Kodiak Sciences Inc. (KOD) Earnings Call Transcript & Summary

Welcome to the 2025 Kodiak Sciences Investor R&D Day. I'm John Borgeson, Kodiak's Chief Financial Officer. Thank you all very much for joining us. We're excited to host this virtual investor event today. Our event is packed with a lot of content, so it will likely go about 2 hours. This is truly an exciting time at Kodiak, and we are thrilled to walk you through today's program covering each of our 3 late-stage clinical assets, tarcocimab, KSI-501 and KSI-101. I would like to remind you that remarks made today include forward-looking statements about Kodiak that are subject to risks and uncertainties. A more complete description of these and other material risks can be found in Kodiak's filings with the SEC. We have key members of Kodiak's management team in attendance and participating today. Dr. Victor Perlroth, Chairman and CEO; Dr. Dolly Chang, Chief Scientific Officer; and Dr. Pablo Velazquez-Martin, Chief Medical Officer. And we are also thankful to have distinguished industry experts, Dr. Charles Wykoff and Dr. Sumit Sharma presenting today. Charlie Wykoff of Retina Consultants of America, or RCA, is well acquainted with Kodiak, having enrolled more than 100 patients across our studies. Charlie is a highly regarded thought leader in the field and recently joined The American Society of Retina Specialists' Board of Directors and has a lot of impact on safety decisions in the community as well as being very active in translational research and clinical trial design. Sumit Sharma is on the leadership at the Cleveland Clinic and is a well-known uveitis specialist, retina specialist and researcher. Sumit is a world expert in uveitis. So we are very excited to have him present KSI-101 today. Charlie and Sumit bring their own perspectives and to talk about Kodiak sciences and put us in the context of the broader field. Looking at our agenda today, Victor will kick off our program by taking us through key messages that you can expect to hear today as well as provide his thoughts on the contents to be presented. Next, Dr. Wykoff will describe how Kodiak's promising late-stage bioconjugates, tarcocimab and KSI-501 are designed to fill the best of both worlds, a science of high immediacy and high durability at the same time in a single biologic, which is a gap still not solved with today's approved medicines. Then we will shift our attention to KSI-101 with Dr. Sharma providing some background on MESI, it causes and the unmet need for the fourth leading cause of blindness and how KSI-101 is poised to address the need. Importantly, and what many are waiting to hear, Sumit will also be presenting new KSI-101 Phase Ib data from our APEX study in both DME and MESI. Continuing the discussion of KSI-101, Charlie will then present an overview of our pivotal program for KSI-101 and how we have applied our learnings so far with KSI-101 into our new Phase III trial designs PEAK and PINNACLE. To help put MESI further into context, Dolly Chang will walk us through our patient journey, which we think typifies the current landscape for patients with MESI. And then Victor will present an in-depth view of the commercial landscape and opportunity for KSI-101 as a first-in-class biologic for MESI. We will then conclude our program with a Q&A. Now I would like to welcome our CEO, Victor Perlroth, with key messages that you can expect to hear from today's event. Victor?

Thank you, John. Thanks, everybody, for attending. It takes a full team to make an event like this happen. I wanted just to take a quick moment to acknowledge the many contributors, the Kodiak team, our advisers and of course, the AV and IT teams. Thank you very much. I'm glad John also mentioned the forward-looking statements and an important reference to the many risk factors in our 10-K and 10-Q filings. We have a full agenda today, and I want to start by saying I have never been as optimistic about Kodiak as I am in this moment. I know that's a big statement to make as Kodiak is more than 15 years old, and we've had many big ups and downs. As I see it, though, there is wisdom to be had from those experiences, and that wisdom is why I have never been as optimistic about Kodiak. Let's start with the KSI-101 program. Dr. Sharma will be presenting the 12-week data today. They are strong. Strong enough to suggest a new unifying molecule in macular edema secondary to inflammation, a leading cause of blindness in the working-age population in the developed world. The simplest message I can impart today to all of you at this R&D Day, KSI-101 is outperforming and is a strong reason to believe in Kodiak on its own. With our market cap at $250 million, there's tremendous room to run. For example, if the expectation for today's KSI-101 data from APEX is north of 7 to 8 letters mean gain, we're seeing 10-plus with this Phase Ib data. If the expectation is north of 50% of patients dry on intraretinal fluid by Week 12, we're seeing nearly all dry on IRF and the same on subretinal fluid also. Our asset is doing really well. Wow. And that's what we hear from the physicians when they call, by the way. We are observing these responses across diverse MESI patient types supporting the bispecific, broad-spectrum mechanism of action that KSI-101 is a new unifier across macular edema secondary to inflammation. This is reminiscent of the early anti-VEGF space. Wet AMD used to be divided into subgroups, predominantly classic, minimally classic, occult, categorizations loosely tied to poorly understood mechanistic ideas and defined more by treatments available at that time, for example, PDT. But once anti-VEGF came around and it worked in all of the subgroups, the complexity of the etiology, the alphabet soup was washed away. Another historical analogy here. Macugen was the first anti-VEGF but was narrow spectrum, only hitting VEGF 165, and it was soon faced by the broad-spectrum anti-VEGF agents. And that's the promise here for 101 in MESI, the ability to shift patients to a safe, potent high-dose bispecific broad-spectrum therapy early in their disease journey and to set the patient up for preservation of vision over the chronic course of the disease rather than a complicated and frustrating trajectory towards a vision loss, which is today's reality. The longer the patients are exposed to the swelling of the photoreceptors, the macular edema, the less likely the patient will regain their starting vision. A simple unifying therapy will likely also mean earlier therapy. One of my closest friends growing up her mother is battling MESI for years now. She ended up with cataracts in each eye from the inflammation and the doctors couldn't repair them. They couldn't operate because of the active inflammation. That was 3 years ago. She's now legally and functionally blind despite having had access to the best doctors, and she still has persistent macular edema. It turns out she had a systemic cancer but the diagnosis was missed and anyway through the critical early ocular phase, the eye smoldered. The potential with 101 here is clear, a new, unifying medicine that lets the ophthalmologist focus on and actually treat the eye. John Borgeson, the other day, his Uber driver, the driver's wife actually, she had been a scientist at Gilead, and she had to leave her job due to MESI despite being on numerous standard of care therapies. And doctors have found no known etiology. She still has recurrent disease, and she is not getting any better. A third person, actually, a founder of a small fund that owns KOD stock has anterior uveitis, in this case, tied to underlying immune HLA-B27 predisposition. He has no macular edema yet but he's been treated during different flare episodes at different times with steroid drops, systemic immunosuppressants, intraocular steroids. He doesn't have by report any macular edema so far. So the point is it's all around us, and it's serious. Today, we also present the beginnings of a commercial opportunity analysis for KSI-101, suggesting north of 450,000 MESI patient prevalence in the United States, of which 300,000 are the trial-eligible patients for APEX and PEAK and PINNACLE, and of which, more than 150,000 are the initial KSI-101 addressable population of severe, chronic, and refractory patients here in the U.S. In physician interviews, the KSI-101 profile was generally considered early second line after topical therapy and first choice for intraocular injection but it may be first line in patients with more severe disease or contraindications to steroids. We are continuing to advance this landscape analysis of KSI-101 in the United States to go deeper. We are also seeing nice tolerability with KSI-101 in APEX, and we have been able to select our 2 top doses, 5 milligrams and 10 milligrams to progress into the registrational clinical program. And as you will hear, and I'm happy to report the Phase III PEAK and PINNACLE studies are already live and screening patients. I'm proud of our team, the time line to get these registrational studies active. By the way, both PEAK and PINNACLE are being operationalized in parallel. They are enrolling at the same sites, at the same time. This is a testament to the fact that at Kodiak we run our own in-house CRO, our Kodiak Cares CRO, which brings time and cost efficiencies and brings us closer to the physician and indirectly to the patient community. The designs of PEAK and PINNACLE, they are all well informed from our APEX interim clinical data, and Dr. Wykoff will talk us through that later. We are pleased to share with you the 101 update, and we have a full module for you. Shifting gears. Let's remember that Kodiak is also poised in the larger retinal vascular diseases market, the anti-VEGF market. With our ABC Platform science, we bring a strong immediacy, a full pharmacologic dose of unconjugated antibody to the strong durability of the conjugated antibody. And we apply this, our ABC Science, as you know, to both tarcocimab and to KSI-501. The DAYBREAK study will show all of us exactly what tarcocimab and KSI-501 can do against Eylea. We'll see the immediacy in the matched loading phase, and we'll see the no gimmicks real-world durability through the 48-week primary endpoint and then through the 2-year study duration. in DAYBREAK, as you may remember, for tarcocimab, we allow monthly dosing and all the way down to every 6-month dosing. And for KSI-501, we will see additionally what the broad-spectrum bispecific mechanism of action can bring to wet AMD patients. And don't forget, that we already saw tremendous safety with our conjugates in the 1-year monthly dosed DAYLIGHT Phase III study in wet AMD. The retinal vascular diseases market, it's still open season. Roche's Vabysmo shows with its commercial success, a mainstay biologic with immediacy and incremental durability. Imagine what can a mainstay biologic achieve if it has a science both of strong immediacy and strong durability. As Charlie will remind us, Vabysmo and Eylea are both 7- to 8-day mean ocular half-life medicines in patients. And with our ABC Science and as Dr. Dave Brown presented at our last R&D Day in September, our conjugates are mean ocular half-life of 20 days, in each of wet AMD, RVO and DME patients. That is a very important result. It is unprecedented in patients. The commercial complexity of the anti-VEGF market is overstated. All of the biologics today and their biosimilars, their data cards are on the table today. They're battling it out in the efficacy zone of immediacy. This is a framework that Dr. Wykoff will be exploring with you in a few minutes. The physicians are clear, yes. These new agents, Vabysmo and Eylea and Eylea HD have a strong immediacy but add minimal new durability. They are incrementally useful but not solving the problem. And of the new technologies being evaluated in the clinic, the implantables and the gene therapies, they are battling it out to demonstrate durability, TBD. And in all cases, we are aware of these new agents are being tested on top of mainstay biologics, with Lucentis or Eylea being given during the loading phase and then Lucentis or Eylea being given as supplemental injections during the efficacy phase. That seems strange to me because what are you measuring actually. In any case, the real prize and the real unmet need is a mainstay biologic therapy with strong immediacy and strong durability in the same therapy. And this is what durability means to me. That's the hard learning. It's what the patients and the physicians need and it's what the field has been searching for, for the last 20 years. In many ways, the field has given up. But this is our ABC science. And it's not relevant at this point what happened yesterday. It's about when we turn the data cards over for tarcocimab and 501, what do they show? We agree with the enthusiasm we're hearing from the community on KSI-101. We remain excited about tarcocimab and 501 for all of the reasons I mentioned and also based on how the GLOW2, and DAYBREAK studies are prosecuting. Yes, and shortly, we will put all the data cards on the table for you. Three molecules today in 4 Phase III registrational studies reading out in approximately 7 months for GLOW2, 13-or-so months for DAYBREAK and approximately 18 months for PEAK and PINNACLE and a BLA expected for tarcocimab shortly after DAYBREAK readout and planning for a second registrational study with 501 towards a BLA filing in 2027 in wet AMD. And for KSI-101, also the potential for a BLA filing in 2027. There's steps to our story behind the science and clinical data of these late-phase molecules, our products are wholly owned, and our science is homegrown and proprietary. We bring our own differentiation to the party, our own patent lives, our own design and manufacturing expertise, our own retinal commercial scale manufacturing and nobody and no country can disintermediate us. As I mentioned, we have our own commercial manufacturing facility specialized for retina and partnered with Lonza. Further, we continue to deepen our technology leadership in retina, in our ABC platform extension, our Duet pipeline programs that will take our ABC science to tens of millions of additional high unmet need patients in glaucoma and geographic atrophy and even our hardcore technology leadership being in Silicon Valley as we are with our VETi program, which is an underappreciated asset of value to Kodiak, an AI headset designed and built for scale, and I suspect we will be hearing more about VETi in the coming months. Retina is a space with tremendous depth and tremendous opportunity. Blindness and cancer, those 2 vie for the top spot of most feared health problems across surveys. There are many commercial biopharma franchises in, for example, oncology R&D. But there really are only 2 major biopharma franchises in retina, Roche and Regeneron. Everybody has 2 retinas, and the disease burden is only increasing across the population. You don't have to take our word for the value of retina. Look at what a big value driver retina is to Roche and Regeneron in different ways, actually. For Roche, it's all about Vabysmo, driving the profitability growth for Roche as a corporation. For Regeneron, the Eylea franchise continues to drive their current profitability. And back to Kodiak, all of this poised opportunity in the specialty sector where it's a very doable spend concept to access and sell into retina, not like oncology or obesity, for example, where it's billions to commercialize. Retina is totally different. It doesn't cost hundreds of millions of dollars to run our clinical trials, more like tens of millions of dollars. And it's a $20 billion-plus market globally where you can have an 80-person commercial team in the U.S. and saturate that market. So while retina is technically tricky and we have technical depth, it is commercially attractive. If you enter the market with the right product designs and the right data, not to mention the attractiveness of retina to pharma at risk of their massive loss of exclusivity over the next 3, 5, 7 years, pharma, who see the potential attractiveness of retina but have no de novo way in, in their time frame. Here at little Kodiak, we have 3 products, investigational therapies ongoing, a diversified portfolio and each one with something special to offer. Tarcocimab, the mainstay biologic, with a full pharmacologic dose of immediacy and the best durability. 501, the opportunity to have better efficacy and all the immediacy and durability of our ABC Science. And KSI-101, a new broad spectrum intraocular biologic with a greenfield market opportunity. And they are in 4 registrational studies today, reading out over the next approximate 6, 12 and 18 months and BLAs that we anticipate can follow in quick succession as the registrational studies read out their clinical top line data. We are a pre-commercial stage ophthalmology medicines company with technology, product, clinical, manufacturing and overall retina R&D leadership. Last September, we laid out the road map, and today, we are in motion, and we are accelerating. Please enjoy the next 90 minutes or so as the Kodiak team, together with accomplished industry experts, walk you through the details. And don't forget to stay for the Q&A at the end. The presentation and the webcast after the R&D day is complete will be posted on the Kodiak Events and Presentations web page. Now it will be on to Charlie.

Be here virtually with all of you, I'm getting a little bit of feedback but I will move forward. So quite a few data points to unpack over the next, I don't know, 10 or 15 slides and I'll go efficiently through some of it that you've seen a lot of before and then I'll slow down on some of the key points that I think are important to make. It's an exciting time in retina. There's a lot of ongoing clinical development programs. And I'm personally excited about many of them, and we'll talk about a few of the relevant development programs also as we go forward. Next slide, please. So this section is meant to unpack tarcocimab. This is a molecule that we have been studying now for a long time. I remember being in the first-in-human trial, I think, back in 2018, and we have learned a tremendous amount about the opportunity of this treatment through many exudative disease states that we'll talk about and many different trials. I think that those learnings have been well applied to the ongoing current clinical trials that are positioning this molecule well to, I hope, the FDA approved in the near future and available for routine clinical use. KSI-501 in my opinion, is a build on tarcocimab with the addition of IL-6 inhibition and a great opportunity there building on pure anti-VEGF with tarcocimab. Next slide, please. So this framework is worth unpacking for a second, right? The concept here is that the current biologics that are available, faricimab and aflibercept and aflibercept 8 milligrams and ranibizumab are quite useful. they have, of course, dramatically changed the landscape of how we manage exudative retinal diseases now for nearly 20 years. And I think the adoption of 8 milligrams aflibercept and faricimab has shown that there is a strong interest and a strong need for patients in our space in general for more durable agents that maintain that rapid and consistent drying capacity, and we'll look at what that increased durability with those newer generation anti-VEGF biologics have been in a couple of slides. The other box here on the bottom right is that there are a lot of ongoing clinical trials looking at implants, in particular tyrosine kinase inhibitors and gene therapies, right? There are 2 programs in Phase III looking at tyrosine kinase inhibitors and 3 programs looking at gene therapies, 1 given by subretinal and 2 given by intravitreal, all in Phase III late-stage clinical trials. I am personally supportive of all of those programs. I think there is a need and a role for agents that are able to provide consistent long-term durability for a segment of our patients with exudative retinal diseases, and we'll talk about those options in a few slides in a little more detail. But I do see an opportunity here, and I think the opportunity exists for a lot of reasons. One is this is a tremendously large space, right? There's a lot of patients with the exudative retinal diseases, most commonly, of course, wet AMD but DME, RVO and DR as well. And I think that there is a huge heterogeneity among the responsiveness of those patients to give an anti-VEGF and the half-life of that given anti-VEGF. In other words, the efficacy effect and the durability effect. And I think there still is a need for more of both. I think there's clearly a need for bolus injections that are able to have a more durable profile. And I think that there is a role for those durable products to have a greater immediacy, if you will, which, in my opinion, really means ability to drive the retinas rapidly. And that's where I'm hopeful that the newest formulation of tarcocimab with a combination of the biopolymer and the free antibody will be able to fill a part of that unmet need. You can go forward. So this -- I don't mean to dive into the details here a lot. But I do think it's fascinating talking to my partners and my colleagues and my friends across the U.S. about, look, what is your adoption to what we think of as next-generation biologics for wet AMD in particular, right? What is your adoption of faricimab and 8 milligrams aflibercept. And I've seen good adoption across many of my colleagues because there is an added benefit. I truly believe that there is in many patients. And that benefit in most cases, from what I have seen and experienced with my friends and colleagues has been increased durability. Now if you listened to the direct-to-consumer advertising out there for some of these molecules, you might interpret that durability to be one thing. But in the real world, that increased durability, I think, has been more modest than what the direct-to-consumer advertising would suggest. That said, I do think it's real. I think many of these patients that transitioned from a previous generation anti-VEGF to, again, faricimab or 8 milligrams aflibercept are seeing an incremental benefit in durability. I think that's why you're seeing uptake of both of these next-generation therapies substantially, I think, across the U.S., and I think this will only grow. And I think that, that highlights the potential role for new therapeutics that are able to extend that durability further. You can go to the next slide. So what is that increased durability with faricimab or 8 milligrams aflibercept. Again, I think the details here of this particular slide are less important than what doctors and patients experiences are. But again, I do think that there is an increase in durability for many patients, not all patients with these therapies. But oftentimes, that's on the order of a few days to a couple of weeks. I think, in the high-need patients. And I think you're seeing that in some of the real-world data sets, there have been quite a few of these presented on podium now and fewer of them that have been published but it does appear that the majority of patients are still on approximately every 8 to maybe up to 12-week intervals in the second year of dosing with these next-generation biologics. You can go forward 1 slide. And so I think that the other angle here to talk about in a little more detail is these -- are these plays on durability. And again, I am very supportive of these just to be clear. Gene therapy, I think, has a very real potential role, again, 2 Phase III trials given by intravitreal are ongoing and a Phase III program with subretinal delivery also ongoing across the U.S. And similarly, for the implants, for the tyrosine kinase inhibitor implants, 2 ongoing Phase III programs, again, very supportive of these, and I think there is a role here. What is interesting though is if you look at the protocol design for all of these programs, there's one consistent theme, which is that these are being given in combination with our standard on-label anti-VEGF therapies that we currently use today. Meaning that there needs to be, we believe, some additional drying capacity given before these implants and gene therapies are then going to maintain a durable state long term. And again, I think that there's value in this, I support these programs but there does, therefore, leave open the opportunity for something that is able to both dry the retina as well as increased durability beyond our current biologic bolus injections that we have access to today. You can go forward. Thank you. And so this brings up again that sort of upper right quadrant, if you will, if you graph this on efficacy and durability, right? Could this be a tarcocimab opportunity where you -- now that we have, in particular the improved formulation with both the free antibody combined with the bioconjugate form, can you have both, can you have this rapid drying capacity and an increased durability in the same bolusly-injected biologic. You can go forward. And so this brings up the bioconjugate and the combined free antibody concept here of tarcocimab, in particular, using this ABC Platform that Kodiak has been working on for many years. So this slide summarizes some of those key points. Remember, the bioconjugate is a phosphocholine-based biopolymer that on a couple of slides from now, you'll see how that changes the intraocular half-life. There's good data from animals that by attaching this bioconjugate to the protein, you meaningfully increase the ocular half-life by about threefold. And more importantly, there's meaningful data from humans based on aqueous humor sampling -- sorry, just go back 1 slide still. Thanks. There's meaningful data from humans showing with aqueous humor sampling after tarcocimab injections that, that half-life can be meaningfully extended with the bioconjugate form as well. And what we learned over the early pivotal trials with tarcocimab is that we probably would benefit from a combination of free protein. This is the darker blue section on the right, giving an immediate drying capacity equivalent to the current on-label anti-VEGF in combination with a bioconjugate form that provides that durability advantage that low tail on the right. You can go forward. Thanks. So this is a fascinating slide to digest for a moment. So on the x-axis here is molecular size, essentially the size or weight of the combined molecule. On the left are all of the biologics that you're familiar with, with the addition of KSI-501 on the bottom right, and tarcocimab on the top. Some interesting points. So tarcocimab is almost identically the same size as faricimab, the bispecific listed just below it. And again, those are -- that's the free protein of tarcocimab at the top there at 149 kilodaltons. And by having an injection, which has free protein in it, the concept is that you're going to have an immediacy effect that will hopefully be a very similar and identical to the current on-label anti-VEGF biologics. And then on the right of the slide, you see sort of this key durability play where this biopolymer has been covalently linked to the biologic, which allows that increased half-life based on the molecular size. You can see a dramatic shift in the molecular size on the left side of this graph to the right side, with the addition of that biopolymer to tarcocimab as well as to KSI-501, the goal being for rapid drying with sustained durability. And I think that we are seeing a consistent signal for this in previous trials where a meaningful number of patients truly can go a substantial interval without having recurrence of disease. You can go to the next slide. And so this just summarizes that point where right here by taking both free protein on the left and combining that with a proportion of the treatment that's going to be bioconjugate, you can hopefully have both, which is immediate drying capacity for the anti-VEGF dependent diseases as well as then a durability signal with the bioconjugate. On the top is the example of tarcocimab and on the bottom is KSI-501. You can go forward. So these next few slides dive into some detail and numbers which are fascinating to think about. And I think one of the caveats here is that there is great heterogeneity across humans for all human diseases, right? Not everybody presents with the same phenotype of wet AMD and not everyone responds the same to each anti-VEGF. And that's why I think it's useful for the space to have multiple options. If you look now at the mean ocular half-life, the little blue dots represent sort of that average half-life, sorry, the half-life for each individual patient and then the blue callout box is the mean average half-life, which is 19.8 days for tarcocimab. But what's fascinating to me is the spread, right? You have some patients with a very rapid clearance that the 10 percentile is 8.3 days, and the 90 percentile is up there at 31.8 days, so quite variable. And this tells me that the ideal clinical trial is not to lump patients and to force them into long durability intervals if they're going to be a rapid clearance patient, they're not going to do optimally. You want to give patients the opportunity to get more frequent treatment when they need it and allow them to have less frequent treatment if their disease is well controlled. I think that's really what the spread of dots tells me. Importantly, then if you compare that to the public data for faricimab, for which the mean intraocular half-life is approximately 7.5 days, again, that suggests a meaningful difference between these 2 molecules. Again, with the caveat that these are different trials, different assets, different assays but there does appear to be a substantial difference in the mean intraocular half-life. And again, we believe this is being driven by that bioconjugate intentionally incorporated into a substantial proportion of the treatment on tarcocimab to allow that extended durability. You can go forward 1 slide. So one of the values of having performed so many trials now with tarcocimab is that we've seen the effect of this molecule in many different disease states. And in the original Ib trial, we incorporated multiple different diseases. And you can see that, that intraocular half-life appeared consistent across wet AMD, DME and RVO, again, with an approximate 20-day intraocular half-life across each of these disease states showing nice consistency across these different exudative retinal phenotypes. You can go forward. So this is the busiest slide in this section but it's worth digesting this for a second, right, because this tries to put it at a patient level. And I emphasized this before, and I think this is really important that this is a heterogeneous disease, and the clearance in a given patient in a given eye can be quite variable from a different patient with a different eye and a different disease state. So if you look, first of all, on that faricimab line, let's take the average patient that sort of middle blue patients. If they're on a 6- to 8-week interval with faricimab and if they go longer than that, they have recurrence of disease based on the half-life calculations I just showed you on the previous slides, you might anticipate that these patients are able to go a week to 2, maybe 3 weeks longer with tarcocimab. And importantly, I'm not saying that this patient is going to go from 6 weeks to 16 weeks, right, that would be unlikely given that this patient is sort of a medium clearance patient, where they're still going to clear a different biologic but because other biologic now has a unique bioconjugate on it, could they have increased durability. And I think the expectation there is that yes, they could and would a 1- or 2- or 3-week interval extension be meaningful, I think all you need to do is ask a couple of patients to that question, then you'll quickly see the answers yes. The goal, in my opinion, is not to get to 16 weeks or 20 weeks or 12 weeks or whatever your favorite number is for every patient, the goal is to get as long as possible safely for each patient. And I think that's the shift that's important to consider. If you then look at the patient doing really well with faricimab, they're out to every 12-week injection, that's the lighter blue on the right. If we switch that now to tarcocimab modeling, with the potential intraocular half-life difference you see that they may be able to go 2 to 4 weeks longer with tarcocimab, increasing their interval, again, meaningfully for that patient. And then if you look at the highest need patients the far left there, that darkest blue patient, someone that really requires monthly dosing, again, these patients tend to be the ones that we think of early in discussions as retina specialists, a, because we see these patients a lot. We're seeing them every month. And b, these are the ones at highest risk of visual function, visual loss and anatomic changes when they're not able to get the frequency of dosing that they need. And for patients like this requiring monthly dosing with our current anti-VEGF pharmacotherapies, again, I would strongly argue that even a small incremental change and increased durability can be quite meaningful for these patients. And again, what you would expect by transitioning them to that longer half-life tarcocimab, maybe an extra 4 to 10 days on their interval. Again, I'm not -- clearly not trying to overstate this, that they're going to be able to go 16 weeks. I don't think they will but an extra week for those patients can be quite meaningful in their quality of life and their need to return to the doctor and also gives them a little bit more of a buffer. Unfortunately, patients develop other problems. And sometimes they can't get back at exactly that one-month visit, so they have a little interval, grace period can be quite useful to optimize long-term outcome for patients. So I think we've seen in the commercial success of both faricimab and 8 milligrams aflibercept, there is a desire for increased durability. And I think every incremental step forward is meaningful for patients in the space. You can go forward. So this is really sort of summarizing what we just talked about in that by ideally combining the unconjugated and the bioconjugate form in both tarcocimab and KSI-501 molecules, we can hopefully achieve that early drying and increased durability for a meaningful number of patients. You can go forward. Right, so this then lays out the structure of what's ongoing and what's coming and what it's going to take to get tarcocimab across the line to get it FDA approved and in the clinician's hands and then also for KSI-501 and Victor reviewed this before but we will go in detail a little bit here into GLOW2 and DAYBREAK, both of which I think are well-designed trials, which have a high probability of success. You can go forward. Great, DAYBREAK. So I would love to take a deep dive here. I think this is a fascinating trial and has actually meaningfully moved our space forward for multiple reasons, and I'll tell you why. So first of all, when I think of a clinical trial design, the first thing I think about is the control arm. Everybody wants to jump straight to the investigational product because it's going to be better than the current standard of care. And that's great. But to me, the most important thing is actually the control arm because I want to make sure every patient in the trial is getting optimal treatment, and I'm not leaving anyone behind. I like this control arm, it's aflibercept gold standard every 8-week dosing after 3 monthly doses that is the gold standard for patients. So you know you're going to have a very robust control arm. The second thing that I look at is quite differentiated in this trial is that I think it's the first pivotal trial in retina to incorporate 2 different investigational products. I like that because it's efficient from a company perspective and also from a patient perspective, right, instead of having to do 2 different clinical trials that are pivotal for these different molecules, we can combine them all into one. And then the third reason, this is quite differentiated and the most important, actually, is the use of a locally deployed AI algorithm to determine retreatment, right? So one of the biggest discussions that will come out of pivotal trial designs when you're looking at durability is what are your supplemental retreatment criteria? What are your rescue criteria? How are you defining durability? And what's nice here is that this is not investigator-determined. This is purely based on a well-understood validated algorithm that is commercially available across in many countries to determine a fluid volume status. And this has been tuned so that patients are able to get treatment as frequently as they need a point that we brought up earlier where I believe strongly for wet AMD, that forcing patients into a given interval despite persistent significant fluid is not optimal for long-term outcomes. I think there's quite a bit of data to support that. So if you look at the individual arms now in tarcocimab, the blue boxes at the top, they get 4 monthly loading doses. And then those patients are going to be evaluated for retreatment at every single month through the 2-year follow-up, meaning that they can get monthly dosing if they need it. And I think that that's great because we know that some patients will probably need monthly dosing for any of the biologics, given their rapid clearance. However, if patients do not need monthly dosing, they're not going to be forced to get it. And the safety net will be once every 6-month dosing during the 2-year trial, which I think is very consistent with previous data that we've seen with tarcocimab where a meaningful number of patients will be able to go extended intervals while maintaining its dry retina. Again, we're not forcing patients to go longer and waiting for them to lose vision. The retreatment here is based on a pure fluid not requiring vision loss to get treatment, which I think is very patient-centric and a strong trial design. And then the last arm there, the green arm, 4 monthly doses of KSI-501 with every other month dosing from there but again, with the caveat, we're not forcing patients to get every other month dosing, if they have activity, the intervening injections visits, they can certainly receive those extra injections to maximize the chances of outcome, a strong efficacy outcome. And I think that the screening here is planning to be closed probably in August and then data to follow next year. You can go forward. Right, so that's the ongoing DAYBREAK program, which will round out the wet AMD package. GLOW2 is also a strong trial design. The GLOW1 results were highlighted in gray at the top there. Remember, there was a strong signal on DRSS improvements. So 41% of the patients treated with tarcocimab in GLOW1 had a 2-step or more improvement on the DRSS, which is the FDA approvable endpoint compared to 1.4% in sham. And then more relevant to clinical practice, on the right, we saw a 90% risk reduction in the development of PDR or center-involved DME, right? The goal in clinical practice when you're treating diabetic retinopathy is actually not DRSS improvement, right? That's really not clinically relevant. It's very relevant from a regulatory perspective. But what is clinically relevant is to prevent the development of a vision-threatening complication, which I think of as proliferative disease or center-involved DME with visual acuity loss. One of the other strengths of the GLOW program, both GLOW1 and GLOW2, I would point out, is actually the inclusion not only of patients with DR, they all had diabetic retinopathy severity levels of a very specific range, 47 to 53 but they also allow patients with DME. And this is critical. They allow patients with DME with good visual acuity. What I refer to as sort of the Protocol V population, defined beautifully by the DRCR network. And that allows us to see the effect in these eyes with preserved visual function with mild-to-moderate DME, and we saw that those eyes did quite well. GLOW2 has a nearly identical trial design, except one additional injection at Week 4, that's highlighted with the purple box there on the bottom left. And that is to allow increased dosing flexibility in the real world, which I think is very useful in optimizing patient treatments. You can go forward. So last couple of slides in this. This just talks about the concept of, well, great, you have GLOW1, let's say, GLOW2 is positive. Is this really going to be used to treat diabetic retinopathy in the real world. We know that very few patients with pure DR without DME are actively receiving treatment across the United States. I think that this is a challenge for the space. And I think we have to demonstrate the value here. One of the frustrations about diabetic retinopathy is that most patients that go blind from this disease process should not go blind. This is a disease that is readily treatable and, in most cases, preventable if we catch these patients early enough in the disease process. And so these high risk, when I think of as high-risk NPDRs with moderate or early DME with good vision, I think that with a therapy that could be given as infrequently as a couple of times a year that may begin to change the paradigm for treatment for some patients with some physicians. And I'm hopeful that we could therefore lean towards preventing more of the needless vision loss from this disease state over time. You can go forward. And then finally rounding out the exudative retinal diseases with the data we have for tarcocimab, this is the RVO data. This was very strong data from BEACON showing very good disease control. And remember in the second 6 months of the trial, 75 patients needed zero or one retreatment in that second 6 months after the fixed dosing in the first 6 months, suggesting again, a significant durability signal and not included on this slide was a direct head-to-head comparison of aflibercept with tarcocimab in the second 6 months. And indeed, there were fewer retreatments, meaningfully given in the tarcocimab population compared to aflibercept, again, what we think of as validating this increased durability signal. And what I think of as the highest anti-VEGF need population, which are the eyes with retinal vein occlusion. You can go forward. So I think this is my last slide for this section, just bringing back the original core concept but I'm not here to disparage any of the other molecules on the market or in development. There's a lot of exciting things ongoing in exudative retinal diseases. We use aflibercept, we use faricimab a lot in clinical practice, and they are incredibly valuable but there do remain unmet needs. And I think that the TKIs, the gene therapies can all provide value, but I do think there's also a significant unmet need for a molecule that has the immediacy of aflibercept or faricimab with increased durability beyond those molecules on themselves. You can go to the next slide. And with that, I'll pass it over, I think, to John and then to Sumit. Thank you.

Thank you, Charlie. That was great. Sumit, can you hear and are you ready to get started.

Great. Next slide, please. We go to the next slide, please. So thank you. So I'm going to be talking about macular edema secondary to inflammation and the Kodiak program here. So I'm happy to be a part of this. As mentioned, I'm both the retina and uveitis specialist. And one of the things that I have always noticed and seen is that we have for a very, very long time distinguished between the cause of macular edema or uveitis. And a lot of the other studies that are out there that have been done have really focused on defining macular edema by the underlying etiology. But the reality is that it's really a spectrum of disease and there's a wide overlap in terms of the underlying etiology, what's driving the macular edema. And what I mean by that is you have pure uveitis, which is almost all inflammation driven and then you have pure VEGF-driven diseases such as myopic CNV. But the rest of these diseases fall somewhere in between, and they realistically have components of both inflammation and VEGF-driven diseases. And so with both systemic autoimmune diseases, with postsurgical inflammatory CNV, they're mostly inflammation driven. However, there is still a large component that is VEGF-driven. And we see that, and we'll talk about that in some of the data that I'll show later on. And then you have your retinal vascular diseases and neovascular AMD that are majority VEGF-driven, but we know that there is a large inflammation component as well. Next slide, please. So when we talk about macular edema secondary to inflammation, we're talking about a heterogeneous group of diseases that are driven by a combination of -- that eventually leads to disruption of the blood-retinal barrier. And it's a combination of inflammation and angiogenesis that's causing it. You get macular edema, which we know leads to visual impairment, and we know leads to morbidity for patients. And we have a potential common therapy that Kodiak is developing in KSI-101. Next slide, please. But we know that this is a very heterogeneous group of diseases. You can define uveitis by either the location of inflammation, so anterior, intermediate, posterior, panuveitis, all of which can present with macular edema, and it probably happens at different rates with the different anatomic locations but we see it with every single type. And then many, many underlying etiologies. They can be idiopathic, which it often is despite an extensive workup. You can have it in juvenile idiopathic arthritis in children as young as age 2 or even younger sometimes, you can get focal chorioretinal inflammation [Audio Gap] because often they present with a combination of both the macular edema from the inflammation, but also with macular edema secondary to CNV. And you can actually see that in this slide that this patient has both. They have both macular edema from inflammation as well as macular edema from their CNV. And then finally [Audio Gap] Next slide, please. But regardless, we know that macular edema is a large portion or a large contributor to the causes of vision loss in ocular inflammation. Overall, ocular inflammation is the fourth leading cause of vision loss in working age adults in the developed world. And 1/3 of the patients with inflammation develop macular edema in the U.S. according to our most recent data. And the symptoms that it presents with can be a wide variety of things, including distorted central vision, reduced visual acuity, decreased color and contrast sensitivity but eventually, it leads to photoreceptor damage and can lead to permanent loss of vision as well. And so it's important to catch and treat these patients early on. Next slide, please. So what causes MESI or macular edema secondary to inflammation. At the end of the day, it's all related to breakdown of the blood-retinal barrier. And breakdown of that blood-retinal barrier is mediated by a number of different cytokines. However, we know that VEGF and IL-6 play a huge role in this, and they're co-inducing in that they promote each other's activity where VEGF promotes vascular leakage and neovascularization, while IL-6 really sustains the inflammation and upregulates that VEGF production. And so that combination feeds on itself. And we have really good preclinical data that shows that early on in preclinical and animal models and in cell models that combination of both IL-6 and VEGF has a greater effect than either molecule itself. Next slide, please. We also know that both IL-6 and VEGF levels are elevated in patients who have both ocular inflammation and macular edema. And we see that in various different levels. And so on the slide on the left or on the left-hand side of this slide, you see that patients with intermediate uveitis and measuring their aqueous humor levels of IL-6, we see there's a wide variety of levels of IL-6 elevation, whereas in controls, we don't see very much IL-6 at all. And then on the right, we see that those eyes that have CNV have higher levels of VEGF in their aqueous humor when they have uveitis versus when they have uveitis without CNV. But interestingly, often these uveitis patients when they're actively inflamed, who have VEGF, sometimes in the absence of CNV and it's the inflammation itself that is causing that VEGF level to rise. But because they're often younger, they have a really strong RPE pump and we don't see overt CNV but they're still inflamed. Next slide, please. So this is what I was alluding to earlier. This is a HUVEC cell model. And what we see on the top in the blue is a high barrier resistance intact tight junctions, and we're looking at the integrity using this model to look at the integrity of the blood-retinal barrier by measuring the electrical resistance in HUVECs that are cultured. And we see that when you supply VEGF in the purple, you get an increase in permeability, when you supply IL-6 in the light purple, you see a similar but greater immediate reduction in the resistance and then kind of levels out to the same level as VEGF. But when you provide both together, you get a greater loss of that barrier resistance than either of those 2 molecules alone. And so this lends credence to the thought of blocking both molecules in order to see an improvement in macular edema in inflammatory diseases. Next slide, please. So what is really the unmet need? And how do we look at this? Well, my clinical experience is that we have a significant unmet need because right now, we really only use corticosteroids as our mainstay of therapy. The vast majority of our patients are either getting immunosuppression. So that's that other biologics section or most often, we treat with steroids. And often, I find that my patients aren't going to fully respond to intraocular steroids. And it's really interesting that, that happens but we see it not infrequently. And very frequently, at least in the U.S., we see a resistance to using intraocular steroids, especially in the pediatric population and even in adults because of really high rates of cataract formation, which will happen eventually with repeated steroid injections in almost everyone and intraocular pressure rise leading to uveitic glaucoma and glaucomatous damage from the steroid response in these patients. And there are many docs who actually will not use steroids and end up under treating our patients because of that. And so we have to be very aggressive. I'm fortunate to have very good glaucoma specialists but I also say to them, I cause a lot of glaucoma because I use a lot of steroids right now because they really are the mainstay of therapy. Next slide, please. And my own clinical experience with topical steroids for macular edema secondary to inflammation has been kind of mixed. So if we look at it in different etiologies, I find pretty much across the board. And those data that will be shown later that matches my own clinical experience is that about 1/3 of patients will be good responders. About 1/3 of patients will be nonresponders or refractory to topical steroids and about 1/3 of them will get elevated intraocular pressure, limiting the use of the topical steroids. And so almost 2/3 of these patients require either additional or alternative therapies after topical steroid use, and it's a fairly large population that has a very high unmet need overall. Next slide, please. And we caused a lot of complications. I was alluding to having very close relationships with a number of glaucoma specialists. And I really do because we have to be really cautious in these patients. So in these patients who have inflammation, you can't proceed with cataract surgery when they're actively inflamed because it's really contraindicated. It can lead to permanent vision loss because of runaway cascading inflammation post cataract surgery. So it's not as simple as saying, oh, you cause cataract with steroids, go ahead and just take the cataract out. Often, these patients have to be significantly immunosuppressed or put on very high doses for long periods of systemic corticosteroids, which also has significant morbidity and sometimes even mortality in order to allow them to get their cataract taken care of. So a treatment that doesn't cause cataract is desperately needed in these inflammatory eyes. And then the other part is a large portion of these eyes will develop IOP elevation when you treat with corticosteroids either locally or even sometimes systemically. And there's concerns about IOP really limit the use of corticosteroids in multiple patients. And so we often will add topical drops to control the IOP, but it's often insufficient and so these eyes often need surgery. We know with the RETISERT fluocinolone intravitreal implant that 60% of patients require chronic IOP-lowering medications, and nearly 40% or 4 out of 10 need a glaucoma surgical procedure to control their intraocular pressure, nearly everybody needs cataract surgery. And so this is pretty much fits with my experience with local steroid use is that while they work in many patients, they don't work perfectly, then they have a high rate of morbidity and mortality that limits their use and often leads to undertreatment of these patients across not just the U.S. but across the world. Next slide, please. This is a patient of mine that presented in 2023 with a 12-year history of panuveitis in both eyes with multiple failed treatments. We can see on the fluorescein angiogram that there is quite a bit of leakiness in the vessels, and it's in a fairly interesting pattern where it's following more along those inferior arcade vessels with some chorioretinal scarring and she continues to worsen with any type of local steroids. She gets elevation of her pressure to 40s. She has a surgery to try to control both the cataract and the intraocular pressure, which is a combined cataract surgery and canaloplasty. The pressure keeps rising despite surgery, so we consider alternative immunosuppression. She has already failed multiple immunosuppressive medications. But I referred to one of my rheumatologists who specializes in this, and her insurance won't approve any additional. So we go back to using local therapy and local therapy is not working so well. She's continuing to get worse. So eventually, because her pressures in the high 30s despite maximal topical drops and oral Diamox, she ends up getting a tube shunt, which is not a benign surgery. Tube shunt surgery is really associated with high rates of complications and even higher in any eye and even higher rates of complications in eyes that are inflamed. And so we often end up significantly hitting these patients with systemic corticosteroids in order to allow the glaucoma surgery to happen safely. Fortunately, she is now doing much better after fluocinolone intravitreal injection. This poor lady has undergone multiple surgeries per eye. And this is just her right eye, her left eye has had a very similar story. So she's now undergone multiple surgeries in order to try to get this inflammation under control, that really is limited to her eyes. She has also taken multiple different immunosuppressive medications that have systemic comorbidities. And if we had a local therapy that could avoid the side effects of cataract and intraocular pressure rise, while controlling her inflammation, it would have been transformative for her. Next slide, please. So there's really a core unmet need in MESI for a potent high-strength, locally administered therapy that is safe. And so we really have kind of a few different things. We have intravitreal anti-VEGF monotherapy that's pretty safe but doesn't have much efficacy, and we'll talk about some of the data in uveitis and uveitic macular edema and in MESI for intravitreal anti-VEGF monotherapy. We have systemic immunosuppressants that are okay efficacy, somewhat okay safety sometimes depending on which one. We have intraocular and systemic corticosteroids that have high efficacy in controlling the inflammation but often have a lot of safety concerns. And so what we would love is a therapy that does kind of -- gives us both high efficacy and fewer complications and a biologic therapy that could target both IL-6 and VEGF disease drivers and at the same time while treating the macular edema potentially be disease-modifying would be fantastic. It'd be good for it to have high strength, be potent and an excellent safety profile, and that would be transformative in the field. Next slide, please. The MERIT study was a randomized clinical trial that randomized patients to either the OZURDEX implant, intravitreal ranibizumab or intravitreal methotrexate in patients who had uveitic macular edema. And we look to see what happens. And so this, on the left-hand side, you're looking to see what proportion of eyes normalize their OCT based on a central subfield thickness. And we see only about half of the eyes at Week 8. And my own clinical experience and the clinical experience of pretty much everyone who uses the Ozurdex implant is that even though it is labeled as a 6-month drug, it really is an 8- to 10-week drug because by Week 12, we're already seeing waning of the effect in the vast majority of patients. And by Week 16, it's completely gone. We see recurrence of inflammation in many. And the improvement in visual acuity isn't very significant overall. The visual acuity gains are best at Week 8 and then wane off by Week 12. Next slide. When you look at ranibizumab, you see, yes, there's some efficacy. It can actually provide a meaningful fluid response in a subset of these MESI patients. So there is some biological possibility to using an anti-VEGF or the addition of an anti-VEGF to anti-IL-6 for treating macular edema secondary to inflammation. And methotrexate overall doesn't seem to do much in terms of normalizing it. But over time, as you continue to inject it, you do see a little reversion and reduction in the overall edema. Next slide, please. So DOVETAIL is a Phase I study by Roche looking at intravitreal anti-IL-6 monotherapy with vamikibart and DOVETAIL was a multiple ascending dose study of intravitreal vamikibart given at Day 1, Week 4 and Week 8 of 3 different doses, 0.25 milligram, 1 milligram or 2.5 milligrams. So all patients got treated. All patients had noninfectious uveitis and concurrent macular edema of at least 325 microns. So it is in adult patients only and about 12 patients per arm. We then treated them at baseline Week 4 and Week 8 and then followed them in an off-treatment observation period up to either Week 20 for the 2.5 milligrams dose, or Week 36 for the other 2 doses. next slide, please. And what we saw was a very meaningful increase in visual acuity and a meaningful reduction in OCT central subfield thickness across the board. And if we look at the overall numbers, we see that there's probably a slightly greater effect on the right-hand side for the orange and black lines, which are the 1 milligram and the 2.5 milligrams compared to the lightest green, which is the 0.25 milligrams, interestingly -- on OCT. But interestingly, in terms of best corrected visual acuity, we see pretty similar gains across the board. And we see that, that effect is sustained at least out through Week 20. And so there's a clear dose response seen in terms of treatment patients with inflammatory macular edema. Next slide, please. But when we really dial down and we look and see how many patients have resolution of intraretinal fluid, only about half at the end of the treatment period, have a resolution of their intraretinal fluid. So that means half of these patients still have intraretinal fluid. And when you look at the absence of subretinal fluid, yes, we resolved that very successfully. But persistent intraretinal fluid is what's more dangerous, and it's what's known to cause greater effects on visual acuity. So when we look at the 15-letter gainers, we see across the board only about 1/4 to 1/3 of the patients gained 15 letters at Week 12 with vamikibart after 3 monthly doses. Next slide, please. So how can we meet this unmet need. And there's a number of ways we could do that. And so one that Kodiak is pursuing is KSI-101, which is a high strength, dual-specific intravitreal biologic, designed to target both IL-6 and VEGF mediated disease. And so it has a potent anti-inflammatory effect through the anti-IL-6 portion by being able to block up to 2 IL-6 molecules to try to normalize the blood-retinal barrier. And on the VEGF side, it's more like a VEGF trap with broad VEGF inhibition that binds multiple targets, including VEGF A, B and placental derived growth factor. We know the VEGF trap is probably the strongest way and the best way that we have out currently at blocking VEGF and this dual pathway inhibition would allow us to target both of these drivers of macular edema. KSI-101 also has a high formulation strength at 100 milligrams per millilitre and a modified Fc region that's immunologically inert to reduce the risk of causing inflammation with this therapy. Next slide, please. And it does really well at blocking all of this. And so when we look at its ability to inhibit both IL-6 signaling as well as IL-6 receptor mediated signaling, we see that there is a strong inhibition with very good IC50s in the picomolar or nanomolar range. And for VEGF signaling, we see that the IC50s are in the picomolar range, very similar to what you see for aflibercept. Next slide, please. And this is a really interesting slide. So this is looking at the ability of each of these molecules to be able to improve tight junctions. And so what we're looking at is on the very left-hand side, you have normal, and you have what the RPE cells should look like. When you apply exogenous VEGF and IL-6 on the second from the left, where there's no inhibitors, you see a significant breakdown of those RPE cells and loss of those tight junctions. When you give VEGF monotherapy, you see some restoration back to normal. When you give anti-IL-6 monotherapy, you see some restoration back to normal. But when you inhibit both as with KSI-101, you see a significant restoration back to normal. And it's superior to either of the anti-VEGF or anti-IL-6 monotherapy. And so this is great because this shows the synergistic effect of anti-IL-6 and VEGF dual inhibition. We go to the next slide. We'll circle back to that HUVEC model that we showed earlier. In blue, again, you have at the very top, the no exposure. In pink at the bottom, we have the eyes that the HUVECs are getting both VEGF and IL-6 applied exogenously. And at 20 hours in the 3 different curves, we see either VEGF plus IL-6 and application of KSI-101. And interestingly, it restores the barrier integrity back to what you see within no exposure, which is fantastic because when you look at each of them alone, you don't get anywhere near that type of barrier integrity restoration. So anti-VEGF gives some restoration, anti-IL-6 gives some restoration but the combination effect is greater than just the summative effect of each of those 2 alone, and this is very interesting because it fits in with the mechanistic view that this is a synergistic effect on each other. Next slide, please. So KSI-101 is really designed to meet that core unmet need that I talked about earlier. It's a dual anti-IL-6 and anti-VEGF inhibitor that has the potential for a disease-modifying effect based on its synergistic inhibition of both IL-6 and VEGF. It has a very high strength formulation with a very high potency. It's given with local intravitreal administration, and the safety profile, as we see in the Phase I study is in line with other intravitreally administered biologics, which is fantastic, and that's the need that I was addressing earlier, a local therapy that can very nicely restore the barrier function and get rid of the macular edema irrespective of the underlying presumed etiology. One of the problems we've had in the field in prior studies has been that we have focused so much on the underlying etiology that we've kind of lost sight of the fact that, yes, this is a heterogeneous group of diseases, but the treatment may be the same, and the treatment could be really well done with a combination anti-IL-6/anti-VEGF. And so what does that look like? As we go to the next slide, we'll go back and circle back to all of those eyes with edema and a single dose resolves the edema in a large portion of these patients, irrespective of the location of the inflammation or the underlying etiology, and this is fantastic because we desperately need this kind of therapy. And if we go to the next slide, we'll kind of dive into some of these results. And so these are all patients that I showed you are from the APEX study and the APEX study was a Phase Ib as we go to the next slide. In both diabetic macular edema and macular edema secondary to inflammation, it's an ongoing study, and I'm going to show you some of the data that we have so far. It's an open-label, multicenter study to look at the safety, tolerability, bioactivity and pharmacokinetics of the KSI-101 at multiple doses in both diabetic macular edema, where it was first in human and macular edema secondary inflammation. So on the left-hand side, under diabetic macular edema, 12 patients were treated, and enrollment is completed, 10 patients have completed the study, 1 patient is still ongoing in the study and 1 patient has discontinued treatment because they were lost to follow-up. In the macular edema secondary to inflammation arm, 41 patients were completed, and again, enrollment is complete, 10 patients have completed the study while 29 patients are ongoing, and 2 patients have discontinued their treatment. One was because of an adverse event of a uveitis flare-up that was consistent with their underlying disease. And I want to really focus on this because I think we have seen with other biologic therapies, uveitis or inflammation or retinal vasculitis and really concerningly occlusive retinal vasculitis from these -- from the therapies, and this is a top of mind really high concern for retina specialists and uveitis specialists. And so I'm always very, very cautious now with any new biologics. We were very, very fortunate with our first 3. So we were incredibly lucky that Avastin didn't cause inflammation because it was never really tested in the eye before it was put in. We were also fortunate that neither Lucentis or Eylea caused inflammation. But since then, we've seen inflammation with multiple different drugs that have been out on the market, including brolucizumab, which was approved, but we've not used very much because of its complications and Abicipar, which did not get approval because of how much inflammation it caused. But here, this patient did not have inflammation from the drug. Their inflammation was a flare-up of their underlying disease. And this is going to be challenging to differentiate sometimes. But we'll talk to it as we get to the safety side. So I'm presenting the preliminary data here. So if we go to the next slide, and one more, please. In DME, we looked at 3 ascending doses, 2.5 milligrams, 5 milligrams or 10 milligrams. Every patient was treated in the study regardless of which dose arm they got at baseline, Week 4, Week 8, Week 12 and Week 16. And the end of the study was at Week 24. Patients were included if they had treatment-naive center-involving DME of at least 400 microns and less than 650 microns and a best corrected visual acuity between 20/32 and 23/50. Next slide. Overall, the baseline characteristics were fairly well matched for a small study. You can't always do great but you see that there's not massive differences in a small study like this. But there are going to be some, and we see that visual acuity can be a little different. But what's interesting is the CST overall is pretty close, 442 to 485 is the range. And 1 out of the 4 in the first 3 doses -- in each of the 3 doses had a -- were pseudophakic. But the others were not. They were phakic. So next slide, please. And we see that there is a clear dose response here in that the 10 milligrams dose had the greatest reduction in OCT CST compared to the 2.5 milligrams and the 5 milligrams doses. And we see that it's rapid. So after that first injection, we see a significant reduction, but we continue to see improvement out through Week 16 with all of these injections. We do see some improvement in both the 2.5 milligrams and the 5 milligrams arms but not nearly as much as we see in the 10 milligrams dose. And if we combine those and look across the board, we see that after that last injection, we're seeing about 160-micron reduction overall. Next slide, please. If we look at best corrected visual acuity level change and improvement over time, we see that there is a rapid and sustained increase up to about anywhere from 10 to 15 letters at Week 20 in the first visit after the dosing period. And on average, it's about 12.5 letters. Next slide, please. But most importantly, this was well tolerated, very few rates of complications. There was 1 patient who had a traumatic cataract from their aqueous humor routine sampling as part of the study. So we didn't think the drug caused it. We think the actual aqueous humor sample caused the cataract formation in that patient. But otherwise, no other AEs were reported and no study discontinuation. No signs of retinal vasculitis or other cataract formation and really a very clean safety data. Switching gears as we go to the next slide, we can do 1 more. And looking at the KSI-101 in MESI, very similar design, 3 multiple ascending doses, 2.5 milligrams, 5 milligrams and 10 milligrams, more subjects, we have a total of 41 and dosing was slightly different in that patients did not get that 16 dosing but we still follow them out to Week 24. They had to have macular edema secondary to inflammation and a diagnosis of active or inactive noninfectious intraocular inflammation that could be acute or chronic. They had to have active leakage on a fluorescein angiogram with a CST of at least 320 microns and same 20/32 to 20/320 Snellen visual acuity test equivalent. Next slide. Enrollment is completed. And overall, the baseline characteristics we can see here is a little bit of a female preponderance which we see overall in uveitis or MESI type studies across the board. We see a mix of etiologies, so anterior, intermediate, posterior and panuveitis. We see a mix of active versus inactive and a mix of unilateral versus bilateral disease. Overall, best corrected visual acuity is about 20/50 to 20/60. And overall, CST is really a bit of a different range between 460 and 528. And here, a larger proportion of these eyes are pseudophakic. Next slide, please. When we look at what happens with the OCT data, we see again an improvement but less of a dose response here. We see that all 3 doses give you an improvement overall in OCT CST. When we look at the 3 different doses, it's 2.5 milligrams and the 10 milligrams are very similar but the 5 milligrams dose has a greater reduction. But when we look at it in the lens of dryness, so getting under 325 microns on OCT, we see that all 3 arms give you an equivalent amount of drying as time goes on. And so -- and we see that it's very rapid. Unlike in DME, where we saw continued improvement throughout, we see that the majority of the improvement is happening as early as Week 4. Next slide, please. Interestingly, we do see meaningful visual acuity gains. And I'll reference back to this, and we'll compare some of this data, and it's always -- you have to be cautious when you compare data across studies because there are heterogeneous patient populations and the patients enrolled in 1 study are not necessarily the same as another study but we do see that there is a significant visual acuity gain and that we see it across the board with all of the dose levels. We go to the next slide and looking at the proportion of eyes that are 15-letter gainers in those patients completing Week 12 we see that there's about half of the patients gained 15 letters. And I'll reference back to the vamikibart data, again, 2 different studies, 2 different study designs, looking at things different, all those caveats apply. But what's most powerful, I think, is the next slide, which looks at the proportion of patients achieving absence of intraretinal fluid and over 90% after the dosing period have no intraretinal fluid or subretinal fluid, which is just absolutely fantastic. And what's really, really fantastic is by Week 4 almost 80% of the eyes had no intraretinal fluid and 90% had no subretinal fluid. That is a massive improvement on the line of what we often will see clinically with intraocular steroids. But as we go to the next slide and look at the safety data, what we don't see is the complications of intraocular steroids. So we did not see elevated IOP in a single patient. We did not see cataract formation in any patients, which is absolutely fantastic. There was an episode of a recurrent uveitis flare up in 1 patient in each arm. And it was consistent with the underlying disease. There was a patient who had a vitreous hemorrhage secondary to their aqueous humor sample and aqueous humor sampling in eyes with the uveitis can be dangerous because when they're inflamed and you stick a needle in that eye, it can lead to complications and that's what I was alluding to with cataract surgery when an eye is inflamed doing cataract surgery can lead to complications and that's what we saw in 1 of the 2 patients that had a flare up. The other was thought to be related to their underlining disease. So this is fantastic. Now we have a therapy that's giving us improvement in macular edema in uveitis and inflamed eyes that is as powerful, may be more powerful than some of the intraocular steroids we use but it doesn't have that side effect profile of cataract or elevated IOP. And this is just incredibly powerful. So as we go to the next slide and look at where this fits in, I want to reference back to the vamikibart data that I was referring to. And go to the next slide, please. And here, like I mentioned before, with vamikibart in terms of 3-line gainers. And again, I will caveat this that you can't compare cross studies directly. But just to give an idea for where things sit, with vamikibart 1/4 to a 1/3 of patients gained 3 lines. And with KSI-101 on the next slide, we see about half the patients depending on the dose level, gained that 3 lines of visual acuity. Go to the next slide, please. When we look at proportion of patients with resolution of intraretinal fluid, we see it's about 50% after the 3 doses of vamikibart and this is different. And with KSI-101, again, nearly every patient had complete resolution of their intraretinal and subretinal fluid after forward doses. And so this is just -- actually after the 3 doses still because the Week 12 data is when they got injected again, but this was after their third dose. So this is just a very, very strong signal of effect. And if we put this into context on the next slide, we can see that it rapidly drives the retina after a single injection. So this is a little bit of a busy slide. So you have DOVETAIL with the 3 dose levels and the baseline CST and the reduction in CST written. We have the PEACHTREE study, which looked at suprachoroidal injection of XIPERE. We have the MERIT study, which I mentioned earlier, that looks at OZURDEX injection versus methotrexate injection versus ranibizumab injection. And we look at how these different meds do, and we see that KSI-101 has a stronger effect than all of them. Again, caveats for different disease populations, different study designs and all of that. But this really is just to kind of give an idea for this. If we go to the next slide, we see that, that dual inhibition really provided some of a synergistic effect and gave us better anatomical benefits than any really of these monotherapies, except for potentially steroids. But as I mentioned, we're getting the drying effect of steroids while avoiding all the complications of steroids. And so we'll go to the next slide. After the 3 monthly doses, we're seeing a drying effect that's on par with or even better than the intraocular steroid injection with OZURDEX. But we are actually seeing none of those side effects. And so this is just absolutely a fantastic effect, and it could significantly change how we treat these patients overall. So in summary, I will close with just some of my thoughts on the next slide, which is that I think that this is fantastic data that's very promising. And if this holds up in Phase III studies, and we see that the safety is really, really good, then we really have the opportunity for a paradigm-changing therapy in macular edema secondary to inflammation. Thank you.

Great. Thank you so much, Sumit. Next up, leveraging off what Sumit was telling us on that strong data. Charlie will walk us through the PEAK and PINNACLE trial designs, taking into account all the learnings we've had from KSI-101 to this point. Charlie?

Thanks, Sumit. Great job summarizing very impressive data, interesting and exciting for the field, MESI. Okay. So I'm going to now try to apply some of those learnings that we've had from APEX into the design of the Phase III program. I think you can go to the next slide. This is a lot to think about in the trial design here, and I think this is again, unique in the field for a few key reasons, and I'll point that out. So first of all, here's the overall structure of the trial, PEAK and PINNACLE. After I go through the general structure, we'll answer sort of what I think of as the 6 most common questions about this trial design, and we'll try to answer each of them sequentially. But the key inclusion are on the left side here, so MESI, what Sumit just described beautifully, macular edema secondary to inflammation, second, a diagnosis of active or inactive noninfectious intraocular inflammation, acute or chronic active leakage on fluorescein angiography. CST Of 320 microns or greater and visual acuity of 20/25 to 20/320. So all patients are going to receive monthly dosing of KSI-101, either 5 milligrams or 10 milligrams for the first 6 months that's through Week 20. And then the primary endpoint is the average of Weeks 20 plus 24. And then in the second 6 months of the trial, patients will be seen for 6 monthly visits and be retreated on an as-needed basis. And the retreatment criteria here are OCT based CST of 50-micron increase compared to the lowest previous measurement or CST simply greater than 320 microns, which again was the enrollment threshold to begin with. So importantly to me, patients are not being forced to lose vision before they get retreated. This is an anatomic decision, which is often and most commonly what we would do in clinical practice when the swelling is coming back, one of the key inclusion criteria, the patient will be retreated again, even if the vision has not decreased, which is optimal from a patient perspective. You can go forward. And then critically, this brings in the control arm now because remember, as I said before, when I think about a clinical trial, the very first thing I think about is the control arm. And in this clinical trial, it's actually sham treatment, which means that patients will get sham injections at each of the first 6 visits and then sham as needed injections for the next 6 months. But this is where rescue criteria are critical because our job as investigators to make sure that we're protecting again, all patients in each of the treatment arms. So what are those rescue criteria. Well, the first one is visual acuity loss of 15 letters and CST worsening of 100 microns from day 1. That would be quite a bit of vision loss. The second one is worsening of inflammation by 2 grades in the anterior chamber cells and/or vitreous haze or progression to grade IV. And then the third is intraocular inflammation complications in the study eye that did not improve and require rescue treatment to prevent irreversible loss of vision per the investigator's judgment. I think this is a great addition because it shows that the sponsor here is aware that all the patients enrolling here are trusting, they're positioned to do what's right for them. They're hopeful that they get the optimal treatment arms, which, in my opinion, would be the 5 milligrams or 10 milligrams arms but they understand that they may be in the sham arm because we're doing this trial program to try to get approval. And yet if they're in the sham arm, we don't want them deteriorating. And if there's anything that is not improving, which is what that third bullet point is, then the patients will be eligible for rescue, which I think is absolutely the right thing to do for patients. You can go forward. Yes, thank you. So the next study design question is, what are the key endpoints here? The primary endpoint is the same for both PEAK and PINNACLE, which is best corrected visual acuity, mean change from baseline to the average of Weeks 24 and 20. So the primary endpoint being there at a combination of Months 5 and 6. And then key secondary endpoints time to 15-letter gain is shared between PEAK and PINNACLE with an additional key secondary endpoint of time to 15-letter loss also in PINNACLE, and we'll talk about why that subtle difference. You can go to the next slide. Okay. So now the next 6 or 7 slides are the 6 most frequently asked questions about these trials with a clear answer to each one. So the first one, are these trials identical. I think the short answer there is that, yes, they essentially are but there are some subtle key differences. How they are identical is that there's 1 master protocol under which patients can be enrolled. So what this means is that study sites will have the opportunity to be in both trials automatically. So it's 1 master protocol, patients with MESI with CST of 320 microns or greater and visual acuity of 25 to 78 letters will be eligible. And then at enrollment, is when it will be determined if they're eligible for PEAK and PINNACLE. This is not a subjective decision. This is based entirely on anatomy, what we think of as disease severity as well as a visual acuity. So if there's moderate-to-severe macular edema, you go left on this flow chart in other words, CST of 400 microns or greater. And then if they also have moderate-to-severe visual impairment, they will go into PEAK, so PEAK is selecting for the worst eyes from a visual acuity perspective and an edema perspective. However, if they have moderate-to-severe edema with mild visual impairment, they will be enrolled into PINNACLE. And then on the top of the flow chart again to the right, if they have mild macular edema that which is less than 400 microns with any visual acuity then they will go into PINNACLE. So overall, PINNACLE is enrolling, what we think of as slightly more mild to moderate disease whereas PEAK is enrolling more of the moderate-to-severe edema with moderate to severe visual impairment. You can go forward. So next question, why are the APEX top 2 dose levels selected, why did we not choose the lowest dose of 2.5 milligrams. And this answer is quite simple. Sumit described this beautifully. This is based on efficacy. We saw the best efficacy signals there with both the 5 milligrams and 10 milligrams dose and we saw the same safety profile, and therefore, it makes sense trying to achieve optimal patient outcomes to select the 2 highest doses. You can go forward. The next key question is, why is mean change in best corrected visual acuity, the primary endpoint and not 15-letter gain or losers. I think this has a couple of different answers. I think the most obvious is that it increases the probability of success, right? I think it's pretty clear that we expect to be successful with 15-letter gainers and loser analysis compared to sham. But best corrected visual acuity, mean change, probably have the highest probability of success. But I think more relevant to a clinician and patient perspective is that I think every letter of visual acuity gain counts. If you gained 14 letters versus 16 letters, it's hard for me to tell a patient in clinical practice, the 14-letter gainer here is not a success, but the 16-letter patient is a success, right? If they've gained 1, 2 or 3 lines, those are all directionally positive for patients. And so I think it's important to capture that a patient population level, and I think best corrected visual acuity does that the best even if regulators are focused again on a 3-line change versus best corrected visual acuity. And if you look at what that data might look like on the right there or the APEX patients -- sorry, yes. On the right, the APEX patients in the 5 milligrams and 10 milligrams populations in showing a mean gain of over 10 letters. And on the left, for a possible comparison is a sham-treated population within PEACHTREE. And if you go forward, thank you. And now we're dividing out the APEX population into what we think of as the PEAK eligible versus PINNACLE eligible patients, again, based on the baseline CST and visual acuity combination. You can see that mean visual acuity can change is still quite meaningful in both populations, although greater in the PEAK population because, again, you're enrolling an enriched population for more visual acuity loss in that patient population. And we know from many trials over many disease states that the worse your vision at baseline, the greater probability you have of gaining more vision. You can go forward. So next key question is why are the key secondary endpoints different between PEAK and PINNACLE? And the first point I would make is that they actually are the same with the addition of 1 in PINNACLE. So the key secondary endpoint of a 15-letter gain is the same and is shared between PEAK and PINNACLE with the addition of 15-letter losers in PINNACLE. And the reason for that is, again, the baseline enrollment criteria. So remember that in PEAK, we have selected intentionally for patients with more severe disease, more severe vision loss and therefore, they're going to have a higher probability of being able to achieve 15-letter gainers. Whereas on the right here in PINNACLE, you can see some patients may hit their ceiling where they are unable to improve 15 letters because we're allowing better visual acuity in the patients within PINNACLE. However, some patients will still certainly gain 15 letters of vision. And then from an anatomic perspective, remember, we're selecting for the more mild-to-moderate macular edema as the case evidenced in the gray scale there on the right, the Heidelberg imaging. And you can see that, that's really more mild edema and while they will probably improve visual acuity wise, you see this patient does improve 6 letters, would be unlikely to expect a 15-letter gainer in a patient with an anatomy such as this. You can go forward. The next key question is how did the APEX data educate the probability of success for PEAK and PINNACLE? And I think, again, Sumit described this well. If you first look on the left here, the signal for visual improvement was strong in both PEAK eligible and PINNACLE eligible patients. You can see that 80% of PEAK patients improve 15 letters or more and that was 25% with the PINNACLE eligible. And again, you would expect this difference because, again, the PINNACLE population has been intentionally enriched or more mild to moderate visual acuity loss. So what could the control arm look like? Well, a good surrogate here, I think, is the PEACHTREE data, again, in the gray on the left side of the box here. If you look at all comers in PEACHTREE, 16% of patients had 15 letters gain or more. And if you look at just the PEACHTREE patients that we think will be most similar to the patients being enrolled in PEAK and PINNACLE that was patients from Israel or the U.S., just 5% of patients that improve 15 letters or more with sham treatment. On the flip side, with prevention of visual acuity loss, you can see that no patients in APEX that met criteria for PINNACLE, experienced 15 letters of loss. And in comparison, in PEACHTREE, we know that 72% of patients receive rescue medication suggesting that they had lost vision, or they were on the way to losing vision at that time. You can go forward. So I think my nearly my last slide here is, right, why are the primary and key secondary endpoints being evaluated at Month 6, Week 24 and not at Week 16 if the regulators would allow an earlier endpoint, why not take that exit and just get done sooner. And I think the answer here is that we saw an APEX a potential time effect where when more patients were dosed for longer, there appear to be improving efficacy over time. And certainly, there are examples, I'll show you one on the next slide in a second where there was essentially normalization of the OCT after just 1 injection and Sumit beautifully how the percentage of patients was quite dramatic after one injection of dramatic reduction in fluid. But there were some patients that continue to improve over time. Hence the hope here is that we can optimize outcomes for patients, both anatomically and functionally with more monthly doses up through the 6-month primary endpoint. And again, again, the primary and secondary endpoints will be evaluated on the average of Week 20 to 24 for mean visual acuity and the categorical endpoints will be assessed at Week 24. You can go forward. So my very last slide, just bringing this back to what Dr. Sharma had described right, that MESI is a new way of thinking about a common pathophysiology of blood-retinal barrier disruption associated with inflammation and VEGF-driven disease. We have lots of examples of this in clinical practice, and it is hopeful that combined anti-VEGF, and the anti-IL-6 treatment may provide a new opportunity for visual improvement and anatomic stabilization in these patients. With that, you can go forward, and I'll pass this over to Dolly to take us forward. Thank you.

Thank you, Charlie. And as a practicing glaucoma specialists, today, I want to take you through a brief journal of 2 patients that living with MESI. We know that this is an incredible -- incredibly difficult type of disease to handle. And so this story, I hope that highlight 2 things. One thing is, why do we need something better. And the second thing is how KSI-101 might help us rethink the entire diagnostic and treatment journey. The first story is from a fellow physician who became a patient herself. She shared this patient with me and showing the staggering number of eye drops she use every day. Her -- she was telling me that her MESI flare up often, even though DUREZOL works but it also caused significant eye pressure rises. So that's probably one of the reasons why she was never treated with intravitreal steroids because of the fear of glaucoma. And this is list the picture of the eye drop that she's taking. She is managing here managing her MESI with a cocktail of eye drops. So you can look at it. She is managing with Durezol, depending on -- multiple times a day, depending on how her MESI flare up. She's also taking an NSAIDs eye drop called ketorolac. She's also taking dilating eye drop to prevent scarring and multiple IOP measure -- lowering eye drops as well. And this case actually reflects a broader issue. There are many patients who are undertreated just like her because of the fear of steroid complication. And as Dr. Sharma mentioned about his clinical experience, we can see that from this study, MESI patients, about 60% of the MESI patients are not responding well to eye drops alone. And also at the same time, about 32% of the patient will experience IOP elevation when treating with chronic DUREZOL. And so these are not rare complications, this is daily dilemma that our patients and treating physicians are facing. Now we are walking through the second patient. This is a 52-year-old healthy woman who presented with bilateral blurry vision and floaters. On clinical exam, we saw mild anterior segment inflammation, some vitritis and scattered yellowish-white retinal lesions. At presentation on OCT, there was no macular edema at that time. And as part of the standard uveitis workup, you can see that she underwent a number of diagnostic workup that include blood testing, imaging testing and a panel of autoimmune and infectious workup, all came back negative, except HLA-A29. And in combination with the clinical presentation that led to a diagnosis which we call birdshot chorioretinopathy, which is the chronic bilateral posterior uveitis. And initially, she was treated with multiple systemic drugs, including oral prednisolone and then later on transitioned to methotrexate. And she is doing pretty well in terms of controlling her ocular inflammation. However, at about Month 6, even though with well-controlled intraocular inflammation, she developed macular edema. At that time, she underwent 3 cycles of IV Solu-Medrol and then started anti-TNF inhibitor, but she wasn't able to tolerate it because of the cutaneous reaction. Then she was switched to Cellcept oral immunosuppression, but her MESI still persists. And that's the time that she started to receive intravitreal Ozurdex, which is steroids treatment for MESI. And then she actually temporarily responds pretty well to the first Ozurdex but then the effect wane after 2 to 3 months and getting the second Ozurdex injection, and then the third one as well. But unfortunately, after the third injection, she developed cataract and also glaucoma that leading to a combined cataract and glaucoma surgery. But even that this wasn't the end as similar to the patient that Dr. Sharma just presented, after the surgery, patient developed permanent intraocular inflammation that required more steroids to control her inflammation, and then that's also causing her eye pressure to continue to rise. So eventually, this patient unfortunately has vision loss from not just MESI and inflammation, but also the complication from taking the medicine, steroids. So where does that leave us? Both cases showed the complexity of diagnosing and treating MESI, where the treatment itself can also become the problem. And then we can see that we have to weigh multiple factors to determine what kind of steroids we are going to treat with the patients depending on the underlying diagnosis. How was the response previously to steroids, what are the risk factors for glaucoma development, whether the patient has cataract surgery or not already phakic, pseudophakic and multiple risk factors to determine on the steroids. But what if there is a local therapy that is highly potent and safe that we can just treat MESI from day one and focus on that to avoid the surgical -- potential surgical complication and the IOP rise and the cataract that we are talking about. So imagine this, if this is KSI-101 and being approved in the market, if it demonstrates safe and efficacious, we are hoping that this could potentially really transform the way that we treat MESI patients. These patients really need a simplistic, safety and strength, highly potent drug to help with their visual outcome. So now with that, I'll just turn it over to Victor, who will walk us through the commercial opportunity for KSI-101. Thank you.

Thanks. We'll work quickly to wrap up and move into the Q&A. But before we do that, we'll jump into a little bit of an introduction. Well, first, a repeat of the problem statement. So ocular inflammation is the fourth leading cause of blindness among the working age population in the developed world, and MESI is a serious complication of ocular inflammation and is the primary contributor to the vision loss and blindness in this important group of people. So we remind ourselves with MESI, so a serious vision-threatening disease. It's chronic and has to do with the disruption of the blood-retinal barrier creating the edema and leading to the serious risk of vision loss. And it's triggered by a variety of underlying systemic and local autoimmune conditions. And as you'll see, it represents a prevalence of approximately 0.5 million patients in the United States, of which 300,000 are trial-eligible and fall within the inclusion/exclusion criteria for PEAK and PINNACLE studies by and large. And within that 300,000, we define and together with physician interviews, an initial KSI-101 addressable MESI population in the U.S. is greater than 150,000 patients. And those represent patients in the U.S. who are contraindicated for intraocular steroid injections or at risk of glaucoma or cataract development due to chronic steroid treatment or are refractory from chronic steroid treatment. So over time, avoiding -- over time, can you hear me? Yes. Over time, avoiding the consequences of longer-term steroid use, together with standard of care matched efficacy can support a first-line therapeutic of choice profile for KSI-101. So in other words, even within the 150,000, there's headroom up towards the 300,000 of trial eligible or even deeper into the 450,000 patients who may have a MESI population prevalence. So we're working to build a profile, right, with a differentiated potent, high strength, broad spectrum dual MOA biologic. And we hope through the data that we've generated today and the breadth of the patients as Sumit and the team and Charlie and everybody demonstrated that there's the potential for a simplified, safer and earlier MESI patient journey. With historically physicians treating patients based on the presumed etiology resulting in a lengthy trial and error patient journey, we offer the promise -- the early promise based on the 12-week data in the APEX study and the studies we're going to perform in the PEAK and PINNACLE registrational program of simplifying the MESI diagnostic in patient journey. And fundamentally, upgrading the ophthalmologist as the primary ocular caregiver and improving patient outcomes across the etiologies. I think there's quite -- based on early physician interviews, which is quite early in our landscape analysis quite a lot of excitement from physicians. They're impressed by the safety and the efficacy profile. They note that it lacks to date. The serious negative consequences of chronic steroid use, including glaucoma and cataract but it has strong efficacy across etiologies on par with current ocular -- intraocular steroids. So just very quickly, looking at the U.S. MESI epidemiology, so what we did is we used 2 separate methods to estimate the population. The first one is a top-down approach where we took all the patients with macular edema and subtracted out wet AMD, DME and RVO as well as other known etiologies such as epiretinal membranes, retinitis pigmentosa, leaving approximately 0.5 million patient prevalence who are MESI patients. The second approach we did to verify that was a bottoms-up approach, where we took the epidemiologic data and added the patients who we know have the etiologies of MESI. For example, we estimate the proportion of patients with uveitis will develop macular edema. So that would be those with known autoimmune-related causes, those with ocular inflammation without a known etiology, and we call them the idiopathic no known etiology group. In the post-procedural inflammation group and adding those together is also approximately 450,000 patients. So the confluence of these 2 methods that's what we mean that lends confidence and credence to the MESI patient prevalence. But we know that the post-procedural, for example, with MESI -- with macular edema, they can often resolve with topical eye drops during the acute post procedural period. And these are not the patients we're targeting nor enrolling. And we know the infectious macular edema patients, for example, although steroids are used in them, but in any case, we're excluding them in our trials. So there are some other macular edema patients, those with epiretinal membranes I mentioned and the retinitis pigmentosa. And although they may benefit from KSI-101, again, we're excluding them from our trials. So it leaves us with approximately 300,000 or 298,000 patients who are KSI-101 trial eligible in the United States. So these data, and they're also epidemiologic, then they're supplemented and supported by practice pattern information. Okay. So obviously, not all the trial eligible patients will be treated with KSI-101 initially. And while the safety and efficacy data are maturing in the community and the payer landscape, what we see here is initially the 455,000 total MESI prevalence, okay? We're moving the acute patients who are post procedural and infectious, leaving 298,000, then perhaps the 70,000 patients who would be well treated as Sumit and Dolly mentioned with topical steroids and perhaps the addition of some oral anti-suppressants. From there patients who will be perhaps treated with single intraocular injections of steroids, right? Maybe in the future, those could become first-line patients for KSI-101. But for the time being, we exclude those. And we end up with those patients in orange here on the right as the 101 initial addressable population for those patients contraindicated by intraocular steroids, those treated with multiple intraocular steroid injections and those who are refractory to intraocular steroids. And all of those are good candidates for the 101, the initial addressable population. And again, as we say, it's north of 150,000 patients. Yes. This next slide quickly is an interesting and preliminary analysis of ophthalmology physician practices. So it's another way of looking at the number of patients. In this case, it looks at the percent of macular edema patients by patient subtype across physician types, ophthalmology types in the United States. So essentially, what percent of the patient case load for each type of ophthalmologist is a MESI patient. So surprisingly, across the United States in all types of ophthalmology practices, the MESI indications represent about 8% of patients with macular edema from all causes. And this is excluding, again, wet AMD, DME, RVO and other causes, which is quite a lot we felt actually. And from a general ophthalmologist standpoint, represents around 26% of their patient volume. And even for retina specialists, the data suggested that as many as 17% of their volume of patients represent the MESI indications. And for uveitic specialist, uveitis, it represented around 40% of the case load, which makes sense. And of course, there aren't that many uveitis specialists in the United States. So this is sort of the beginning of our landscape analysis. I think just to remind ourselves, and this was sort of an interesting quote. I mean physicians were impressed with both the rapid response by Week 4 that we were seeing with 101 and also the diversity of the etiologies that are responding to KSI-101. And as we kind of said and Sumit and others, this is a very nice quote by retina specialist. It's not much different than using anti-VEGF to treat DME, the AMDs and the RVOs. Those are very different diseases with very different pathophysiology. But at the end of the day, the medicine is the same and it works well in all 3 diseases. I didn't see that before but seeing these pictures and seeing the data you showed me, I don't see a reason why I wouldn't want to use this medicine as a unifying therapy across all of these different etiologies, what we call MESI. We include in the deck that's on the website, some backup slides for landscape analysis and some physician interviews. So in summary, I'm so proud of the portfolio of the opportunity that we have in front of us here at Kodiak. We talked about KSI-101 in MESI. We talked about tarcocimab and KSI-501 in the anti-VEGF market, and Charlie articulated the very nice 4 quadrant analysis and our focus as a biologic in that upper right quadrant. We also talked about the pivotal studies across all 3 molecules, the 4 studies that are in progress and the expected time lines for the top line data readouts for those studies. Kodiak as a company, we're in motion and we're accelerating. And that's why I've never been more excited and optimistic about what lies ahead for Kodiak. Thank you very much for participating in the R&D Day, and we're now going to open it up to Q&A and questions.

Our first question comes from the line of Michael Yee of Jefferies.

Thank you for a very comprehensive overview and thank you to the 2 doctors. Maybe just a question for the doctors. On the MESI plan, can you describe your expectation for the Roche results? I presume you think those will be positive. I think you were saying it's about 20% to 30%, they get above 15 letters and that Kodiak results will be significantly better than those results, but those would set the initial bar. Maybe talk about that and Roche coming first. And then on VEGF and tarcocimab, I know maybe that's still going on, of course, trying to finish the execution there. Maybe for Dr. Wykoff, you could talk a little bit about how you expect those results to play out. And I know that there's been some increasing questions we've gotten about the TKI. So do those matter at that point and this point? And maybe just how do you compare and contrast.

[indiscernible] our data. As I caveat it, it's very hard to say and compare across studies. But what we do see, and I think what really will drive some of this is the rate of resolution of macular edema or the rate of resolution of intraretinal fluid in that 50% rate with the vamikibart molecule versus KSI-101 getting a stronger reduction in overall edema that I think that synergistic effect really does play a role. And I think that, that is a key differentiator here and would lead towards at least on looking at the 2 Phase I studies that the effect would be much stronger for KSI-101.

Yes, I think that the tarcocimab question, both the TKI and then the trial readout. I think DAYBREAK really kind of puts it all on the line, if you will. I think that we're going to see how durable tarcocimab in this bioconjugate with the free protein really is. And I think based on all the data that we have; we expect to see significant signals of durability. But what's nice is that we're not shoehorning patients into certain buckets, right? You're not forcing patients to be Q12 when they have persistent fluid that might be getting worse even though they haven't lost vision, which is what many other trials previously have done to kind of game the system, if you will, to show a signal of durability when it may not be accurate. And this trial really puts all on the line that the threshold to retreat monthly is actually very low. It's just above noise. So there's basically any significant fluid left in the retina in the central 3 millimeters, the patients will continue to receive monthly dosing. So I think we're going to get a really good feeling for true durability out of DAYBREAK. I'm impressed the design is so patient centric in that regard. And then the question of how that is going to stack up against the TKIs. Again, as I said before, I am supportive of both of those programs. We have 2 programs that are in Phase III for tyrosine kinase inhibitors. I think there's a role in clinical practice for tyrosine kinase inhibitors. But I think that each program has its strength and weaknesses. And I think from a TKI perspective, I think we have learned that while there is a durability signal, the immediacy of those drugs may not be as robust in many eyes as bolus anti-VEGF, pharmacotherapy. And that's why those trials are designed with a series of anti-VEGF injections upfront before patients receive the tyrosine kinase inhibitors. So that's quite a different paradigm than tarcocimab, which is a molecule that has both immediacy effect and then a durability effect because of the bioconjugate. And so I think that there's a role in the space for both, and I think that they are just different development programs looking at slightly different patient populations within AMD.

Our next question comes from the line of Michael DiFiore of Evercore ISI.

And thanks for putting on such a terrific and comprehensive event here. Just thinking about Phase III for KSI-101. When we think about just the baseline characteristics, to what extent may having active flares or inflammation at baseline influence outcomes in a much larger set of patients compared to Phase I. I mean are these predefined subgroups that you plan to look at. And just kind of want to get your thoughts on how we should think about risk here in terms of just confounding factors.

Sumit, do you want to take the question first?

Sure. Yes. So I think one of the interesting things about the Phase I design is that we see there is a mix of active and inactive patients, and there was quite a range of that throughout the -- in the study. And I think in terms of baseline activity, I think you'll see a similar mix in the Phase III. I don't think it's going to be all that different because we had about a little more than half that were inactive. So about 40% across the board that were active, and we saw improvements across the board. Yes, there is always some risk when there's active inflammation of something else happening but I don't think we've seen that, and we didn't see that with the vamikibart studies either, which had a similar set up. So I think overall, I would actually say a low risk overall.

Yes. And just to add to Sumit's answer. So if you focus -- Sumit talked about the safety of the KSI-101 molecule in MESI patients. If you look at the footnote on that slide, that one patient that had recurrent inflammation that had the vitreous hemorrhage, it's a patient that had very significant inflammation at baseline. I think plus 3 anterior chamber cells and haze. So very significant and active inflammation, angry inflammation as we call it. And if you look at the footnote as well that patient did really well with, I think it's plus 24 letters currently and no inflammation. So as Sumit was mentioning, we don't see any difference in treatment response in active versus inactive in this small subset of patients. And like this kind of like individual patient-level data helps to support that, and we don't expect any difference in a larger set.

And maybe just to add on top of Pablo. So if you're looking at the trial inclusion and exclusion criteria, we did require patients to be on stable immunosuppression or regimen that a patient doesn't anticipate to add additional -- escalate additional therapy for uveitis. So in other words, generally, patients are relatively well controlled. They may have active inflammation but not in a fulminant activate -- fulminant active inflammation at baseline when they enter the clinical trial.

Our next question comes from the line of Anupam Rama of JPMorgan.

This is Billy on for Anupam. Thanks for the detailed overview today. One for the KOLs on the call for us, if that's okay, is just looking between 101 and vamikibart, how are you seeing like relevant patient populations for each of these drugs? And then of the 150,000 patients, how do you think that split kind of works.

So I think for vamikibart, you don't have the postoperative patients, and you don't have some of the other categories that are included in MESI. And so I think the patient population is much broader for KSI-101 because of this new definition of macular edema secondary inflammation. And I think that, that broadens that overall patient population here. And I think that the overall group is maybe even larger than that 150,000 number gets at because as I was intimating, there are a large number of these patients who get undertreated because of the concerns of intraocular pressure elevation.

Our next question comes from the line of Gena Wang of Barclays.

This is Justin on behalf of Gena Wang. Looking at Slide 68 and 69 , it seems like in DME, KSI-101 shows the dose response and CST change, but not for the change in BCVA letters, but then on Slide 94, there does seem to be a better dose response in the MESI patients but the 5 milligrams group still had a greater proportion of 15 letter gainers than the 10 milligrams group. So how do you guys interpret this? And are you still confident that we will see a dose response in the primary endpoint for PEAK and PINNACLE? And also, if you don't mind, I have a second question, just switching gears briefly. Can you also comment on any specific indications you're targeting first with KSI-102 and 103. And overall, how do you see them complementing your existing pipeline?

Sumit, do you want to start, and I can continue.

Yes. So I think as I mentioned, the DME population is a little different and DME patients tend to respond a little slower and that's not unusual to see that difference. I think it's hard to compare between the 2 groups. But what's -- the more interesting portion for me is when you go over to the percentage of eyes that are really dry or getting under that 325-micron threshold, that proportion is greater across the board, and it's for the UME group or the MESI group, where you see almost every eye is getting underneath there. So yes, we don't see as clear of a dose response but it's also a much more heterogeneous population. And if you look at the baseline characteristics, they are slightly different between the groups that total amount of edema is different between the groups. And so I think it's really hard to compare there. I think what is interesting on the visual acuity side is we are seeing a difference, and that fits with that there being still some level of a dose response.

Yes, if we can go to Slide 74, This is what Sumit was talking about. So what is important, well, you can interpret the DME data in that way and it's quite evident, it's up for patient cohort for each dose level, right? So it's a smaller sample. Here is larger. And what Sumit was saying like what is important is where you get to, right? The magnitude of the gain has to be with -- has to do with the baseline CST. So what is nice to see is that level of drying is at 325 or below is achieved with all of them. And basically, some of these like 325 is like the threshold, and it depends on how you measure it and some of these patients with chronic inflammation with chronic therapy, they can go atrophic a bit. So then their normal could be 250. So that -- like that band of dryness is the sweet spot and all of them get to the same level. So that's what it's nice to see. We don't think that there's a dose response. What we see is that all those levels are quite bioactive.

You want to talk a little bit about the DME data for 101, Pablo and...

I think Sumit summarized it. If we go to Slide 68, and like this was the first in human. This was more towards the safety, and as Sumit was showing like that safety slide is as good a safety slide as you will get. And so that is the check that we wanted. Again, here, you can interpret the difference of magnitude of the 10 milligrams dose being superior like having superior dryness. But the reality is that the curve on the right is a bit more informative, right? It's -- there is bioactivity in all of them. And here, what you can say in a 4-patient cohort per dose level, 10 seem to be better and actually kind of quite supports our decision to go with a 5 and 10. If you look -- if you want to see it that way for the PEAK and PINNACLE Phase III program, I think that, that supports it well. But again, we don't think that difference in magnitude is real. That's why we showed both curves.

Sumit, you mentioned you may have to run in a moment.

Sorry, but thank you.

We appreciate all your contribution. Thank you so much. We're still available for a couple of questions.

Actually, no further questions in queue at this time.

Okay. All right. Well, listen, thanks very much. Thanks, everybody, for listening. The deck will pop up on to the events and presentations website. The webcast will also be there in a little bit longer, and we thank everybody, including the KOLs for presenting. Thanks.

Thank you.