed that we had at the end of the first quarter $385 million. We're very well financed, and we're have a cash position that would allow us to do an incremental Phase II proof of concept study with 102 with those resources. The next question is from Fiona Jia from Jefferies. How do you think the CRP data from the Phase I trial can translate to larger and longer Phase II and beyond 12 weeks? Any reason to believe prolonged NLRP3 suppression will have any safety impact? Paul, you wanna take that one? Sure. I mean, based upon other studies where inflammatory mediators in this cascade have been modulated, you know, it just makes us believe that this should continue on for as long as the drug is present at therapeutic concentration. It's our belief that the CRP will continue. In terms of increasing the magnitude, we'll just have to wait and see with longer exposure what happens. It's already quite good. Anything beyond that would just be upside. From a safety perspective, you know, keep in mind that certainly when you're inhibiting inflammatory mediators, there's a hypothetical risk. The difference in our drug is, for example, versus an antibody, is we're only inhibiting the IL-1β that's associated with the NLRP3 inflammasome. There are other inflammasomes, there's other cell types that can certainly launch an IL-1β response. We're not completely inhibiting this, which we believe will translate to less potential risk, for example, related to immunosuppression Yeah. Yeah, similarly with IL-6, it's interesting that these drugs are achieving similar CRP reductions but only reducing IL-6 by about 50%. It's like a milder reduction versus an antibody potentially, which could give you a theoretical advantage from a safety perspective. We'll see how that translates with human data. One second. Next, Thomas Shrade from BTIG. The ability to reduce lipofuscin could be active very early in GA pathogenesis. Do you have thoughts on how to identify patients earlier in the disease? Brian, that one's for you. Oh, thank you. I think that's exactly the right question. Retinal imaging will be key, especially fundus autofluorescence, which can identify elevated lipofuscin RPE, potentially paired with AI-based modeling to identify patients likely to progress before GA atrophy develops. Thank you. Next, another question from Yasmeen Rahimi. Dr. Hafler, how does the IL-6% change correlate to functional endpoints? Do you view that mechanistically, NLRP3 would work equally well in both indications that we're considering, DME and GA? What other retinal diseases would NLRP3 show promise in? Maybe Paul, do you wanna take that one, the% change in IL-6? Sure. I think it's coming up later. You know, obviously, we believe that if you can get approximately 50% inhibition in IL-6, it's reasonable to assume that you're gonna get some effect on functional endpoints. Do you wanna do answer the mechanistic part of that question, Brian? Are you on mute? Absolutely. Oh, there you are. Yeah. mechanistically, I think, you know, I think we don't know whether NLRP3 will work better in DME or GA. I think it's why we need to do the clinical trials. Yeah. Next, another question from Sam. How do you think about the commercial opportunity of an oral NLRP3 inhibitor combined with an injectable anti-VEGF? Does the requirement of an injectable drug as part of the combo negate the compliance benefits of an oral? You wanna take this one, Dov? Yes, my pleasure. The important way to think about this question is around segmentation of the market. Patients are treated differently depending on the stage of their disease. There is a group of patients who don't get injectables that have watchful waiting, so diagnosed disease, they're wet, but don't yet have decreases in their ophthalmologic indications. That's an ideal group you could treat with an oral and extend that period. There's a group which you try to do VEGF injectable-sparing, and oral could potentially allow you to increase those intervals. There's a group that has VEGF or not, is non-reactive to VEGF, or they're resistant to VEGF. Those, of course, could be potentially treated with an oral. In addition, the study will have a monotherapy arm, so we'll be exploring BGE-102 as a monotherapy against VEGF monotherapy and VEGF in combination. There's some potential to understand already in the initial study the effects of the oral therapy alone. Thanks. One more question from Mike. On the Phase I-A/I-B/II study in DME, what is the threshold for IL-6 reduction that you would view as a win? Remind us if we should expect to see changes on endpoints such as BCVA as at eight weeks, or would we require a longer follow-up? Paul, you wanna take that one? Sure. Yeah, as you said before, if we got 50% inhibition, we consider that very significant from a clinical perspective. At eight weeks, things like BCVA, it's unlikely you'd see the maximal effect. We are looking at this exploratorily, and hopefully we will see some trends. Actually, that's why we're doing this study. The other thing that we'll be doing is measuring inhibition of IL-1β in the aqueous, and if we could correlate the degree of inhibition with magnitude effect, that'll help us to understand what we expect and what doses to select. We believe, and we're hopeful that we will see trends at eight weeks. Certainly, in the OCT-related measurements, that's more likely to show benefit. BCVA, we hope to see an improvement in BCVA, but it's unlikely to be the maximal improvement that we'd see when we, if we treat longer. Thanks. We'll squeeze in one last question, from Sam. This one's for Brian. How exciting is the data for drugs targeting IL-6 in ophthalmology indications, and how does this impact your enthusiasm for targeting NLRP3 with 102? Thanks, Sam, for the question. I think the IL-6 data is definitely encouraging and validates that upstream inflammatory pathways can be clinically relevant in ophthalmology. NLRP3 is upstream of inflammasome biology and could affect multiple downstream mediators, including IL-1β. I think the positive IL-6 data has increased my enthusiasm for targeting inflammation and NLRP3. Great. Great. Thanks, everybody.