Hi, everyone, and thank you for joining the H.C. Wainwright 26th Annual Global Investment Conference. My name's Arabella, and I'm an analyst on the corporate access team at H.C. Wainwright. H.C. Wainwright is a full-service investment bank dedicated to providing corporate finance, strategic advisory, and related services to public and private companies across multiple sectors and regions. We have a total of 24 publishing senior analysts and over six hundred and 36 companies covered across all sectors. Please visit hcwco.com for more info. At our global investment conference, we have over six hundred presenting companies in multiple sector tracks, including life sciences, cryptocurrency, blockchain and fintech, technology, media and telecommunications, clean tech, metals and mining, and growth. Please join us for one-on-one meetings, corporate presentations, and panels that will be available live and streaming on September 9th to 11th. With that being said, have a productive and enjoyable day, and I'd like to introduce Anirvan Ghosh, the CEO of Unity Biotechnology. Thank you, and thank you for the invitation to participate in the H.C. Wainwright Global Investment Conference. I'm Anirvan Ghosh, CEO of Unity. Before I start, I'd like to note that during today's presentation, I'll be making some forward-looking statements. I'd encourage you to review our SEC filings, including our most recent 10-Q filings, for additional details about Unity Biotechnology. At Unity, I am supported by an exceptionally talented and experienced leadership team with deep experience in drug development, commercialization, and product and business strategy. We are also supported by a team of advisors in our steering team and advisory team, who are leaders in the field of retinal drug development and have presented data from Unity Biotechnology at various scientific and international conferences. At Unity, our primary focus is to develop a new class of therapeutics for retinal eye disease, where the current standard of care has failed to provide full benefit to a large segment of the population. Our lead indication is diabetic macular edema. The mechanism that we're exploring also should be applicable to diabetic retinopathy as well as to geographic atrophy. The key differentiator for Unity is the development of a class of drugs called senolytics, which work by a mechanism of action to eliminate senescent cells, which are damaged cells in the eye that can lead to inflammation and disease progression. Over the course of the last several years, we have found that senolytics are able to lead to restoration of healthy retinal architecture and can lead to improvement in retinal function. We believe that senolytics could be a valuable treatment option for patients who are suboptimal responders to anti-VEGFs. The lead program is UBX1325, which is a Bcl-xL inhibitor. We believe that UBX1325 could provide greater durability than the current standard of care, which anti-VEGF, which needs to be given every other month, as well as to provide benefit and vision to patients who are suboptimal responders to anti-VEGF treatments. Last year, we shared that after a single injection of UBX1325, also called foselutoclax, patients gained vision compared to their anti-VEGF plateau through 48 weeks, or almost one year, and needed significantly less anti-VEGF for those patients who didn't need any rescue treatment. Following that, we initiated the ASPIRE study, which is a phase IIb study, where we are evaluating UBX1325 head-to-head against the standard of care aflibercept. We recently shared that we had just completed enrollment in the ASPIRE study, and we are on track to share 24 week primary efficacy and safety data in the first quarter of 2025, so we have a busy and exciting period coming up in the next few months. I want to take a minute to share with you what the current standard of care is and where UBX1325 could provide a differentiated option for patients. The current standard of care is aflibercept, which is an anti-VEGF-based mechanism, and more recently another product was approved in the field, called faricimab, which targets VEGF and Ang-2. While many patients benefit from these treatments, a significant fraction of patients do not get to driving vision or do not get to 20/20 vision, despite being on anti-VEGF over a long period of time, and in fact, most patients over anti-VEGF will lose vision over time. We believe that UBX1325, by its novel mechanism of action, could provide benefit to those patients who are suboptimal responders to anti-VEGF or who need a lot of anti-VEGF for treatment. Our target profile is of a drug that could achieve six-month durability for at least half of the patient population, which would be significantly longer than the current standard of care, which requires a treatment every other month. An exciting feature of the mechanism of action is that we see evidence of growth of healthy vasculature into ischemic areas of the eye in our preclinical models. This is well-differentiated from anti-VEGF-dependent mechanisms and suggests that we might have a possibility of disease modification with UBX1325. Let me spend a few minutes now to tell you about the senolytic therapeutic hypothesis and the preclinical evidence that drives the clinical program. In the course of disease, as shown on the left-hand side, vascular cells can end up in a state called a senescent state. These are vascular endothelial cells that secrete inflammatory factors, do not form good junctions with their neighbors, which leads to vascular leak and eventually leads to degradation of retinal function and loss of vision. We have found that senolytics, such as UBX1325, can lead to the selective elimination of senescent cells, thereby restoring healthy junctions between neighboring cells, which reduces vascular leak, reduces inflammation, and leads to improvement in retinal function, which we believe could translate into improved vision for patients. This is an illustration of the cross-section of a blood vessel, where the senescent cells sit and how a senolytic mechanism would work. In this cross-section, you see on the left in blue, a senescent cell that is in a highly inflammatory state, secreting inflammatory factors leading to vascular leak. Upon treatment with senolytic agent, you get an elimination of senescent cells, the restoration of endothelial cells that are healthy, taking that place, leading to improved perfusion and eventually to improved vision. Let me share a couple of key preclinical data slides that illustrate the, the mechanism of action of UBX1325 and other Bcl-xL inhibitors. Here, we're sharing data from a diabetic disease model, which leads to loss of vision, loss of retinal function over time. In this STZ model, animals are treated at the beginning of the treatment paradigm, then either treated with a control vehicle or with Bcl-xL inhibitors at week 11, and then we examine the retinal architecture and inflammatory state. You'll note that in the bottom left, that in this disease model, there's heightened inflammation, as evidenced by the increase in IL-1 beta, IL-6, and TNF-alpha, and then when the animals are treated with Bcl-xL inhibitors, there's a significant resolution of that inflammation. On the bottom right, we see a measure of vascular leak, as assessed by tissue albumin. The middle panel shows vehicle-treated animals, and in this diabetic model, you see a significant increase in albumin at the tissue, indicating leakage of blood vessels. Whereas after treatment with a Bcl-xL inhibitor, you see that fluid leak is significantly reduced, suggesting the possibility of improved perfusion. Another striking example is the impact on retinal architecture. These are examples from a mouse model of oxygen-induced retinopathy that has some core aspects of pathophysiology of retinal diseases, such as diabetic macular edema and age-related macular degeneration. In the middle images, you see what the pathology looks like. You see the abnormal-looking blood vessels, which are the neovascular tufts, and at the bottom, you see these dark areas next to the center of the eye, which are the ischemic areas of the retina. Strikingly, after treatment with UBX1325, we find a restoration of healthy blood vessels, as shown in the top right image. You can see in the bottom right image that the ischemic areas of the eye are significantly reduced. All of this is quantified on the left. We believe that UBX1325 could provide significant resolution of the pathophysiology of disease, which should eventually lead to improved outcomes. Let me now turn to our clinical development plan. Last year, we shared data from our BEHOLD study, which is a phase II study of UBX1325 in a sham-controlled study. In that study, we shared 48-week efficacy data, and as I shared at the top of this recording, we saw significant improvement in vision in patients who had reached their anti-VEGF plateau. At the bottom, you see the ASPIRE study. This is a phase IIb head-to-head study against aflibercept. We initiated the study towards the end of last year. We just completed enrollment in the study, and we expect primary efficacy data, 24-week data, in Q1 of next year and 36-week efficacy and safety data in Q2 of next year. I'm going to review the BEHOLD data with you because it creates an expectation for what we might see in the ASPIRE study. But before going into that study, I just want to give you a sense of what the treatment response looks like in patients who have been on anti-VEGF for an extended period of time. This is data from the registration study of aflibercept, the current standard of care. You'll note on the left-hand panel that the patients typically improve vision over the first six months, and beyond that, there's no further improvement in vision, even with continued treatment. That is shown in the expanded image on the right-hand side, where you can see that between week 24 and beyond, even with every other month of aflibercept treatment, vision stays within about a letter. For many patients, that plateau vision is a suboptimal plateau. Often, these patients do not reach 20/20 or 20/40 vision, and they have significant impact on their lives. Our question in BEHOLD was to ask that if you take these patients who have reached their anti-VEGF plateau and give them a single injection of UBX1325, could we provide them with additional benefit in visual acuity? The design of the BEHOLD study is shown over here. In BEHOLD, we enroll patients with diabetic macular edema who had to have had the disease diagnosed for at least six months and had to have at least two injections of anti-VEGF in the prior six months. In our dataset, on average, they had four injections of anti-VEGF in the prior six months, indicating they're high-need patients that are getting injected in the eye every six weeks. They needed to have extended fluid in the eye. The criteria was over 300 microns, but in actuality, they had about 440 microns of fluid. So these patients were really not responding well to their anti-VEGF treatment, and they needed to have a visual acuity deficit of 73 letters or worse.... In In actuality, the average incoming patient had about 60 letters of vision. So these are patients who have been on anti-VEGF, and despite treatment, have fluid in the eye and visual acuity deficits. These are the baseline characteristics of patients in the BEHOLD study. You can see that they're very well-balanced, about the same age, about the same disease duration. I'll draw your attention to the fact their incoming BCVA was about 60 letters, and this is important because BCVA is our primary efficacy endpoint. I'll also note that the prior anti-VEGFs the patients were on is also well-balanced. As in common clinical practice, you see about half the patients had been on aflibercept before enrolling in our study, and about half the patients had been on bevacizumab or Avastin. The first analysis we conducted was about the reduction in treatment burden. I mentioned to you that these patients coming in were getting an anti-VEGF every six weeks. In this Kaplan-Meier curve, we're looking at the need for anti-VEGF treatment in patients who have gone on the sham arm or the UBX1325 arm. Each downward notch on the right-hand panel is an injection that a particular patient received. You can note that right in the beginning, the first eighteen weeks, the sham patients continue to accumulate anti-VEGF injections, and that continues all the way through 48 weeks. On the UBX arm, you can see right from the beginning, the patients who do need an anti-VEGF injection need it later, and perhaps more remarkably, after about 18 weeks, there's very few additional patients who need the treatment, such that over half the patients needed no anti-VEGF treatment for a whole year, and this is a striking departure from their pre-enrollment treatment of about getting an injection every six weeks, so we see that and, pardon me. We see that UBX1325 can reduce treatment burden. Let me now turn to a couple of measures of visual acuity and retinal structure. This is a graph showing the change in BCVA, or best-corrected visual acuity, from baseline through week 24 and through week 48 in the UBX-treated arm, shown in blue, and the sham-treated arm, showing in gray. In this case, we have excluded all post-rescue data if a patient got rescued with an anti-VEGF treatment. You'll note that essentially throughout the entire treatment period, the blue line is above the gray line and significantly separated. At every time point, except for one time point, we see that there is a large and statistically significant benefit for being on the UBX arm compared to the sham arm, such that at 24 weeks and 48 weeks, which were predefined analysis time points, the patients on the UBX arm have had about a six-and-a-half letter gain in vision compared to where they started in the study. In the sham arm, there's no evidence of any gain in vision. Furthermore, I'd remind you that in the sham arm, about half the patients had needed an anti-VEGF injection. So the patients who remain in the sham arm until the end of the study, in many ways, are the best of the sham patients. So we wanted to see if there's another way of capturing all of the patient's trajectory, and that is shown over here. This is an analysis called last observation carried forward, where if a patient gets rescued with anti-VEGF any time during the course of the study, we keep that data point and move it forward so that it is included in the data set at the end of the analysis. So there's no anti-VEGF contamination in this data, but all patients are included. Here, as in the previous slide, you can see patients on UBX1325 have a rapid improvement in vision, which is then maintained all the way through week 48. On the sham arm, you see that there's a continuous loss of vision, such that the separation between the arms continues to expand as time goes on. Let me now turn to retinal structure. One area of attention for physicians is to see if there's accumulation of fluid in the retina, and that is often the main reason that patients get an anti-VEGF injection. When you take patients off of their anti-VEGF and randomized to the sham arm, as shown in gray, you see there's a rapid accumulation of fluid, and that is largely maintained through the duration of the study. In contrast, on the UBX arm, following a transient increase in fluid, which is still at all points less than the sham arm, there is gradual improvement such that there's no net accumulation of fluid, and the retinal structure is maintained. So, this says that it has the ability to maintain retinal structure, and the fact that you're not accumulating fluid largely accounts for the fact that you don't need to give these patients additional anti-VEGF injections. The last observation carried forward analysis for this patient group is also shown over here. And once again, you see this in this analysis, patients in the sham arm gain a lot of fluid, typically above 75 microns, which leads to the need for anti-VEGF rescue treatment, whereas the patients who are on the UBX arm have significantly less fluid in the eye, which does not require them to have anti-VEGF injections. Another very important criteria is the need for rescue or the need for anti-VEGF treatment. I told you that these patients were coming in needing an anti-VEGF every six weeks. In a course of 24 weeks or 48 weeks, we expect pretty much every patient to need an anti-VEGF injection. You see on the left-hand side that patients treated with UBX1325, majority of them did not need any anti-VEGF through the duration of the study, and those who did need it, needed it very rarely. In contrast, in the sham arm, only about 20% of those patients could go without a rescue treatment, and the vast majority, about 80% of the patients, needed treatment during the study, indicating that UBX1325 can significantly reduce treatment burden and the need for anti-VEGF treatment. I also wanted to highlight the safety profile of UBX1325. For retinal drugs, the safety profile, particularly any sign of inflammation, is something that physicians and patients care a lot about because it can be hard to manage. We're happy to share that so far, the safety profile of the drug has been very favorable, so that there have been no instances of intraocular inflammation, endophthalmitis, retinal artery occlusion, or vasculitis, and the adverse events have been well-balanced between the sham and the treated arms. Most of the adverse events are minor, and none of the adverse events are related to drug. All of this is important because it allows us to continue to develop UBX1325 and hopefully launch it as a commercially viable product, so in summary, from the BEHOLD study, we learned that patients who are sub-optimal responders to anti-VEGF can benefit from a new mechanism of action. On UBX1325, these patients who needed a lot of anti-VEGF and had sub-optimal vision coming in, when you took them off of anti-VEGF and put them on UBX1325, they gained over six letters of vision. They needed much less anti-VEGF for those who did need it. Over half the patients did not need any anti-VEGF, and we had a favorable safety profile. So for this patient population, clearly, UBX1325 was a very attractive option. Based on those data, we initiated the ASPIRE study to generate direct head-to-head data against aflibercept, as it will have an important implication for product positioning. Let me share with you the design of the ASPIRE study and our expected data readouts. In many ways, this study is quite similar to BEHOLD. Most importantly, the patient population is very similar to BEHOLD, so that we're not taking any risk going from the BEHOLD study to ASPIRE study in terms of likelihood of finding a patient population who might benefit from UBX treatment. As shown in the bottom line, bottom left, patients coming into the study had to have a diagnosis of diabetic macular edema and had to have had at least three injections of anti-VEGF in the prior six months. They have to have BCVA between 70 and 30 letters, and they have to have fluid in the eye of at least 325 microns. These criteria are all quite similar to the BEHOLD study. The slight adjustments that are made here are really based on the data to further refine the patient population who are most likely to benefit. The total duration of the study is 36 week. The study is randomized 1-to-1 and has about 25 patients per arm. Now, looking at the design, you'll note that there are a couple of additional features that were not there in the BEHOLD study. Importantly, in this case, when the patients are enrolled, before they're randomized, they get three loading injections of aflibercept before they're randomized. The reason for this is that although we are taking patients who have had prior anti-VEGF treatment, we wanna make sure that they have reached their anti-VEGF plateau, so that on the aflibercept arm, there's no possibility of further gain in vision. Once they have had these three injections, which is quite common in many phase IIb head-to-head studies like this, they're taken off of this anti-VEGF and randomized either to an aflibercept arm or the UBX arm. On the aflibercept arm, they'll be given three injections of aflibercept at zero, eight, and sixteen weeks per label, and the primary analysis will be at 24 weeks. On the UBX arm, you'll note a couple of things. One is that they do get matched injections of UBX at zero, eight, and 16 weeks. And at the very first visit, they have a dual injection of aflibercept and UBX. You'll recall that in BEHOLD, they only had a single injection, and I want to comment on this modification in this arm. So it is quite striking that with a single injection, we got significant improvement in visual acuity, and we don't really know whether additional injections might further improve vision for the patients. Now, we want to give the patients the best vision, vision they can have, so we thought that by giving them an injection at eight and 16 weeks, we can further increase their confidence that we have optimized their UBX1325 treatment regimen. But we still expect that beyond that, they should not need frequent treatment based on the mechanism of action. Also, by having a balanced treatment, we can have a fair head-to-head comparison with aflibercept. In the first injection, before switching to UBX1325, they get this one aflibercept injection, and this was really informed by the timing it takes for the UBX effect to kick in. We noticed that very early on, and you might have, you might remember this from the CST data, that there's a slight accumulation of fluid in this arm before it starts to... Sorry, before it starts to dissolve. We believe this is because once you remove anti-VEGF, there's accumulation of fluid, and the cytolytic mechanism takes about eight weeks to kick in. To prevent increase in fluid during that initial period, by giving these patients an aflibercept injection at week zero, we can clamp any increase in fluid, allow the UBX effect to kick in, and from that point on, we hope we can maintain the patients on UBX by itself. The primary endpoint of the study is going to be BCVA change from baseline to week 24, which we expect in Q1 of 2025. The secondary endpoints include a number of measures that are common in retinal assessment, but most importantly, we'll also look at control of fluid as measured by CST change from baseline and the proportion of patients who do not need any anti-VEGF. Now, while this 24-week data will give us a very good sense of the relative efficacy of UBX versus aflibercept, we wanted to take the opportunity to use this study to also learn something about durability. As you recall, in the first study, we were able to take patients out to 24 and then 48 weeks with very few anti-VEGF injections. So in this case, we have extended the study to 36 weeks so that there are no planned treatments beyond week 16. In the aflibercept arm, once they're taken off of aflibercept, we'll have a sense of how many of these patients need additional anti-VEGF treatments between weeks 16 and 36. And on the UBX arm, we'll have the opportunity to assess, if and whether, and to what extent, we need to give anti-VEGF rescues in that arm. This allows a real direct comparison of the durability of effective UBX1325 compared to aflibercept, which will help us in the design of our pivotal study. The 36 data is expected in Q2 of 2025. So right now, we're exactly where we wanted to be. On the heels of the positive data in BEHOLD, we initiated the ASPIRE study. We've had great engagement from patients and physicians. Many of our investigators are the same investigators we had in BEHOLD. We have initiated planning for our phase III study based on these data, and we'll be sharing that in the months to come. And, throughout the coming quarters and, into Q1, we expect to have study updates and, deliver 24 week primary datasets in Q1 of next year. Thank you very much for your attention and for your support of Unity Biotechnology. Thank you so much for such a great presentation. We really appreciate all the time and effort that it takes to prepare it, and we're grateful you could attend our global investment conference this year. With that being said, thank you so much from the entire H.C. Wainwright team.