BioAge Labs, Inc. ($BIOA)

Welcome to the 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 BioageLabs 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 bio age management team and by 4 leading external experts who will share independent perspectives on the science and clinical opportunity. Joining from BioAge are Dr. Kristen Fortney, our Co-Founder and Chief Executive Officer; Dr. Paul Rubin, our Chief Medical Officer and EVP of Research; and Dr. Dov Goldstein, our Chief Financial Officer. We're also joined by 4 distinct 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 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 in retinal disease and on the DMA 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, 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 agent data sets that platform validated through ongoing partnerships with Novartis and Lilly has produced a pipeline led by BGE-102. BGE 102 is our oral brain patent and NLRP3 inhibitor and 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 and OB subjects and 87% to 93% of subjects achieved normal normalized CRP below 2 milligrams per liter. This is the critical threshold and believe will correspond to cardiovascular benefits. And then 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 test rich here, our cardiovascular risk trial. It's 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 emetic for obesity that has the potential to increase weight loss and help improve our 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 name immunity activated by metabolic stress. It can drive sustained inflammation that's directly linked to cardiometabolic disease and shorter 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 and 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, and our Phase I data shows it as the attributes needed to address inflammation-driven disease across multiple organ systems. So just to walk you through a few of the highlights here, we have potential best-in-class potency demonstrated by our 1-point nanomolar, IC90 and the human ex vivo whole blood stimulation assay. We've shown 24-hour IC90 coverage, the 60-milligram once a day dose. And as I already mentioned, we've seen really profound potential best-in-class CRP reductions with 87% to 90% of subjects showing normalized CRP reduction after 2 to 3 weeks of treatments in line with anti-injectable anti-IL6 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. And we have large safety margins coming out of our 3-month GLP tox study. We also have potential best-in-class CNS penetration with a 0.7 KPU CSF and a very strong IP position for our novel chemistry. One of the unique features of our molecules is our novel binding site. So as you can see on the left here, the spine inside indicated in purple is where many of the other NLRP3 inhibitors bind including MCC950. And in contrast, by the way, it has a novel binding site, which leads to potential advantages. We can bind both inactive as well as active NLRP3. On the bottom right of this slide are 3 papers that we put out over the past couple of years about our novel chemistry, novel biology and also novel binding site. And I'm going to hand it over now to Dr. Matthias Gayer, our Structural Biology collaborator to take you into more depth on our [indiscernible] insight.

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 inflame [indiscernible]. And there are 3 ways that makes the BGE-102 compound different from any other compound that is in the clinic. At first, this is [indiscernible]. It consists of 3 domains. You see the regulatory nastomaine. You see the sensor [indiscernible] at the bottom and an ADP binding side. And what we discovered as biochemists [indiscernible] is the BGE-102 binding side, which you see here at the top, it's close to regulatory Helix, which is required for membrane attachment. And that's where the company is binding to. You see here in the hinge between these 2 remain the MCC950 binding site, which is already targeted by the Pfizer and [indiscernible] ex since 20 years. And we determined the structure, the infrastructure of BGE binding to NLRP3. And that's shown here in green, you see nicely at the top how these compound glues the regulatory helix at the bottom in order to fix it and inhibit its rotation. And the MCC950 mining site is shown here in the hedge, the site is less accessible in between these 2 domains. And looking at these filing sites, the NLRP3 protein exists in at least 3 different confirmation. So what you see here to the left is NLRP3 bound to ADP. That's the inactive state. And the [indiscernible] 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 these AAPA. So this is the active state but only that is the part of no return. So when this active state went 10 proteins come together and from this disk assembly, which is shown here to the right. So this is the NLRP3 [indiscernible], and that's the signaling competence there that lead to inflammation. And interestingly and importantly, the BGE-102 binding site is accessible in all 3 states. So this means that not only the active state can be targeted or the active state, but even the signaling competence state, for instance, for providing degradation. And that's a huge pharmacology approach because it's able even to active to target hyperpigmentations of these proteins. And the third feature is that BGE is selected for NLRP3 specifically. And there's not just one, not like receptor and NLRP3, but 22 in humans. There are 14 LRPs and another 8 [indiscernible]. And within this family, already the closest summer to NLRP3, which is NLRP as in the 26 residues that makes the binding site for BGE-102, already 8 residues are different to NLRP3. You see the NLRP10, 6 and 1, but they have 13, 15, 16 residues different. And that's shown in this cartoon here to the right 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 not like receptors. And this provides a lot of specificity for BGE-102 for specifically targeting NLRP3. So to summarize this, there are 3 structural features that said BGE-102 apart from any other compound that is in the clinic against NLRP3. And that's the binding side here at the top is unit from every other inhibitor. That the binding site is accessible both in the resting state as well as in the active display confirmation. And thirdly, that the BGE102-binding site is selective for an free within the inflammasome family. And with that, I'd like to thank you, and thank you 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 hsCRP. The obese cohort was particularly interesting in that patients that do have obesity are representative of patients that might be later studies in cardiovascular disease is that they have both risk factors and have increased in inflammation. The study consisted of 3 components: the single ascending dose study, which consists of 36 subjects as well as 90B subjects, and we looked at doses between 10 and 120 milligrams and the 60-milligram dose we looked at both fed and fasted. The multi-ascending dose cohort was healthy volunteers that included 18 subjects at 60 and 120 milligrams for 14 days and a multiple ascending dose cohort, which consisted of obese subjects were CRPs at baseline were greater than 3 and this was 41 subjects where we looked at 60 milligrams for 21 days and 120 milligrams 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. And this particular group in our Phase I was designed to mirror our Phase II eligibility criteria in subsequent trials. Next slide. Now 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, and we showed potent suppression of [ ion beta ] which is kind of the main marker for the activity in NLRP3 inhibitor. Also, 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 made to moderate, self-limited, and there were no dose-limiting toxicity 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% [indiscernible] suppression after a single dose for 24 hours at both the 60 and 120-milligram doses. And interestingly, when we measure CSF levels via lumbar puncture, we showed that at these doses, we exceeded the IC90. In obese subjects, 86% CRP reduction of both the 60 and 120 milligrams were seen and 87% of the subject to 60% and 93% at 120 milligrams 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 [indiscernible]. The adverse spend rates were comparable to placebo. And as you could see, it was 61% versus 59%, which is also typical of a Phase I study. And there were no clinically meaningful changes in vital signs, in laboratory analysis or electrocardiograms. Now 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-30s and meaningfully elevated CRPs, again, similar to the population we plan to enroll in subsequent trials in Phase II. There were 2 active cohorts plus placebo, 60 milligrams, where there are 19 subjects, 120 milligrams showed 14 subjects and placebo with 8 subjects. The median baseline CRP varied between 4.85 and 6.3%, which is well above the 3 milligrams per liter high CD risk threshold. It was a clearly diverse population, and this included 31.6% African-American representation in the 60-milligram 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 events and all 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 thromacytopenia 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 100 to 120-milligram range. And this is very, very good for creating a foundation as to how we want to select our dose. There was also a dose proportional exposure between the 10 million to 120 milligram. Next slide. With repeat dosing, both the 16- and 120-milligram doses showed accumulation approaching steady-state trough concentrations above the IC90 for IL-1 beta confirming full 24-hour target coverage with once-daily dosing. Both doses maintain trough above the human ex vivo in IL-1 beta IC90 and that's in near steady state by day 14 and both clear the IC90 threshold and could explain this comparable downstream biomarker effect. Next slide. Now an important differentiator is the fact that BGE-102 the blood brain barrier and chose CSF concentrations at the 120-milligram level well above the IC90 by day 14. The 60-milligram was also above the IC90 at this day 14 level. And in fact, the KPU CSF of 0.7 is the best that we've seen reported. And the fact that this drug just gets into the brain allows us to potentially explore CNS-related chronic inflammatory conditions. And the same molecule can also address retinal disease. So it establishes this possibility for us having this pipeline and appeal concept. Now moving forward from Kinetics to target engagement, we demonstrated 90% IL-1 beta suppression at the 60-milligram trough and 98% on at 120 milligram, 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. We looked at IL-1 beta suppression over a 24-hour period after a single dose after a dose at day 8, and then again, after a single dose on day 14. And what you could see here on day 1 is that you do see corresponding to the Cmax, a relatively robust inhibition of IL-1 beta 10 hours, but it reverses as the drug levels decrease. So it suggests that this effect is indeed reversible. By day 8 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. So we believe that we can achieve and this is measured complete inhibition of IL-1 beta throughout a full 24-hour period. Now interestingly, when you look at the PK at 8 of the 120-milligram dose. We know that if we gave 90 milligrams, we modeled this, we will achieve the same levels at 90-milligram at steady state. So we could essentially achieve the same level of inhibition using a dose as low as 90 milligrams. Next slide. Now I'd like to move on to the obesemed cohorts. As we mentioned, we believe these are particularly relevant because they have both cardiac risk factors as well as a hyper-inflamed state, as indicated by increases in CRP. Next slide. Now as mentioned, our Phase I included 2 obese med cohorts, and we looked at a 60-milligram dose and 120-milligram dose. And this was specifically designed to evaluate exploratory marker end points in the population we do intend to treat in Phase II. As you could see, the obese population had a baseline BMI between 32 and 42 baseline CRP greater than 3. They were not allowed to be on incretins. And we looked at the 60-milligram dose for 21 days, the 120-milligram dose for 14 days. We believe that data from these cohorts directly influence our ability to choose appropriate doses for our Phase IIa study. Next slide. Now interestingly, both the 60 and 120-milligram dose showed an 86% medium 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 16 120 milligrams at or near the ceiling of the hsCRP dose response curve allows us to explore both potential doses or at least the exposure is 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 1 by day 7. This is well below the 2 threshold that we believe cardiovascular benefit begins to kick in and as demonstrated by the [ CANTOS ] trial. Now when you look at it, in both cases, independent of the dose, you're seeing by day 7 that the CRP levels are driven down to approximately 1. So they both performed the same way even despite the fact that the baselines were slightly different with the 60 being higher than the 120. And then this is maintained throughout the full observation period. Next slide. Now as mentioned, getting CRP below 2 has been shown to be clinically relevant in terms of decreasing outcomes significantly. So this is an important level. When we look at the numbers of subjects that reached that threshold, we're quite struck by the consistency of the drug. We could see that 80% -- 87% of those patients at 60 milligrams and 93% of those at 120 milligrams reached this level. And interestingly, we got 60% to 71%, we're actually below 1. And the belief is that where 2 is clinically relevant, the lower the better, where you can get continued benefit by drugging this even lower. So this links our data to the outcomes in the CANTOS trial. And remember, when in the CANTOS trial, those subjects that had a CRP below 2 showed a 25% reduction in MACE. Looking at IL-6, you can see that both the 60 and 120 milligrams had significant decreases in measured IL-6 levels ranging between 55% to 78% in the 60-milligram and 58 to 60, 120 milligrams, and it was clearly different than placebo. And again, this confirms the fact that our drug is hitting its predicted targets that reducing IL-1 beta resulting in IL-6 decrease, ultimately reducing CRP. Next slide. Now where we didn't have elevations in IL-6 as an entry criteria in the CSF for this particular trial, we did find that 2 subjects when we explored these did have elevations in IL-6. And in both cases, the drug drove IL-6 levels down by day 14. Now we believe this is related to CSF production and reduction in 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. So again, it's underscoring the fact that we can look at this drug as a potential therapy for chronic inflammatory conditions in the brain. We also saw that both the 60 and 120-milligram doses resulted in comparable decreases in the levels of fibrinogen, another important risk factor, ranging between 23% and 30%. So 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. So 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 IIa study as part of our prioritization of enabling a Phase III start by the end of next year. Next slide. Now 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, cause 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 going to 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 LDLs a risk factor are not redundant with lipid-lowering. 60% of the 25 million ASCVD patients have elevated CRP. Now 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 primary extents of its larger primary prevention population. We believe we can achieve this with this mechanism. We believe, again, that over 80% of statins are prescribed by PCPs and that's also because of the oral highly preferable way that this is administered. So again, we believe that this can emulate that particular lesson, which has been taught by these drugs. Also, when we 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 side. Now we've designed our Phase IIa 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 4 arms, which includes placebo, 30, 60 and 90 milligrams once a day, 40 per cohort with a 12-week treatment period. Our eligibility for this study is very similar to our obese mad cohort while we'll see BMIs of 32 to 42, CRPs greater than 3 and having 1 additional CV risk factor in addition to obesity. The primary endpoint of 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 per liter and below 1 mg per liter. Exploratory endpoints will include Lp(a) fibrinogen, IL-6, MRI, which we'll 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. Now we believe the 90-milligram high dose is rational because, as I mentioned before, 90 milligrams at steady state will provide exposures that are comparable to the 120-milligram dose of 1 week. And if you recall, that 1 week 120-milligram dose provided maximal or optimal inhibition of IL-1 beta. So we believe we can achieve that with the 90-milligram dose at steady state. And then the other doses along with the 90 will allow us to characterize the full dose response curve. And 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 athlestrotic cardiovascular disease. Let's start with the next slide. So 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 side of the debate with [ Paul Ridker ] arguing, it was just an association and not causal. And of course, over time, 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. So when we discuss inflammation and heart disease, it's important to point out the concept of residual inflammatory risk. And when we consider a patient in the in your clinic or that you're evaluating for risk, you think about different types of residual risk. And 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 and 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. So what's the magnitude of that risk when you think about it. And when you look at it in different ways, the CRP being the broader way to think about it, and then IL-6, which is a -- the actual cytokine that induces CRP production. Both of them predict major adverse cardic 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 3 years. Next slide. So what does this residual risk as it compares to other residual risk factors like elevated LDL or elevated LPA? Of course, both LDL and LPA are very important targets of therapy. LDL has been our mainstay of preventing cardiovascular disease. LPL 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, hence, by far the greatest relative risk reduction. So not only is residual inflammatory risk very common, but from an associated hazard ratio, is actually the most potent of all the residual risk factors. Next slide. So 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. So we still talk about lower is better for LDL levels. And now the new guidelines have endorsed below 70 or even below 55 for high-risk patients. When it comes in residual inflammatory risk, the stand only brings those. So that CRP level down very modestly so that CRP remains elevated as a marker of that residual inflammatory risk. So the question is, what can we do about that residual inflammatory risk. And now we have evidence of benefit for modifying their risk through the cytokine pathways. Next slide. So here's an illustration of the targets for reducing inflammatory risk. And we look at the very upstream of NLRP3 inflammasome, that's what simulates a different cytokine release. So we can target it IL-1 beta, upstream or IL-6 downstream. And when we think about how to improve that RECIST associated with cardiovascular disease, and it's multiple targets to consider. I'm going to focus right now on the IL-1 beta first and then talk about IL-6 next. So let's go to the next slide. So 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 the risk marker. But the CANTOS study changed all that. We had 3 different doses of canakinumab an IL-1 beta inhibitor and placebo. And 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 carticevents was reduced by 15%. And if you look at the typical MACE 4 Phase III, which is [indiscernible] a 0.83 hazard ratio of 17% reduction of cardiovascular events. Now the point though is that when you 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 benefit is even greater in up to a 50% reduction in mortality, if the IL-6 levels or CRP levels are lower achieved 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% to a 20% reduction with LDL-lowering therapies, GLP-1 is about 20% reduction. When we think about anti-inflammatory therapies from CANTOS treatment, achieving a CRP below 2 or IL-6 below the lowest tertile we see a 30% and 35% relative risk reduction. So 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. So now I want to move on to my own development of ziltivekimab. And again, we started the development of ziltivekimab before the CANTOS trial. When the CANTOS trial came out, 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. So we see that a very prominent dose effect, even though a very low dose of ziltivekimab, an IL-6 ligand inhibitor resulted in very prominent CRP reduction. Next slide. So we look at on-treatment responder analysis. All 3 doses achieved a very prominent benefit on getting CRPs below 2, which was the threshold in which the CANTOS trial show this tremendous morbidity mortality benefit. Next slide. However, it's also important to point out that anticytokine therapy affecting the inflammasome, we see benefits across the board on multiple biomarkers that are associated with aplastic cardiovascular disease. And I point out these 3 because these 3 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. So we see these very prominent benefits of an IL-6 inhibitor across the board affecting what we think are causal factors for [indiscernible] chronic cardiovascular disease. Next slide. And now with ziltivekimab, acquired by Nova Nordisk after the RESCUE Phase II trial, I'm very gratified to see that 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 alphecronic cardiovascular disease. And this ZEUS trial is important because it 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 with [indiscernible] that had ASCVD and CKD, there was a very, very, very profound absolute benefit. And what's important about that is because when you have CKD, chronic kidney disease, and inflammation, LDL-lowering therapies are not nearly as effective. And so this is a population where LD lowering does not seem to be the main driver of reducing cardiovascular advances. So that's also being looked at across the board in acute coronary syndromes or in heart failure. And there are others that are now looking at the same approach, producing 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 hsCRP, which is important because it's upstream. And now we have, as you'll see 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 atlascrotic cardiovascular risk. Next slide. So here is the potential that if we go upstream with NLRP3 inhibitors, oral inhibitors, we also block IL-1 as also as pyroptosis as well. And you look at the effects of IL-18 as well from the CANTOS trial, that also is a contributor in that residual risk -- in the lower the IL-18 level, also the lower cardiovascular. So the benefit here of having an upstream inhibitor does provide that additional cytokine protection that you don't get from IL-6 inhibition alone. So I'm excited about where we are with both IL-6 inhibition and now the oral approaches within our 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. Now 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. Now 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. Now this will be a new mechanism in the space previously dominated by single MLA 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 with complement inhibitors. They're both heavily saturated around single mechanisms. Our drug would have a lower treatment burden where it's oral versus intra-ophthalmic injection, which can be up to monthly. And it drives real-world adherence. Current outcomes lag clinical trials due to noncompliance. So 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 2 eyes with an oral drug. So 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. Now NLRP3 sits the nexus of disease biology in both diabetic macular edema as well as geographic atrophy. The upstream triggers are different, but 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-1 beta, IL-6 and VEGF resulting in vascular leakage and vision loss. Pyroptosis and endothelial cells, another effect of the NLRP3 inflammasome contributes to the disease process. So blocking NLRP3 can also by decreasing pyroptosis at additional benefit. In geographic atrophy, cellular debris, such as [indiscernible] 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 IoT and pyroptosis that we mentioned previously. And monotherapeutic antibodies do not address these multiple downstream factors. Now we've done multiple preclinical models that kind of confirmed that this particular mechanism does have potential benefit. For example, an ascription mouse model as demonstrated here, this is a diabetic retinopathy orally administered 102 monotherapy restored retinal vascular integrity in a dose-dependent fashion. So a clean preclinical readout, the readout, the PGU reaches the retina therapeutic exposures and modified diseases. So this was, I think, a very interesting and relevant outcome. In this study, forcing angiography showed a reversal of retinal vascular leakage back to our health controls at both 20 and 50 milligrams per kilogram. [indiscernible] which is a measurement of vascular integrity show that tight junction integrity was preserved at the microvascular level. And this was shown with a model therapy. There was no anti-VEGF combination needed to demonstrate this vascular protection. Now BGE-102 also addresses the systemic risk factors driving diabetic macular edema. In a diet of used 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. So we can improve not only directly affects 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 home IR was improved at day 26 with oral BGE-102 therapy. And the effect size was in line with what was seen with semaglutide subcutaneously administered. It also recapitulates, as I mentioned, is NLRP3 knockout mouse phenotype, confirming on-target mechanism for the metabolic benefit. So in summary, the 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 HEP 3 mice, which are mice that are more comparable to normal healthy [indiscernible] as they age. And we compared this to age-matched controls. Now interestingly, these animals with age develop [indiscernible], which are very similar to what's seen in geographic atrophy. And we're able to study the ability to reduce these -- the accumulation of these [indiscernible] 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. Now 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 intravitreally anti-IL-6 antibodies are 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 in anti-VEGF plus BGE-102 arm and a sham plus BGE-102. So 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 percent change in intraocular IL-6. This is a PD study demonstrated -- 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 as we're seeing both structural and functional signals. The treatment will be through 8 weeks with follow-up after that 8-week period.

We'll now turn to Dr. Brian Hafler, Associate Professor of Ophthalmology and Visual Science at Yale School of Medicine.

Good afternoon, and 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 retinal disease with the primary focus in diabetic macular edema, and then share how the same biology mix set into dry macular generation 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. And 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 now to complement existing anti-VEGF therapy or in selected patients potentially provide an alternative approach. In diabetic macular edema, the initiating stresses metabolic. Chronic hyperglycemia leads the oxide stress with activate [indiscernible] pathways in the retina, including microglial activation, ammulogliad cell dysfunction. That inflammatory [indiscernible] can then activate the NLRP3 inflammasome. Once NLRP3 is activated, we see downstream production of inflammatory cytokines, including [indiscernible], IL-6 and TNF alpha. The [indiscernible] can contribute to blood retinal barrier disruption, faster leakage and ultimately, macular edema. So in diabetic macular edema, NLRP3 acts as an upstream inflammatory amplifier. Several mediators relevant a leakage and retinal thickening. In geographic atrophy, the biology is different at the initiating step, but the inflammatory logic is similar. The initiative stress is driven in part by [indiscernible] and accumulation. Dosing can activate an immune pathways, including microglial activation. That again converges on NLRP3 inflammasome activation. A [indiscernible] degeneration NLRP3 activation leads inflammatory signaling including IL-1 beta and contributes to retinal injury and degeneration. And over time, that can cause geographic atrophy where we see loss of the RPE and photoreceptors. Diabetic [indiscernible] is one of the major cost of the vision loss in patients with diabetes. We have effective therapies, especially intravitreal anti-VEGF agents. But the real-world burden remains high. in pivotal and real-world studies, patients offer require repeated intravitreal injections. And in the first year treatment, treatment intensity can be substantial. In protocol to a median of 9 intravitreal injections were given in year 1 across treatment arms. And this matters for reasons first achievement burden is high for patients. These are often working age individuals, pending 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. So all anti-VEGF therapy has changed its standard of care there remains room for differentiated mechanisms. And that's what oral therapy becomes especially interesting. An effective oral than for patients could produce procedure burden, expand treatment options and address disease biology that is not fully captured by VEGF inhibition alone. Now I want to move from the clinical burden to the human biology. Because of rational for targeting NLRP3 is not simply that oral dose is convenient. The rationale is that human diabetic macular gene has an inflammatory component, and this component is measurable. And one of the most important pieces of the rationale comes from human aqueous humor studies. In the 124-patient study, eyes of diabetic academia showed higher levels of multiple [indiscernible] and angiogenic mediators compared with diabetics without macular edema. And these included IL-1 beta, IL-6, IL-8 VEGF. And what's important is not simply that these markets were elevated. And the key point is that inflammatory markers correlated with anatomic measures of disease, including macular thickness, macular volume and disease severity. And 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 a 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 particular 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 target an NLRP3 is engaged in relevant biology we would expect to see also targeting IL-6. And the important question will be why the modulation of inflammasome-related biology shows that a clinical signal in diabetic macular edema related to visual acuity. And in this randomized Phase II clinical trial patients receiving [indiscernible], which blocks IL-6 in combination with ranibizumab every 4 weeks demonstrated a trend towards a consistently greater improvement in vision compared to [indiscernible]. And taken together, these data suggest that blocking IL-6 in addition to standard anti-VEGF therapy may provide incremental visual benefit beyond [indiscernible] VEGF alone. [ Lamivudine ] is an oral nucleoside analog reverse transcriptase inhibitor developed as an antiviral drug that suppressed the inflammasome activation indirectly, including through NLRP3 like signaling an exploratory clinical data for randomized trial at valuing [indiscernible] beauty at week 4, the [indiscernible] group showed a 9.8 ladder best-corrected visually acuity signal compared with minus 1.8 letters in the control group. And this release suggests that modulate inflammasome biology may have clinical relevance in diabetic macular edema. And the reason this matters is that we're not exciting from a purely theoretical mechanism, but we have human inflammatory biomarker data and exploratory clinical evidence suggests that this pathway may be relevant to visual outcomes. BGE-102 is an oral inhibitor of the NLRP3 inflammasome. It's important because NLRP3 subset several inflammatory mediators relevant for retinal vascular disease, including IL-1 beta, IL-6 and TNF alpha and diabetic macular edema, the disease involves several overlapping processes. Beta box stress, vascular dysfunction, inflammatory activation, breakdown of the blood retinal barrier and ultimately, fluid accumulation of the macula. And anti-VEGF therapy targets one of the most important downstream drivers of vascular leakage. But NLRP3 inhibition is the potential tact earlier in the cascade by reducing inflammatory signaling that could contribute to leakage and retinal injury. And because it's oral, it's differentiated from current injection-based therapies. And that oral profile was not a minor feature in retinal disease, how of administration is essential to the patient experience. And this is a cartoon showing the mechanism of NLRP3 activation in microglial cells leading to the cytokine release from a view of recently published in seminars amenopathology. And these data from a paper I published in [indiscernible] at communication, showing that [indiscernible] a downstream factor of NLRP3 as VEGF expression and retinal vascular leakage. And IL-1 beta is one of the key downstream cytokines produced after NLRP3 inflammasome activation. The top roasters intraocular injection in PBS in the mouse eye where the photoreceptors in the bottom and the gains the layers on the top. And the control is relatively limited VEGF-A expression. The bottom roofs intraocular injection of IL-1 beta, we see increased VEGF signal in the retina as shown by yellow colocalization on the right. And this matters because it shows that VEGF-A and part downstream of inflammatory signaling. So mechanistically, if we inhibit NLRP3 upstream, we may reduce our beta signaling. And if we reduce abated signaling, we may also reduce VEGF-A link vascular leakage. And I'll now shift to the second part of the presentation, the role the NLRP3 inflammasome in dry mac degeneration because NLRP3 maybe broader relevance beyond retinal diseases like diabetic macular edema to also geographic atrophy. And this review recently published during the left panel of healthy eye with the optic nerve in the macula center. In both [indiscernible] and age-related [indiscernible] in the past macular. And the right panel shows an aero macular atrophy from RPE and photoreceptor loss. [indiscernible] contain inflammatory signals in the outer retina that can activate the NLRP3 inflammasome. And this provides an important mechanistic bridge between AMD pathology and inflammasome activation. And in dry mac degeneration geographic atrophy, inflammatory activation are thought to contribute to the progressive degeneration of the RP and photoreceptors and reusing components in yellow can activate NLRP3 which can contribute to cell death. So NLRP inhibition becomes a rational strategy to explore geographic atrophy. This is a cartoon of a healthy retina on the [indiscernible] review recently published. And the right panel shows the retina with dry mac degeneration. [indiscernible] oxidized lipids and amyloid beta which is a pro-inflammatory component relevant to geographic atrophy. In the mouse model mac degeneration on the right, subretinal amyloid beta causes RP degeneration, some of the lack of healthy RPE. And in the NLRP3 knockout mouse, the RP is protected and the healthy RPE percentage returns to normal. As 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. And then the next question is whether inflammasome inhibition has shown signaling hema geographic atrophy. And early clinical data from an intravitreal flamersome inhibitor implant, KA in geographic atrophy. In the low-dose cohort, there is a 53% reduction in GA lesion growth at month 3 compared to untreated eyes. And this directionally interesting and consistent with the broader hypothesis that inflammasome biology may be therapeutically relevant in geographic atrophy. And for context, [indiscernible], a C3 complement inhibitor sort of 17% reduction in leasing growth at 12 months in the [indiscernible] Phase III trials. And the data useful human signal because the inflammasome inhibition can be explored clinically in geographic atrophy. And fluoxetine, which is a weak inhibitor of the NLRP3 pathways retrospective evidence of decreased macular generation incidents. And taken together, the mac degeneration data suggests a NLRP3 inhibition may be relevant beyond diabetic macular edema to also drive a generation 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, and I have the privilege today of talking to you about diabetic academia in 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. And the average age is about 60. So some of these people are still working at the time of diagnosis. What are the reasons? Well, elevated HbA1c is the largest risk factor for diabetic macular edema progression. That is a long-term test indicating 3 months of the average glucose, and it indicates the higher number, the worst control they have. So this is characterized now by central vision loss with distortion. And you can see on the right what normal vision would be and the further right, you can see the effects of having diabetic macular edema. The treatment standard of care today is still anti-VEGF therapy. However, anti-VEGF therapy does have some problems. So first of all, it's an intravitreal injection that has to be given frequently. And even with intravitreal injections, not all patients will do well. diabetic mac 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 event accumulates in the macular, which is visible on the OCT, which is an area down below. And 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 is if 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. But again, over a long period of time, this can progress to structural damage on the Anti-VEGFs initiated become the for Senervaling vision loss. First line, again, as I said, was anti-VEGF and the second line would be intraocular steroids which carry what's 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 8 weeks and continue that treatment, we can maintain their vision. But in the real world, this doesn't occur, the number of injections that are given in the real world are much less than our given in clinical trials. So 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. But less injections are given. And this unfortunately correlates extremely well with poor vision than one would expect from clinical trials. Here, you can see the real world with 4.2 gain a 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 lose an anachronic basis. But even with strong compliance, even when the patients come in, 50% of the patients in the clinical trials continued to have a persistent fluid even when they use aflibercept that the system [ iberandebizumab ]. And you can see here from the columns, the number of patients with persistent fluid at 4 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 can 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 [ inactcontrole ] about 25% or well control is about 20%. If an oral agent was present, treatment can 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 irreversible central vision loss. We know dry matter generation is overall, the leading cause of blindness and geographic atrophy is a form of dry matter 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. So 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 a loss of central vision, poor low light acuity, meaning that the patients need more light to be able to read, see menu and even drive at night. It causes blur to distort the vision. And 5 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 our preserving vision or improving vision. And geographic atrophy is really characterized by continuous neurodegenerative decline using build up an initial IRP begins to dysfunction and the RP cells lead to photoreceptor degeneration as the photoreceptors are the ones that convert light into visual signals. The patients lose the photoreceptors and they lose areas of vision, and they eventually get to atrophy at which time they have areas what we call, Scotoma, where in those areas that patients cannot actually see. The effect of geographic atrophy and 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 a way back. They don't know who they are. The approved complement inhibitors in the first year will reduce growth by 15% to 20%. But again, the visual acuity continues, unfortunately, diminish. You can see here 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 2 studies, the OAKS and DERBY trial here. And 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, but still no improvement of visual acuity in any of these treatments that we have available. The complement inhibitors are really only prescribed by 10% of patients, mainly because of the fact that the -- 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, but the central vision is unfortunately impacted and there's a very high treatment burden. The treatments given to be 4, 6 or 8 weeks. The office visits for the caregiver and the patient are burdensome. And the injection sites, given injections every 4, 6 or 8 weeks, the elderly patient is not easy. So 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. So this is an area that the oral agents can really make a big difference. It can be used in an earlier stage of dry macro generation. What happens is you have drusen dry macro generation 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 macro generation, which is very, very common except for taking the ART supplements and asking patients to eat a Mediteranean diet. There's a number of approvable end points. So 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. And one of them is the easy layer that's being evaluated in several trials. It's a photoreceptor rich band served on the OCT. It's a crucial biomarker for assessing the RPE and photoreceptor health and it's correlated very well with vision loss. And the FDA has said that reduction and easy attenuation loss precedes the GA and is a strong predictor of visual function and recognized as an approvable endpoint. Stealth, which is a subcutaneous injection has gotten FDA approval for the easy attenuation as an endpoint. And so 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 an important catalyst coming up this year for BGE-102. Our cardiovascular risk study is starting soon and will read out by the end of the year. Our DME study is starting mid of this year and really out mid of next year. And we're on track to submit an IND for our APJ agonist by the end of the year. Our collaborations are progressing well, and we have a very strong cash position. Next slide. And with that, we're happy to take your questions.

How translatable is surpassing the IC90 in CSF to penetrating brain tissue. Do we know what potency is being achieved across brain regions. Paul?

Yes. 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 Island beta within the brain. So we've proven that, 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 interstitial in the interstitial space within the brain. So we believe that, yes, the IC90 and the CSF should be very correlative to what's actually active in the break.

Next up, Mike Ulz from Morgan Stanley. Seen is 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?

Yes. 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 midrange to complete inhibition at safe doses. So I think that does provide an advantage that if it requires 90% plus, we can do that, at least we showed safety in our Phase I trials or if you need lower, that's easy just by reducing the test. So 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.

And whether it gets into the brain or not as well, yes. Next up, Andy Shah from William Blair. Given the rapid onset of 102, did you gather patient-reported outcomes in these Phase I studies? And if so, what are some initial patient feedback on 102? That's an interesting question because these massive employment information changes happen super fast. But I don't think we're really looking at this, yes, Paul.

We didn't. Yes, it's actually a great suggestion. In retrospect, maybe we wish we did because we did see these rapid, but we didn't have any specific patient-port outcome instruments looking at quality of life or overall well-being. So we didn't have anything.

Another question from Andy, is there a biological difference among ASCVD patients presenting with elevated CRP and those who don't. Michael, do you want to 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 and they tend to be those that have insulin resistance, cardiometabolic risk, central obesity, chronic kidney disease. It turns out they also have very high morbidity and mortality in general. So 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 102. So it's -- if you understand the type of patient that you can see in a clinic, they do stand out in those regards. But there are other factors, like, for example, they could have inflammatory diseases, RA, inflammatory bowel disease that also would put them in that high residual inflammatory risk. So 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 can we see pursuit of other indications materialize? So broadly here, I mean, that was a interesting data set that came out additional validation that IL-1 beta is involved in that disease. As you know, there's many indications where NLRP3 is implicated and where there's initially some validating data from IL-1 beta or IL-6. So we're really evaluating many different potential indications, looking for derisking human data, and there is the potential for us to add those over time if they need our bar, if they meet our hurdle. Next up, a question from Yas Rahimi from Piper Sandler. How does ZEUS need to show -- what does ZEUS need to show to establish inflammation as a key cardiovascular marker and how do we connect the dots between IL-6 and NLRP3? Do you think us is the right population and hasn't run long enough to establish CRP as a key risk marker? Michael, that's for you.

Sure. Well, I think just to step back, I mean, ZEUS was designed based on CANTOS. And we picked within the CANTOS population, those that would most likely benefit from an anti-inflammatory therapy. So those that got their CRP below 2, which is almost 100% of patients on ziltivekimab in the Phase IIb trial. Those that had chronic kidney disease and, of course, pre-existing cardiovascular disease. So it should work robustly on absolute risk retina. This is very high risk and I mean I can't speak to exactly what the duration and patient numbers are. But we know what I've heard is that the veterans were very high as predicted and the powering of the study, you achieve a 20% rental risk reduction is likely to be achieved if the Cantos read-through with zilti does equally materialize. So I think how that relates here is that we likely will see it. So that will validate IL-6 inhibition directly as a benefit. However, I think one of the key findings, 2 things could happen that really would help, I think, provide a good avenue for 102 as an oral therapy, of course, as said of an injectable, but also that if there's still high risk even on treatment, that implicates maybe IL-1 as an additional target that can further reduce that inflammatory risk, which would be a very positive finding. That may not happen right off the initial data readout. The other, of course, any related IL-6 safety issues or injection site reactions or things like that, that could be push people to an oral. But 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 we have a very appealing therapy for clinicians once this validates the benefits here in a prospective trial.

Next, 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 commented a little bit on our sort of appetite to go beyond these indications. And we're really looking for, again, it's like a large menu of potential indications to pursue. So 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. For example, are really excellent by penetration. So -- and I'll let Dov speak to our cash runway and how that -- what capacity that gives us.

Yes. We put out Q1 results this morning where we disclosed that we had at the end of the first quarter $385 million. So 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 Gio ] from Jefferies. How do you think the CRP data from the Phase I 102 trial can translate to larger and longer Phase II and beyond 12 weeks? Any reason to believe for long NLRP3 suppression will have any safety impact. Paul, do you want to take that one?

Sure. I mean, based upon other studies where inflammatories in this cascade have been modulated. It just makes us believe that this should continue on for as long as the drug is present at therapeutic concentration. So is 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. So anything beyond that would just be upside. From a safety perspective, keep in mind that certainly when you're inhibiting inflammatory mediators, there's a hypothetical risk. But the difference in our drug is, for example, versus an antibody is we're only inhibiting the IL-1 beta associated with the NLRP3 inflammasome. So there are other inflammasomes, there's other cell types that can certainly launch an Inba response. So we're not completely inhibiting this, which we believe will translate to less potential risk, for example, related to immunosuppression.

Yes. Yes. Similarly, with IL-6, it's interesting that these drugs are achieving similar CRP reductions but only reducing IL-6 by about 50%. So 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. Next, Tom Shrader from BTIG. The ability to reduce lipofuscin could be active very early in GA pathogenesis. Do you have thoughts on how do I identify patients earlier in the disease? Brian, that one's for you.

Thank you. I think it's exactly the right question. Retinal imaging will be key, especially [indiscernible], which can identify elevated life of use in RPE potentially bear with AI-based modeling to identify patients likely to progress before GA atrophy develops.

Next to another question from Yas. 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 and what other retinal diseases would NLRP3 show promise in?

Maybe, Paul, do you want to take that one, the percent change [indiscernible].

Sure. I think it's coming up later. Obviously, we believe that if you can get approximately 50% inhibition on IL-6, it's reasonable to assume that you're going to get some effect on functional endpoints.

Do you want to answer the mechanistic part of that question, Brian?

I mean I think still -- I think we don't know whether NLRP3 will work better in DME. I think it's where we need to do the clinical trials.

Next, another question from Sam. How do you think about the commercial opportunity of an oral NLRP3 inhibitor combined with an injectable anti-VEGF? Is the requirement of an injectable drug are part of the combo negate the compliance benefits of an oral? Do you want to take this one, Dov?

Yes, my pleasure. So the important way to think about this question is around segmentation of the market. So patients are treated differently depending on the stage of their needs. There is a group of patients who don't get injectables that have watchful waiting. So diagnose 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 to 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. And then there's a group that has VEGF or not -- isn't -- nonreactive to VEGF or they're resistant to VEGF and 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 in VEGF in combination. So there's some potential to understand already in the initial study, the effects of the oral therapy alone.

One more question for Mike. On the Phase Ib/II study in DME. What is the threshold for IL-6 reduction that you would view as a win? Also remind us if we should expect to see changes on endpoints such as BCVA at 8 weeks? Or would we require a longer follow-up. Paul, do you want to take that one?

Yes. As we said before, if we got 50% inhibition, we consider that very significant from a clinical perspective. At 8 weeks, things like BCVA, it's unlikely you'd see the maximum effect. We are looking at this exploratory [indiscernible]. Hopefully, we will see some trends. And actually, that's why we're doing this study. The other thing that we'll be doing is measuring inhibition of IL-1 beta in the [indiscernible]. And if we could correlate the degree of inhibition with magnitude of effect that will help us to understand what we expect and what doses to select. So we believe and we're hopeful that we will see trends at 8 weeks, certainly in the OCT related measurements, that's more likely to benefit. But BCVA, we hope to see an improvement in BCVA but it's unlikely to be the maximum improvement that we'd see if we treat [indiscernible].

We'll squeeze in one last question from Sam. And this one's for Brian. How exciting is the data for drugs targeting IL-6 and otology indications? And how does this impact your enthusiasm for targeting NLRP3 with 102?

Thanks, Sam, for the question. I think the IL-6 state is definitely encouraging and validates that I assume inflammatory pathways can be clinically relevant in ophthalmology. And NLRP3 is up semi-inflammazome biology could affect multiple downstream mediators, including IL-1 beta. So I think the positive 6 is increase my enthusiasm for target inflammation and NLRP3.

Great. Thanks, everybody.

Thanks. Good job. Thank you. That was good.