Element is we have technical leadership and ownership in-house in the company, which allows us to execute in a timely and very cost-effective manner. We have a diversified late-stage pipeline with three shots on goal, each in a FDA-facing development plan, with filings as early as, say, mid-2026. Tarcocimab is 90% of the way completed, both from a spend, let's say, and time standpoint. The clinical and CMC costs have already been incurred, and the enhanced formulation is designed to deliver both the pulse and the durability in the patient. We believe that there's still a very poised commercial opportunity in the marketplace for our ABC medicines, for Tarcocimab and also for KSI-501, which is our bispecific conjugate and brings the potential for both greater efficacy and the signature durability of the ABC platform. KSI-101 represents a greenfield commercial market, the ability for near-term data starting in Q1 of next year. And as an uncorrelated asset to the ABC platform, is important as part of our broader diversification and is a fast follow dual MOA possibility with very high strength. And as a company, it's important to remember that we have tremendous independence. We have the flexibility to make the right choice for each Kodiak asset at each moment. We own global commercial rights to all of our molecules. We've built a complete and approved high-volume commercial manufacturing facility for Kodiak ABC medicines, and we have the freedom and flexibility on how best to commercialize our molecules if approved. And our cash runway is expected to support operations into 2026. We, we try to be a learning organization, and through our journey, we've gathered key insights to transform these learnings into actions. Starting with our phase I-B study, where we dosed patients initially in January of 2019. What we saw was a well-tolerated profile with a six-month predominant durability profile, and we moved quickly to put tarcocimab into pivotal studies. What we saw in our DAZZLE study was strong durability, but we also saw the first sign of an immediacy deficit in wet AMD, in terms of the overall activity through the loading phase. And we also had an overly aggressive study design, which at that time was maybe asked for and appropriate, but was really not needed. Our BEACON study in RVO reinforced our durability. In the GLEAM and GLIMMER studies, although we saw a six-month predominant durability profile and strong immediacy, an increased cataract rate specific to DME was noted. The GLOW1 study generated tremendously strong data with all patients on six-month dosing. The Ursus facility is now approved, as I mentioned, for commercial manufacturing, and it's already working and has made the enhanced formulation which was released in November of 2023. We decided to expand our pipeline in February of this year, adding KSI-501 with its durability and the potential for greater efficacy. And we also added KSI-101 to the pipeline at that time. The GLOW2, DAYBREAK, and APEX studies are now enrolling, and just more recently, in the last month, we finalized an analysis of our human ocular PK data supporting our signature durability profile. So a number of very positive findings. tarcocimab and the platform are well tolerated. A differentiated six-month durability is real, and ocular PK data supporting that durability, so it's a true platform. But we also identified really critical and important issues that we decided we couldn't live with, and we needed to fix: the immediacy deficit in wet AMD, the increased cataract rate specific to DME, and taking overly aggressive bets on our clinical study designs. The actions were to build an enhanced formulation to course-correct issues identified both in wet AMD and DME, new study designs educated from prior studies anticipated to have a higher probability of success, and to diversify the portfolio into KSI-101. We thought we would address at the beginning four questions that we've gotten from investors, and we would tackle those head-on before we got started. So why are we running another wet AMD durability study for Tarcocimab, given the failure of the first study? Well, why did DAZZLE not meet the primary endpoint? The first is that we undertreated a minority of patients, forcing all of them onto Q12-week dosing, which was not tolerated by that small number of patients. And we compounded that by having a weaker immediacy of our drug through the loading phase, which we hadn't known before, before the study. And the combination of those led us to fail the non-inferiority endpoint. So how do we solve the undertreatment? Irrespective of the drug tested, some patients require frequent and monthly dosing. So in DAYBREAK, our new wet AMD study, we had a fourth loading dose. We allow dosing as frequently as monthly. We do proactive or what I call pre-active treatment until dryness, and we detect disease reactivations earlier using new tools and new approaches that Dr. Wykoff will discuss. In solving the weakness in immediacy, the problem was the slow loading of the high molecular weight conjugate in some patients, and Dr. Brown will discuss that. The solution is a basal bolus type enhanced formulation combining conjugates as well as unconjugated free protein. And the free protein portion alone for tarcocimab has a VEGF binding equivalent to 1.3mg of aflibercept, plus the full power of our conjugate. And therefore, we continue to bring the uncompromising-... What about question two here? Will the cataract imbalance seen in the GLEAM and GLIMMER studies impact the success of tarcocimab and KSI-501? So why did the GLEAM and GLIMMER studies not meet the primary endpoint? And the reason is an unforeseen increase in late-onset cataract adverse events. So this was specific to patients with advanced diabetic eye disease. So the problem is the mechanical insult to the lens capsule, which is known to be more fragile in DM patients who have swollen lenses during hyperglycemic episodes due to the gel-like consistency of the Tarcocimab old formulation and the high force needed to inject it and the prolonged time to do so. And notably, what's important is that the cataract rate in wet AMD patients on monthly Tarcocimab was lower in the DAYLIGHT study than it was with the Lucentis, the comparative. So the solution, you know, is the enhanced formulation of Tarcocimab with less biopolymer amount, significantly reduces the injection time and force, which decreases or eliminates any potential insult or issue to the lens capsule in DM patients. So we believe that the enhanced formulation would be expected to bring the cataract rate back down to the levels associated with a biologic if we were to run another DM study. Question three, what's the commercial opportunity for tarcocimab and 501 in an increasingly competitive landscape? And we'll spend a little bit of time here because I think it's an important overview. So, is there space for new treatments in retinal vascular diseases? So intravitreal anti-VEGF biologics are the mainstay of therapy for patients. And despite limited differentiation, Gen 1.5 biologics, the Vabysmo and Eylea HD, they have significant market uptake. They have high efficacy, but limited true durability, and our guests today will be able to discuss that together with us. There remains a high interest and a high need for a mainstay biologic with high efficacy and high durability. Tarcocimab and 501 have the potential to be meaningful products in this marketplace. The science of our platform, now and of our enhanced formulation, delivers immediacy and durability. Tarcocimab and 501 are being developed as mainstay biologic monotherapies for all patients, treatment-naive, treatment-experienced, mild patients, and severe patients. Pivotal studies support a wide range of dosing from monthly to six-month dosing. If successful, the initial BLA package for Tarcocimab could provide approval for three indications at once: diabetic retinopathy, retinal vein occlusion, and wet AMD. We have complete commercial flexibility in our approach to how we would commercialize these medicines. With a differentiated clinical profile, along with creative and thoughtful commercial strategies in a $14 billion-plus and growing marketplace, Tarcocimab and 501 have a meaningful commercial opportunity if approved. What do we mean when we say a mainstay biologic? Well, Tarcocimab and KSI-501 are being developed through our development plan as mainstay biologics, monotherapies that provide high efficacy and durability in a flexible one-month through six-month label. If you look at Eylea and Lucentis or Eylea HD or Vabysmo, that's what the current industry is set to manufacture, to approve, you know, and to provide to patients. Initially, Eylea and Lucentis as Gen 1, and Vabysmo and Eylea HD now. But the jury, you know, has come back, and we understand in the clinic and for our retina physicians, how those agents are performing. I think they don't show true durability necessarily. They may show some, you know, mild improvement, but they don't definitively solve the problem, where you want to have high efficacy and high durability. And that's really where Kodiak is developing towards with both Tarcocimab and KSI-501. They're intended to follow in the Gen 2.0 agents that follow directly from the biologics and as a mainstay biologic. Whereas other novel therapies that are, say, earlier in development than where Kodiak is, the TKIs and the depots, right, or whether it's gene therapies, those are largely alternative therapies or adjunct therapies for different subsets of patients after evaluating the mainstay intravitreal biologics. So maintenance agents to be used in a subset of patients after intravitreal biologic monotherapies have established disease control. Question four: Will our cash runway last through top- line readouts of ongoing clinical trials? Well, our cash runway is expected to support operations into 2026. We believe we have increased our probability of success utilizing our historical learnings and corrections. So in Tarcocimab, the GLOW-2 has an additional loading dose compared to the unequivocal GLOW-1 data that was very strong. DAYBREAK optimizes treatment for each patient and incorporates our enhanced formulations, and these address our two key insights of undertreatment and immediacy deficit. So with Tarcocimab, we're running that in DAYBREAK as a durability arm, and in 501, we actually have a different objective, and are running 501 to explore optimal efficacy with intensive dosing. And in KSI-101, we bring an uncorrelated asset to the pipeline with an early 16-week primary endpoint GM. So we believe and anticipate a high probability of success in these studies with readouts, let's say, for GLOW2 in early 2026 and DAYBREAK in the first half of 2026. A nd KSI-101 beginning to generate data, open label starting in Q1 and Q2 of next year, and dosing pivotal studies through 2026. Our studies are run fully in-house without a CRO, increasing efficiencies and reducing cash requirements, and we own commercial rights to all of our molecules, both ex-US and US. So we can decide to act on the option to partner and retina as an area of high partner interest. So we anticipate approximately $200 million in cash and equivalents at the end of the third quarter of 2024, just in the next couple of weeks. And importantly, we remain committed to raising capital at the right times and in the right ways to enable cash runway through critical milestones, while maximum preserving value for existing shareholders. An important summary of our clinical programs and timelines is included. We're actively enrolling for tarcocimab, the GLOW-2 study. We're actively enrolling for tarcocimab in KSI-501 in the DAYBREAK study. We hope to complete enrollment for the GLOW-2 study by the end of this year or early next year. For the DAYBREAK study, we hope to complete enrollment towards the end of Q1 or early Q2 of 2025. For these 48-week primary endpoints, that drives the timing for top line data readouts. Okay, into early Q1, let's say, for GLOW-2, and for say, mid-Q2 in 2026 for DAYBREAK. Meanwhile, in the KSI-101, we have the APEX phase I open label study that's similar to the Roche DOVETAIL study in their anti-IL-6, where we'll be sharing open label data on different cohorts and different dose level cohorts in patients with inflammation. And we plan to begin enrollment in our key clinical pivotals in early 2025. So in summary, with three clinical programs leveraging Kodiak's fifteen-year history, Kodiak is at a decisive moment and represents an exciting investment opportunity. So Tarcocimab and 501 is our conjugates, with upcoming milestones coming out of the GLOW-2 and DAYBREAK studies. And for KSI-101, as an interesting, novel, separate greenfield opportunity, our phase I-B APEX study clinical data will start to be disclosed in early in the first half of 2025, with phase III initiation a similar timeframe. So what is our vision for Kodiak in 2026? Top line data readouts for KSI-101 from twin pivotal studies in inflammation with a BLA in preparation. Tarcocimab, a BLA filing, and diabetic retinopathy RVO will be supported by five successful studies, including GLOW-2 and DAYBREAK, if successful. For KSI-501, where we want to be exploring the potential for better efficacy than existing agents, we'll be one study away from registration. We expect between now, by the end of this quarter, approximately $200 million in cash to support our operations into 2026. Very quickly, we'll talk a little bit more at the end, the concept of continuing to further our ABC platform, an evolution that allows us to bring drug cargo in the biopolymer, and where you can have the antibody or not. But we've shown that the biopolymer alone has the same exit profile and the same half-life as the conjugates. So bringing diverse APIs like peptides and small molecules into the polymer, having a drug antibody ratio of up to 100 or 200 as needed, we've shown we can do that, we can release those on command, and it leverages the proven safety record of the ABC platform. A new combination of targeting high drug loading, mixed API formats, and tailored drug release is real, with application to ophthalmic and systemic disease. We believe, based on the fact that it really leverages all of the knowledge and expertise and capabilities, resources, and even commercial manufacturing capabilities of our existing ABC platform, we can move those new programs that Dr. Chang will talk about quickly into the clinic. On that note, with that introduction, I'm going to bring Dr. Brown up here, and he's going to begin to walk us through some exciting science that we've been doing. Thank you very much. Charlie and I are happy to be here. Unlike a lot of my colleagues around the country that do Investor Days, Charlie and I are not a monkey. You wind up and you hear what the company tells you. So we're both very candid, for better or for worse. I'm going to start with some data that I presented at Retina Society and some initial data before that at Macula Society, that I presented to Kodiak, and I said, "You need to do this, because this may prove why you actually ought to continue on this platform." This talk is talking about I was asked initially to give a talk for the Royal College of Surgeons in England as the keynote speaker on why is twelve weeks the new norm? And so the problem is, spoiler alert, for most people, twelve weeks isn't the new norm, and both clinicians and the investment community thinks that this drug is a 12-week 16 -week drug, but in the clinic, it's not. And why is that? So MARINA and ANCHOR, this is a paper I wrote in 2006, seems like a long time ago, that started the anti-VEGF with ranibizumab. And you see, if you give an effective anti-VEGF consistently and constantly, you have a vision gain that maintains that gain. If you look at a lot of our trials over the last three or four years, you have that gain, and then it tapers off because we undertreat. It's all an attempt by marketing to say that I've got a 12 - or 14-week drug, et cetera. So when we tried to use ranibizumab quarterly, this is the PIER trial, and what it shows is three doses, and then you lose all the gain on average over the course of twelve months. So the interesting thing is, there were some patients that did okay, and even on quarterly dosing with ranibizumab. And I went to Genentech, and I said, "Can the reading center tell us if you maintain a dry retina with quarterly dosing, did you maintain that vision gain?" And the reading center couldn't do that. I had written this paper with Carl Regillo, which defines a few things we look at a lot today, subretinal fluid, intraretinal fluid, sub-RP fluid. I got the original pictures from PIER, and we had two images, and I read them all in a mass fashion, 6,000 images. I'm crazy. It showed that if you maintained a totally dry retina, in other words, no intraretinal fluid, no subretinal fluid, not 100 microns, not losing vision, not all the stuff that we don't do clinically, you maintain vision with that orange curve, versus if you didn't control your wet AMD quarterly, you lost that vision. So this is the first time we showed that absence of OCT fluid correlates with vision gain. But for the purpose of this discussion, the most interesting thing to me is: What's different? Why do a 1/3 of the patients in PIER do okay with quarterly dosing with a drug that we know the average patient can't get by with? I'm going to convince you that one of the major components is drug clearance. We know that axial length increases, pseudophakia, vitreous syneresis, that means more liquefaction of the gel. All those things increase drug clearance. We thought, but wasn't proven until this, that anti-drug antibodies probably increase drug clearance. This is public knowledge from the FDA filing data for tocilizumab, showing that if you have any drug antibodies, you'll need to go to a more frequent dosing, Q8, is statistically significant, point zero four. What do we know about the half-life of drugs? The most one, the one we've given eighty million doses, aflibercept, we don't know that much. All we know is a five-patient study. Let me repeat that. Five patients is the only thing out there on drug clearance with aflibercept, but for some of the data I presented at ASRS. And what it shows that the mean somewhere around 10, 11 days median. But the interesting thing is, if you look at the five patients, four of them were along that curve, but one of them had a half-life of 3.7 days. This is a published paper by Diana Do, showing that some people really clear drugs fast. What do we know about clearance in other drugs? This is the best data we have, and it's in the Genentech filing data. It's public knowledge, fda.gov. And you see that the average half-life of faricimab is a little less than 8 days. But here's the most interesting part. 10% have a half-life of less than five days, and 10% have a half-life of over 11 days. And does that correlate with increased dosing? They did the work for me. They actually show the logistic regression of probability of needing more frequent dosing. Like, if you clear a drug faster, your statistical needing more frequent dosing is 0.0005. This is in 628 patients, not 5. The FDA made them do a lot after bevacizumab, and most wanted to do it, and they published the data. So this is, this is requiring Q8 or Q12. Again, if you clear drug fast, you need more frequent dosing. This is in diabetes. You see the same kind of curves, interestingly, a little bit less, less frequent half-life. It's probably due to glycosylation and maybe breakdown of blood-retinal barrier, but the frequency of needing more frequent dosing is directly correlated. So how does this relate to the waiting room, my waiting room? These are all angry patients waiting for their injection, and all our trials are treatment-naive, including all the Kodiak trials. So in a treatment-naive population, there's a normal distribution, where you got average clearance in the middle, and then you have lucky people, like this guy, and he's a slow clearance guy. So he's the type that, even with ranibizumab, can probably go 10 weeks, 11 weeks. You know, with the aflibercept, that's that amount of number. Where is he in my clinic? He's not there very often. He's only coming in every three months. Then you have this part of the bell curve. If he's not there very much, really goes away. So our clinic, and the actual drug volume of sales, is really skewed to those patients that need drug all the time. A lot of my clinic is guys like this guy. This is a Muppet, and he's saying, "Why me? Why do I need dosing all the time?" And he's the type that has fast drug clearance. So he's this part of the bell curve, and where is he in my clinic? He's there every month. So there's 3x as many of those as the slow clearance guys. So all my clinic is this guy. So this is anti-VEGF molar equivalency. In other words, if you take aflibercept 2 mg s, what is one, then ranibizumab is about point five to point six. Faricimab should be 2.3, and by definition, aflibercept is 4.0, right? Because it's 8 mgs. Take half-life, and go down to 4 mgs. Another half-life, you're down to 2 mgs. It should give you two extra half-lives. So people come in with a distribution. My answer, my question, is 12 weeks the new norm? If your half-life is 10 days and you double it, you get 21 extra days or three weeks longer. If you're this lucky guy, and your half-life is 14 days, you double it, you get a month longer. But half my clinic is these guys. They've got a half-life of five days. You double it, he's only getting 10 days longer. So is 12 weeks the new norm for the average person? Maybe. For lucky, slow clearance time, he may even go longer. But this guy, the guy that's half my clinic, five weeks is his new norm, even with the fancy new faricimab, an 8 mg Eylea. But it's better than monthly. So what I'm telling you is, if you have a drug that actually lasts longer in the average patient or in any patient, it's incrementally better. If you look at it, aflibercept is incrementally better than ranibizumab, and it's a $10 billion drug, right? It's not that much better, but it's better. So the question is, can Kodiak do something to make their drug where you get the same curves that maintain, but go longer between doses? So currently available options, increase dosing frequency, block additional targets, molar blockade. With the ABC platform, theoretically, we should be increasing drug half-life. Does that pan out? So what I'm going to show you is, is it needed? It's definitely needed. Half my clinic is needing more frequent dosing than Q seven or six with faricimab with 8 mgs. They showed in the, in their trials, and the problem with the trials was it started with brolucizumab, with Beovu. Beovu, the agency, lets you do this trickery where you had one group that you treated three doses in Q1, and the other one, you had to have so much fluid or so much vision loss. In real life, I would never let your mom have increased fluid or have lots of vision before I retreat. It's like a horse race where you handicap one group, but then you let the other run fast, right? You're definitely going to show that you have less doses because that's just built into all the trials. With that, you know the trials, but they showed five- to six-month durability with their dosing criteria. It's hard to correlate that to the other drug because it wasn't a fair horse race. The conjugate design should be with a bigger molecule, should make a slower half-life. This is the data from Genentech, and this is published, where they took ranibizumab, and they made ranibizumab bigger, different formulations, and they showed that the half-life correlates with the size of the protein in a linear fashion. This is published in Translational Vision Science and Technology. This is a big boy. This is sort of the sumo wrestler of our drugs. This has, you know, instead of being 140 kilodaltons, this guy's 950. Ranibizumab, if you remember, 48 kilodaltons. Brolucizumab was 26 kilodaltons. Really, really small. That's why they could pack so much in. And if you look at molar equivalency, here in this big molecule, you still have pretty close to the molar blockade of aflibercept HD, 3.5 versus 4. So what about potency? If you look at binding affinity, and again, they gave me not much time to go over 8,000 slides. So this is all online, and we can talk about it more. But basically, if you look at an inhibition curve, tarcocimab, really close to aflibercept, actually may last a little longer down at the end, at the end of the curve. The IC50 is almost right at the same. This is the cool thing, ocular animal half-life, and that's one thing where you can test. You know, you can get rabbits, you can put all these drugs in. You see that the distribution of tarcocimab goes to the retina, and there was some argument that big molecules couldn't get there. This is interesting, the ocular half-life is eleven days in rabbits, versus about four days for aflibercept and faricimab, and about three days for ranibizumab. The big question is: How does that correlate to all that human data I showed you with faricimab? And this is the cool new data that they did, and I'm pleased to show it to you. So in the phase I-B study, which was the longest, biggest I-B in the history of retina that I've ever heard of, they actually had patients, and 47 patients, that as they were needing redosing, they got AC taps every time they were redosed. So in a lot of these patients, there's four or five doses that you can get a good dose response curve. You really only need two, but if you have four or five, you can really see it as linear. This is all the patients here on the right, and it shows you, just like the faricimab data, that there's some patients that clear Tarcocimab faster than others. But in these point lists, like individual patients, you'll see that it's a pretty nice linear distribution. Like, in those patients, you're really seeing a nice linear distribution to tell half-life. So of their ocular distribution, 45% had a half-life over 20 days. That's bigger than anything you've seen in any of the stuff from faricimab. And I presented in a poster at ASRS, that's bigger than anything we've seen with aflibercept. 36% are 11- 20 days, and 19% are less than or equal to 11 days. So this is superimposing the data of what I showed you from faricimab and then tarcocimab, showing you that on average, it's got a lot longer half-life. So it really should last longer if it has the strength to control the disease. This is in that I- B that had AMD, RVO. Here you see that distribution varies in all the diseases. But if you look, the half-life in most of the mean medians, that sort of certainly greater than 11 days, it's only 10% of faricimab data. So here you have human half-life in accordance to the others. And so you see that it's way bigger, and it goes along with that molecular weight, and that's probably the reason. So the durability, like I said, it's going to get tested in a more head-to-head trial that Charlie's going to talk about, DAYBREAK. If you look at the DME didn't meet their endpoint, that's the visual acuity. Victor mentioned this. If you look at pseudophakic patients, the visual acuity on that top curve looks the same. Here you see an AMD that it meets their endpoint. If you had those that couldn't go five months, it did, and again, you're getting rid of a third of the patients that couldn't go that long. Because they sort of went along the pathway of both brolucizumab trials and the faricimab and HD trials, where you try to make it look like at everything, everybody's 16 weeks. I've shown you before, that's not real in the clinic. Like, we don't have patients. I don't have anybody in my clinic with either faricimab or eight milligrams that can go 14 and not 16. In other words, if you don't tolerate any fluid, no one can go that long. This is their diabetic retinopathy. This is actually some of the best data they have. They show, you know, a 29% increase over sham, which is the approvable target for a two-step retinopathy prevention or improvement, and then a reduction in risk of 89% of sight-threatening complications. In RVO, it's probably their best evidence of durability. This is not my favorite graph to show it. I think maybe in Charlie's deck, but basically, you had a considerable number of patients in the evenly matched last six months that needed less dosing with Tarcocimab than they did of aflibercept. It's about 30% less. So what does this mean if it's really more durable? One, is there a problem, first of all, with their trials on the loading dose? Like, on the loading dose, it didn't look like it tried as good, and that's a problem because you need it loaded, and that's why they came up with this, that immediacy gap, is what they call it. You know, not being as strong as the, as the reference product, which is unconjugated. And that's why the new formulation is kind of like a sustained release, where you have a load, a bolus of instantly available drug, plus your Tarcocimab, which is released at the rate of the bioconjugate. So the enhanced formulation we're going to talk about, basically, it's taking 80% conjugated, 20% unconjugated. Victor talked about four plus one. It should be the same amount of active drug, but you're given one that should be enough to control the initial curve while your other drugs are building up. Here you look at that. Go back to those molar equivalencies, tarcocimab at 1 mg should be about the same as 1.3 mg of aflibercept, which certainly should control AMD. It's actually equivalent to more than a ranibizumab dose, and my first slides I showed you, MARINA, ANCHOR or ranibizumab 0.5, and I think we would all take that efficacy if it was our eyes or our patients. How much unconjugated protein is it? You know, it sure looks like it should be for AMD. They're not doing a DME study, so jury's out on that. But for AMD, if it's really bioavailable, it should be enough to control the disease. And like any other trial, you don't know till we run the trial, and that's why they're spending the money to do it. Here you see the. You got to show contribution of components to the agency. The unconjugated protein should give you a pulse, that should help you bridge that gap that we saw in the first loading doses of RVO and AMD. And closing that gap is what needs to happen, because even if it lasts a long time, if it doesn't dry out the redness, it's not commercially viable. The potency looks the same. The lines are on top. If you're looking at [FRET check] binding in preclinical assays, it's a cell-based assay. And bringing it all together, I bring my same people here. You know, the lucky guy is gonna be fine with having an immediate bolus of the enhanced formulation, but then should have quite a long time of extended dosing. The frequent flyers, we call it, the ones needing lots of injections, he's not gonna go five months, right? Here he is, we got him out 60 days. But if you can get any of those out to eight weeks, that's a commercially viable product. It's actually a commercial winner. Like, if I can take my four and five- weekers and actually get them to seven or eight weeks, there's. You know, that will-- you know, patients will demand it, doctors will demand it. Will this product do it? We'll see. We got to run the trials, and Charlie's g talk about that. Are you sacrificing durability? You know, you should have quite a bit of conjugated drug. You should, the four milligrams should do it. Again, it's sort of a compromise, and I think it's a reasonable scientific-based guess at what they should do, and I agree with this. What about the cataract? Is it gonna fix it? I don't know. I mean, it's really kind of hard to figure out why the cataracts are there in the first place, and I'll show you this. If you look at DAYLIGHT, there was actually statistically a little more cataracts in the wet AMD with aflibercept than there was with Tarcocimab. Is it something just with the diabetic lens? It may be. Diabetic lenses swell, and every time you're hyperglycemic, your lens swells, and you get a hyperopic shift, and every time you get hypoglycemic, it shrinks. And it may be that lens capsule, because it's having to change so much, something changes in it in the diabetic eye. We don't know. This is porcine pig lenses, and if you stress them with a lot of stuff, almost anything gives a cataract, but particularly glucose, hydrogen peroxide. Certainly, if you microwave it, that's probably not a great thing to do to your crystalline lens. And so they, what they did is they looked at these pig eyes, and they put the untreated eyes, and then the old clinical formulation, and then the enhanced formulation, and they're all the same. Like, the drug itself doesn't seem to cause cataracts more than the untreated with the original formulation. Peroxide certainly does. Microwave certainly does. So if you look at it, and this is a little tough slide to understand what it's showing, but what this is, is what if you combine a hyperglycemic situation with their drug? Could it be the combination of the two? And what you're looking at in this second panel here, the green is oxidative stress damages. Untreated versus old clinical formulation, versus enhanced formulation, the second column is all with high glucose. You're not seeing any difference, so it's not really the combination of the drug and glucose. It must be something to do with the lens itself. One hypothesis is the diabetic population is younger, so they have a more formed vitreous gel. If you have a more formed vitreous gel, it may be that if your drug is more of a big gel, it may sit around on the back of the lens capsule and cause more problems. There's a secondary effect of doing this enhanced formulation, where you basically dilute it with the unconjugated drug. It makes it way easier to inject, and it makes it where it disperses easier. So it's possible this will decrease that problem in diabetics. They're not doing another diabetic trial, so, you know, until the drug gets out there, we won't definitively be able to tell this. But it's reasonable to think that it may help, and you don't really know until you do it. So the solution is, this is the new drug versus the legacy drug. The new drug is injected in two to three seconds versus eight to 10 seconds. I've given a billion injections, and 10 seconds in the eye is a long time. You can see where maybe some of that was lens damage, maybe the needle hit the lens, although they were really good investigators in this trial. I can tell you from a commercial perspective, now that we have Syfovre, we're used to really viscous drugs, and so we're better at injecting viscous stuff. But still, commercially, people like drugs that don't take as long and is not as hard to inject. So if this drug comes out commercially, it will be better, better to have this formulation. The injection force is reduced by half. This is a model just showing you the old formulation versus the new formulation. To be honest, this is more like an old vitreous, because old vitreous is more liquefied. Young vitreous is more like jello, so in a diabetic population, you may get even more pooling than what you're going to see here at the top of the eye by the lens than you do in this. So this is the old formulation and the new formulation, and you see the new one is already done while you're still squirting in and pushing on the old clinical formulation. And so that dispersion should help potentially with the cataracts, but also with commercial acceptance, if we get that far. So this same formulation is in all the new medicines I'm telling you about, the combination with the polymer and the VEGF trap that's got IL-6 and VEGF blockade. So that's in the same principles of decreased injection and more disbursement equally applies to KSI-501 as it does Tarcocimab. Same VEGF, same anti-IL-6 potency, as the preclinical assays, and less time and force, which is always a good thing, for those of us doing eight million injections. We're going to have a roundtable discussion now, and--w e're good? Open mic. You can ask about anything. Trump, Harris. The British Parliament. We're good. Yeah. Thank you, Gena. Thank you. [audio disortion] Well, thank you very much, Dr. Brown. That's super helpful. Very comprehensive overview. So I do have a few questions that I can throw up. You know, one is the longer half-life is so important for durability. So what do you see the initial loading dose cannot be too well? I think it could be slightly different mechanisms, maybe if you can elaborate a little bit. And if the initial loading dose control cannot be as good, just simply have a longer half-life as we compare to the previous half. Would that be overcome, because then there's a slightly maybe different durability profile, just we can obviously looking at the half-life, if one drug controls better than the other, so the half-life may be another thing, comparison with the different factors we need to take into consideration. So the second question is, we talked a lot about the half-life of antibodies. What about the biopolymer? You know, could that be? I know we talked about this consequence in terms of injection, but what about biopolymers, the half-life in the eye? Will over time, you know, the accumulation of the biopolymer, will that also be the underlying cause of the safety concern? So in terms of the half-life, the unconjugated part should have a half-life. There's no data on this, but that should have. It's the same size as another antibody. It should have a half-life pretty similar to what you see with faricimab or Eylea. They're about the same size, the unconjugated one. Your hope that you control that initial disease activity, and then you have enough ongoing VEGF suppression to keep it. It looks like in their RVO data, at least in that second six months, they're able, with the same head-to-head retreatment criteria, they had less doses than aflibercept. So I think once they get loaded up with the conjugated, you're okay. Certainly, Victor and Pablo has spent a lot of time thinking about this, and I'll let them answer. Your thoughts? Yeah, I think the data that we see. We believe that the conjugate just takes a little bit of time to, you know, to get to where it needs to go and to be effective. And so now, anytime you give a dose, we're always going to have the one plus four. So you're always going to have the one of the unconjugated that's going to, you know, essentially bridge us to where the conjugate then has had time, you know, to get to where it needs to go and to do its thing. And so in any situation, you're going to be essentially better off. Yeah, the way I think about that question, it's a good question, is to separate, to kind of dive into the weeds a little bit more about the drying capacity and then the durability capacity, and those can be separated. So for example, the liquid TKIs out there that are in development, I hope they all get approved. I'm very supportive of those programs. But we've learned through most of those programs that they don't have a really strong drying capacity, and that's why you see the trial designs as you do in all of those programs, where they're selecting a subpopulation of wet AMD patients. That's very important. They're not the high-need patients, because you may not have that immediacy effect with the TKIs, but there may be a huge durability benefit even when those patients that don't need that immediacy effect. From my perspective, I certainly hope that this four plus one or one plus four dynamic can improve that efficacy. Worst case scenario, even if it doesn't, and it is me speaking, there's still potential value because I do believe the PK data, and I see that durability as a huge value add in the space. If you can have both, that's the optimal outcome. I think it's important to be able to look at those factors in the table. In terms of the safety, you know, this molecule seems pretty safe. I mean, whenever you look at a clinical trial, you always see 1%-2% inflammation rates because we're looking at the anterior chamber every time. And we have different investigators looking, and we all call things different, like trace cell versus one plus cell. Like, there's no-- A retina guy will call it nothing, and then my uveitis partner will go, "Oh, there's one plus cell there," or whatever. Really, it's not important unless you think it's clinically significant enough to give prednisone or to give treatment for it. And so that rate really was no different than the aflibercept rates, correct? Yeah, I think- You know the data better than me. Yeah, I think maybe our rates might have been one point north, for example, but more similar to faricimab. You know, honestly, across the studies, I think our blended rate is in this three. Yeah, it's close to three, and it's similar to the blended rate of faricimab in their first study. Yeah, when I, when I think about safety, I'm glad these questions keep coming up. The question is really about safety, and you're bringing up safety. To me, to see a monthly dose trial through a year, data, I think it was called DAYLIGHT. But to see monthly dosing for a year in a wet AMD population and not see a difference in the cataract rate and to have this consistent lens clarity is quite meaningful. Because the, the thing I was hearing with your question is, is there a buildup of the polymer, and is that going to change the safety profile over time? I think we've, I mean, as definitively as you can in phase III programs, answer that with monthly dosing consistently in a phase III program with no differentiation. But we're smart as a field. I'm glad you're looking at this. I mean, back in the Vioxx days and the Lucentis days, like, there was wholesale missing of safety events that we should have been identifying in phase III programs earlier on. And so I'm glad the field is looking at this. This is super important, and there's a lot of programs out there with safety challenges, and we're learning to recognize those and manage it early. I think everything that I'm seeing so far, especially with the huge number of injections, I think the team said over 15,000 injections in 2,500 person years of management with faricimab, is quite reassuring. I think we've learned is you may not know the full story until you're commercial. Like, these really rare events, which can have a palpable, right? We've seen it all on a very large program. So, you know, we as clinicians, we do think about the safety more than we used to because we've seen it in multiple programs. It's real, but so far, I'm not seeing anything that we're concerned about. You know, and thank you. Thank you. You know, that's really a great dialogue. One thing, you know, to remember is that our polymers are conjugated permanently to the antibodies. It's part of the antibody biopolymer conjugate platform. So nothing falls apart, like it has the activity, and all of that is leaving the eye, right, on a consistent basis. So there's no, like, a, you know, accumulation of the polymer, say, separate from the protein. That's not the design. This isn't something that, degrades over time, leaving a polymer residual in the eye. There's no residual. It's always leaving, and we feel very good about the amounts that we have, you know, from the data in the other thing that's nice is that we're not conjugating the PEG, which I think is fairly standard for other agents, and is really a platform extension approach for other medicines. But we're really the only company that's conjugating something very different, which is our phosphorylcholine. And so that's importantly another differentiation in the overall platform. Because PEG is complex, you know, as part of a lot of the COVID vaccines, and so there's a lot of complexity perhaps, and concerns around things that relate to PEG being injected into the eyeball where, once it's there. With that, I think we'll move on to the next part of our story, so we move on to Charlie. Yeah, thank you Thank you. Great presentation, Dave. Okay, again, it's great to be here with all of you and to go through our development pipeline, essentially, for the molecules we've already been discussing today. So there's essentially three sort of sections here, and I'll go through each of the molecules, where we are in the development pipeline, and what we're thinking about. I guess the big picture that I would give you from my perspective is we have quite effectively bent the epidemiologic curve of blindness with our current anti-VEGF agents, and they are dramatically beneficial for patients. That's. It's amazing to see that at a patient level. And this is not new. We've been doing that now for twenty years. But that said, I do firmly believe that we have huge unmet needs still in the field. These fields are huge. A tremendous number of patients in the U.S. and around the world getting injections. I see two big unmet needs, as Victor pointed out. I think durability is a huge unmet need. I think the burden on patients and caregivers is tremendous and cannot be overstated. That said, patients are willing to come in frequently because they care about their vision. We've seen that repeatedly. Durability is a huge unmet need, and I think it remains so in the field, and then secondly, I think new mechanisms of action is the second really, really unmet need out there. We have been so lucky that VEGF inhibition has gotten us this far for so many different diseases. We've got to expand beyond VEGF, and the field is actively doing that. There's a lot of really promising molecules out there across retina, and I think that we'll talk about one of those in particular today, IL-6. So with that background, you've heard about the platform. You know, looking back at some of the earliest data we presented, 2020, I think, was the first time we presented some of the I-B data. You know, we all looked at that data and said, "Hmm, this is uncontrolled data," which, looking back, misled us in some ways, and we've called out those failures directly. But I think that durability profile that we saw, that signature of durability, I think that has continued to resonate through the trials in direct head-to-head comparisons with Lucentis. I think that that is being driven by the biopolymer conjugates. I think that's still quite meaningful to me, and I think those have a useful place, potentially in my clinics. But here are the three molecules we'll talk about. We'll go through each of them specifically. So Tarcocimab, we see a tremendous amount of data around KSI-301 or Tarcocimab over six studies. I mean, it's amazing that the team has persevered. I mean, there's a lot of incredible development across retina over the last twenty years. I think most programs would have quit. They would have seen some of those failures and walked away. I know that was some of the discussion early on after being generated, that I was part of, and those were hard decisions. But I think the team did see value there. I see value there, and I think that there is still a road to be had, and I think the end isn't that far away. And that's my hope from a commercial perspective, because I think the durability signal is potentially real, and the DAYLIGHT study is going to make that definitive because they've really put their money where their mouth is with that design, which we'll talk about. And then, the last point here is that the development pathway is now relatively clear. There are three successful trials, and they have two ongoing that are highly de-risked from my perspective. So again, this is the durability data, and each of these trials was designed with durability in mind. So of course, they all have that, you know, benefit and flaw to them. The two that I would call out for me as most meaningful are the RVO. They summarized it well, but this is the highest VEGF burden disease of all of these exudative retinal diseases that we have. And so to be able to say 75% patients are going, six months with no more injection, is quite meaningful in a disease that is a tremendous burden for known frequent injection long term. And the second one is, of course, the wet AMD data. That DAZZLE 59%, which is colored because it was a failed trial, but that durability signal, I again, I do think is real based on what we've seen, and we'll look at that in some detail. So this is a summary of the positive trials in blue, and then the ongoing trials over there in purple. The positive phase III trial, wet AMD, RVO and DR, laying the foundation, and then the thought would be that they may just need one more trial to get registration, but then having two ongoing to hopefully give the entire package of all 80 indications as early as 2026, which I think is good for the space. So this is a summary of some of the FDA interactions. I've been involved with some of this directly, in particular with the GLOW 2 discussion. When GLOW 1 was positive, the FDA gave quite positive feedback that they were in alignment with study design with GLOW 2, in particular with the control arm, which we'll talk about, as well, the dosing frequency, and then DAYBREAK, also, there's alignment here with the FDA on study design. I think it's a quite unique study design from a retina perspective, where two different molecules are being incorporated. I think that's elegant. They can move the space more rapidly forward. We've seen other spaces do this. Oncology, for example, is doing a lot of these combination trials, and I hope that's where retina can go in the future. If we can learn more efficiently cost effective, it's time- effective, it's better for the space, the more that we can learn about all of our molecules and development. There's alignment there with the FDA, again, on the control arm. Finally, on the right, you know, there's this concept of having a new formulation, and that always does bring up a wild card, right? There's a lot of programs out there that would love to just switch their formulation in the middle of developing program. It's always a question mark. How does that work? You have to start over again. And it's nice to have clear feedback from the FDA that a single additional phase III program would be enough to successfully bridge that formulation to the go live formulation. Okay, diving a little bit of detail into these study designs. This is the ongoing GLOW II trial, which is actively recruiting at sites across the U.S. Remember, the output in GLOWI, summarized at the bottom, was highly, significantly positive, so 41% of the Tarcocimab patients achieved a two or more step DRSS improvement compared to sham. Quite meaningful. And so one of the thoughts was, let's just do exactly the same trial. Why, why, why change it at all? I think it would have been successful if that was done. But there was one change made to it, and that change was to add an additional loading dose. The question is, well, why? Well, from my perspective, that was not needed from an efficacy perspective. The difference between the control arm and the active treatment in GLOW1 was overwhelmingly positive, and additional treatment I do not think is necessary to achieve a larger two-step DRSS improvement to ensure security. Rather, I think that's a valuable addition because of potential future on-label dosing frequency. You know, a reality in clinical practice is that the label matters quite a bit to how the carriers determine how frequently we can give these medications in clinic. You're seeing that in particular with the Eylea eight milligram dose, where the shortest interval is seven weeks, 49 days. As Dave beautifully described, there's a lot of patients that need more frequent dosing with both Eylea HD as well as Vabysmo. So we in clinical are seeing these patients who really need frequent dosing, even in drugs that are designed to be super durable. That's one of the reasons why that four-week interval is included there. So there's three monthly doses eventually, when this is approved for diabetic retinopathy. The primary endpoint, again, is one year of two-step DRSS changes. Then this is DAYBREAK. I think this is a great trial design, and we'll talk about the blue box that's here with Tarcocimab, and we'll come back to the same slide we talked about KSI-501, the next little subsection. We really incorporated the learnings from the previous studies into this to increase the chances of success. What do you see? We see four loading doses with Tarcocimab, and then you see these monthly PRN visits. This is essentially a capped PRN design, where patients will be treated every six months definitively. They won't go longer than six months, and then they're eligible for up to every month dosing if needed. We'll talk about what those retreatment criteria are. Again, I want to come back to the green boxes when we get to 501 in a second. This summarizes the flaws from DAZZLE and then how those have been brought into DAYBREAK. And it's amazing, how many get to be able to talk about flaws, and one of the first words Victor said was failure earlier. Those words are not usually used in context like that, but I love that because we have learned a lot. We've had three failed trials, and we would like to obviously avoid failed trials, but we have had failed trials, and they give an amazing opportunity to learn from them. I mean, in our space, we want to go from phase I- phase III across all the indications, all the medicines. We want to get there fast. But sometimes, if it doesn't work out, it's good to pause and then incorporate those learnings, and that's what we've done. So the first flaw with DAZZLE was the underdosing concept, and that's why there's that fourth loading dose. It's also why we're now having the unconjugated component. The second was the reactive dosing, right? To wait until there's recurrence of disease is not optimal, and therefore, is a very clear treat to dry approach here with DAYBREAK. We'll talk about in the next couple of slides. Loose retreatment criteria. This is still very much a debate in the field, right? It's CST, it's vision, what's the right criteria to retreat? And you'll see here, will be extremely strict. And then lack of immediacy, again, that enhanced formulation will hopefully address that. This was the DAZZLE data that Dave and Victor showed earlier. By five-month durability and 59%, that percentage stands out to me as differentiated, right? These, the OCT and visual acuity curves are just that subpopulation. With that comes the challenges, of course, we're not looking at the back. This slide sort of outlines why we changed the retreatment criteria. I think this is super important, and this is highly differentiated from every other program out there for retreatment. We're always talking about the DAA, the disease activity assessment, disease activity criteria. The questions that we put forward is, okay, let's say the OCT is 354 microns. Let's say the patient has lost five letters. Let's say they've lost five letters from their best corrected visual acuity. What do all those mean in a vacuum? It's really hard to know what those mean in a vacuum unless you have the entire clinical picture. The clinical picture, us retina specialists, really revolves around OCT imaging, and that's where we're going now with DAYLIGHT, really almost exclusively OCT-based decision tree, which is what we do in the real world. So what about this? What if you look at the central one millimeter? That's what most programs do. They look at CST or something a little beyond that. And again, this image is chosen because they're a little ambiguous. What are we looking at? You got a little PD there. There's no intraretinal fluid. Is that subretinal debris? Is that the telangiectatic debris? I don't know. You can't tell. But if you look a little broader, and this is the 3 ml zone, here it becomes quite obvious. I would say almost all practicing eye specialists would look at this and say, "Yes, there's obviously disease activity, and that eye deserves to be treated, even if they haven't met some very select disease activity criteria." That's why this trial has moved to a very fluid-based treatment algorithm across the 3ml down centrally to catch any novel disease activity, and this is a summary of it. This gets into the details, but essentially what's happening in DAYBREAK, the ongoing active and trial, is that OCT images are being uploaded into an algorithm which will give you essentially a real-time output of presence and amount of intraretinal and subretinal fluid. And then based on that, decision to retreat is being made. Again, this assessment is across the full three-millimeter central area, and it's essentially at the level of detection. There's not some large amount of fluid that's needed to be retreated. Essentially, if there's any real fluid, that is going to be treated monthly in these patients. Again, that's to ensure optimal efficacy in these patients because we believe the durability will pan out. Some patients will not need it very frequently, but we want to make sure that patients who need it more frequently do get it, so they get the optimal outcomes as well. That's the first chapter, probably the longest new chapter. The second is KSI-501. This brings in all of the learnings that we've had over the previous six trials with conjugation, the bioconjugate, into a new molecule. Victor and Dave have talked about this. This is a VEGF trap, so it doesn't require the VEGF inhibition, similar affinity as Tarcocimab, and then also bringing in IL-6 inhibition. The reason I like this is this is the second biggest unmet need that I meant, I mentioned, which is we need new MOAs. The goal here on the far right of development here is can we achieve better efficacy? This is different than that durability play, which I think is relevant. This is, can we do better than pure anti-VEGF inhibition. This, again, is a design for the core molecule itself, very similar and near identical to Tarcocimab, except now it has been altered to have IL-6 binding, and on top of that is the VEGF trap component, which captures the central growth factors, VEGF-A and VEGF-B, very similar to Lucentis. Now, there is a lot of data stretching back years looking at IL-6 as a potential target. You see a lot of other sponsors out there looking at targeting IL-6. This is looking at aqueous humor IL-6 levels, and they correlated with anti-VEGF treatment response in wet AMD, and particularly among patients that were less responsive, we saw a higher IL-6 concentration. This is data from a large wet AMD trial, HARBOR, and also a large DME trial called VISTA, again, showing a correlation here of IL-6 levels with outcomes. In particular, higher IL-6 levels, both of these were the highest quartile of IL-6 levels in the blue trajectory, achieved less visual gain than patients with lower IL-6 levels in both of these disease states. This is a preclinical model looking at blood-retinal barrier integrity, and you can see the dual inhibition here with KSI-501 directly seems to restore integrity of the vascular endothelium at the bottom, as well as the RPE cells. Again, both of the blood-retinal barriers appear to be restored with inhibition of VEGF, as well as IL-6 with KSI-501. So what data do we have so far with 501? We do have human clinical data. This is a phase I data that's been presented, which was four different doses of KSI-501, up to 5.2 mg s per injection of the antibody plus the bioconjugate. And this was at five clinical sites across the U.S., monthly dosing and observed through 24 weeks. Limited number of patients here, so I'd avoid overinterpreting this. Seven treatment-naive eyes, nine previously treated eyes, and most importantly, I think to me, is the blue boxes here. I think it's a lot easier to interpret treatment-naive patients, especially when the numbers are small, and you're seeing a robust improvement in anatomy. Most importantly, to me on that bottom left graph, which is staying dry through 16- 20 weeks, with some slight increase there at 24 weeks, again, suggesting that the drug is wearing off at that time point. On previously treated eyes, similarly, you're seeing a similar visual acuity gain and then similar anatomic improvement. Again, small n values and previously treated patients are notoriously heterogeneous in a phase I population. This is looking at categorical visual gain. The 10-line gainers is a majority of patients in both, and then 15-letter gainers, I think the 40% is what I would expect and want to see in the treatment-naive population. But to see a quarter of patients there improving 3 lines or more in a previously treated population, does potentially suggest added value in IL-6. So now back to the same slide we looked at before, but focusing on the green trajectory, right? The nice thing here is that it is, in some way, a direct head-to-head comparison with Luxturna 2 mg, right? Luxturna 2 mg s is the control, three monthly doses and every eight-week dosing. KSI-501 is four monthly doses, again, incorporating the learnings that we've had over the six trials with tacozumab. And then from there, is every eight-week mandatory dosing, but again, allowing more frequent dosing with the same treatment criteria as used in the tacozumab arm. So a very sensitive dial there. Any fluid will drive additional therapeutics, treatments up to every month. And again, the goal there is to look not at durability for this molecule in this trial, but is to look squarely at outcomes, right? Can we do better for these patients with IL-6 inhibition? I think it's a very important question in the field. Do we really need to go back to monthly? This gets back to what Dave was talking about. I really think that the commercial landscape has skewed the clinical perspective. It's not reasonable for patients to come in expecting to go every 16 weeks, unfortunately. It's led to a lot of frustration among patients to be told something commercially, when it's just not panning out to be the case. Many patients do need monthly dosing, for example, with Eylea 2 mg This is the best paper looking at this. This was Glenn Jaffe's work, published in Ophthalmology in 2016, and this is a great paper. On the left, it shows that monthly aflibercept compared to every other month aflibercept are identical outcomes, critically among patients that are dry, so the OCT really can predict outcomes, but then on the right side of this graph, you see a separation of curves, and what's driving that separation? If I'm a patient, I want to be in the light pink or the light purple curve at the top. I want to have more vision gain, and that's what my patients want me. They want to see better, and they'd rather get more injections and see better than get less injections and see worse, and what you're seeing there is that the dark purple line is every eight-week injections of two milligrams of aflibercept compared to the lighter purple at the top, which is every month injections among patients with persistent fluid. So we know in clinical practice that fluid correlates with need for dosing. It's not a perfect correlation with visual function, but it's what we use clinically to drive frequency for these patients. Right, the last of three chapters here is KSI-101, and we'll talk about the design of this molecule in a second. This is differentiated because it does not have the bioconjugate. Otherwise, it's the identical protein structure, the antibody itself as KSI-501, again, without the conjugated form. And the concept here is to go into a different space. So this is inflammatory retinal diseases with associated macular edema, with some fascinating possible means for accelerated development. We know that uveitis and inflammatory diseases more broadly are a common cause of vision loss, and within those patients, macular edema is one of the most common causes of vision loss. We currently do have therapeutics for this. This is not a population of patients without options, but they all have specific challenges with them. Both local therapies or steroids, as well as systemic therapies, all have their limitations. Again, coming back to data on IL-6, we've seen elevated levels of IL-6, both in the aqueous on the far left and the vitreous in the center there among patients with inflammatory diseases, including specifically uveitis. And on the right, the interesting observation here is that VEGF may be playing a role in these patients with macular edema in the setting of uveitis and other inflammatory diseases. This may be a multi-component disease process, and targeting both IL-6 and VEGF may be important. This is great data put forward by Roche. This is from the DOVETAIL trial that was presented last year, looking at a monoclonal antibody inhibiting IL-6. And importantly, this was proof of concept in humans, that an intravitreal injection with, again, monotherapy IL-6 inhibition can lead to visual improvement and OCT improvement in a dose-dependent fashion, indicating IL-6 is important for this patient population. Critically, however, when I look at this data, I see here on the far left, you see meaningful improvements in IRF in the portion of patients without internal fluid. But then the other side of that is there still is about 50% of patients with persistent IRF after three monthly doses, again, with IL-6 monotherapy in this program. So that brings us to KSI-101. But again, this is the same protein antibody structure here with the IL-6 inhibition, as well as the VEGF-A, B, and PlGF of both factors being blocked by the trap formation there at the top of the molecule. And again, this does not have the bioconjugate formulation to it, because the play here is not a durability play. The play here is: Can we be as effective as possible in this patient population? And that's why the formulation is even stronger at a 100 mg/ml. So this is a design of the ongoing APEX study. This is a I-B trial looking at both DME patients at the top and what we're calling a MESI population, or macular edema, secondary to inflammation, and actively recruiting. There's five loading doses in the DME patients and four loading doses in the uveitic macular edema, and also a broader inflammatory population with macular edema, with the anticipated primary endpoint for the phase III program being there at 16 weeks. So a very early readout, again, agreed on with the FDA at this time point. These phase III trials, PEAK and PINNACLE, phase II-B/III, are not ongoing now, right? This is dependent on the readout from the I-B APEX trial, which is ongoing. So if those are positive, the plan would be to look towards this sham-controlled trial in patients with inflammatory diseases with macular edema, four monthly loading doses, and then an as-needed retreatment paradigm from there, with a primary endpoint, again, early in this trial at the next 6- 16 weeks. The other potential interesting angle here is an even faster mechanism to get to clinic, which is to look at pediatric uveitic broader inflammatory disease population with macular edema, and this represents a substantial number of patients in uveitis clinic. So this is just summarizing all of those three molecules that you've heard many times today, Tarcocimab, KSI-501, KSI-101. If I had to pick one or two things that are most important to me for each of these, I would say from a Tarcocimab perspective, it's that we've had a lot of learnings over a lot of trials. I think that those have been well understood as well as we can understand at this stage, and then meaningfully inform the design of both GLOW2 and DAYBREAK going forward. KSI-501, very excited to have a new mechanism of action in the space. I think that means we need that in the space to move it forward to get better outcomes for patients. And importantly, we apply all of the learnings from the bioconjugate, from tarcocimab into the 501 development trajectory. And then finally, 101, right, steering us in a completely new direction, I think helps diversify the team. And I think it's good for patients with inflammatory diseases to see possibly a combination of VEGF and IL-6 inhibition. With that, pass it back over to you, Victor. Thanks, Charlie. Great. Thank you, Charlie. That's a wonderful overview, and we appreciate that. I'm going to run through what some of that means. What is the opportunity for Kodiak with what we've described so far? One of the things that's important to remember at Kodiak is these are very high-prevalence diseases, and there's a tremendous opportunity for the patients to solve these problems, but also a tremendous commercial opportunity. We're playing in the big leagues as a mainstay biologic, trying to access some of the benefits to the patient in the red. It's a $14 billion market growing towards $20 billion. In wet AMD, what we call the established Gen 1 anti-VEGF agents achieve modest vision gains in the real world, and as we heard today, require frequent injections to maintain the vision. The Gen 1.5 agents provide modest dosing interval extension in the real world. So I think what's important, and what we've heard multiple times from our experts, is that the Q 16-week or the every four-month numbers that may be quoted in the direct-to-consumer advertising are actually not being achieved or even close to that, in clinics. Interestingly, although the 45% Q 16-week number is what's shown in the first arm wet AMD clinical trials, in recent independent U.K. from real-world data, what we see is actually that Q 16-week patients represented maybe 18% of patients in the real world, or in a year one study from Liverpool, Q 16-week patients represented 0% of the patients on the vabysmo. And again, the Gen 1.5 agents don't provide additional vision benefit over the Gen 1.0 agents. As Charlie mentioned, the data that we generated in everybody on six-month dosing, the GLOW1 diabetic retinopathy study, was very strong data. With U.S. prevalence for diabetic retinopathy patients at around eight million patients, fewer than 1% of whom are currently treated. This represents a very interesting opportunity for Tarcocimab and for public health. And to a large degree, I would say that's due to treatment burden with the existing anti-VEGF therapies. So it's really a watch and wait approach, and what we know is that disease progresses when it's untreated. Despite the limited differentiation, you know, of these agents, whether it's Eylea over Lucentis or the gen 1.5 agents of the Vabysmo or HD over Lucentis and Eylea, I think it's important to remember and recognize that each incremental improvement has resulted in blockbuster commercial opportunities for these mainstay biologics. And I think it's been especially illustrative to see how quickly Vabysmo has built their commercial potential, despite what people would presume to be a complex and perhaps saturated market, remembering that Avastin still represents around 50% of the injections. So despite that, we've seen Lucentis grow into Eylea, Vabysmo grow much more rapidly than people anticipated, and Eylea HD will soon, we think, fix their not having monthly in their label profile, and broaden their profile, and perhaps grow their revenues more aggressively. But if you look at what we're trying to build with Tarcocimab, what we call the gen two profile of good efficacy, strong immediacy, and the best durability, we'll have, we believe, if successful, a very broad label and something that may even represent more than incremental improvement. With each 1% share in the market estimated to translate into $200 million-$300 million in net sales, which is quite substantial given where Kodiak is trading today. And as we mentioned earlier, our objective with our development is to develop Tarcocimab and 501, our ABC medicines, as mainstay intravitreal biologic monotherapies that themselves prime the patient and provide the durability, the high efficacy and the high durability, with a label that goes from every one month through every six months. So, hopefully more than incremental improvement on top of the mainstay agents in delivering a level of durability that suggests why would we want to go to more exotic technologies when a biologic can service? When the biologic, the Kodiak biologic can service the unmet need. Just to talk for a second about the opportunity for KSI-101. We think it has the potential to be an important and differentiated medicine in the retinal inflammatory conditions, which we see as a greenfield market segment. Stepping back a little bit to talk about a relevant case study, we don't, pretend to be able to achieve the level of success of Tepezza, Tepezza in thyroid eye disease. But I think what's important to recognize is that at its time, was also a greenfield market opportunity. Launched into a nonexistent market, there was a high unmet need with no approved therapy, and sales approached blockbuster status even in the first year of launch, substantially outperforming the management expectation of $30 million-$40 million year one, so you know, with KSI-101, there is a greenfield market opportunity, a broad patient pool, a high unmet need with no approved locally dosed intravitreal biologics. Furthermore, it's a very interesting gateway indication from ME or UVE or macular edema associated with inflammation, all of those in a bucket. Those are gateway indications for our molecule to a broad set of diseases, which could include, down the line, all retinal diseases that have inflammation and macular edema, and we have spoken with the agency on this question, so what's special about KSI-101? The dual inhibition, what I call a predominant anti-IL-6 mechanism, supplemented with the anti-permeability of the anti-VEGF trap, and a synergistic effect of both of them together on normalizing the blood-retinal barrier function versus anti-IL-6 monotherapy, the data that Charlie shared. So the potential for it to actually have some level of disease-modifying capability and a very high strength formulation at 100 mg/ ml. So therefore, a very high potency provides the firepower needed to treat angry inflammation and macular edema, sort of a sledgehammer type approach for these patients. We're exploring different types of accelerated development for the molecule, including options in pediatric UM patients. So Kodiak's clinical portfolio has the potential to provide continued revenue stream starting from 2027, with a built-in life cycle management and risk diversification. 101 is a revenue potential diversified away from our ABC medicines. 501 has the potential for best efficacy and signature durability as a next-gen product to fast follow our own Tarcocimab. Meanwhile, Tarcocimab has the potential to bring the best durability and strong immediacy. Incremental market share can translate into meaningful revenue for Kodiak in these time frames. Let's remember that Kodiak owns full commercial rights to our portfolio, which allows us the flexibility in our commercialization decisions to support adoption of our products. Also, I think another important element of Kodiak's capabilities and resource and experience is the longstanding and significant investment that we've made in our own commercial scale manufacturing facility, which positions us to launch multiple ABC products into large and growing markets. Here you see the grand opening of Kodiak's Ursus facility together with Lonza, which, as I mentioned, mechanical completion was in the first half of 2022. It was commissioned as a GMP facility in January 2023, and we released a GMP commercial scale product of the enhanced Tarcocimab formulation in November 2023. A number of the different PPQ batches that are required for the BLA have already been completed. For example, the antibody components of Tarcocimab, those PPQ batches are already completed as a drug substance. Furthermore, the PPQ batches for the OG-1802, what we call the biopolymer, that's used for the conjugation. Those batches have also been completed in Ursus, and we're working now to begin the PPQ batches for the tarcocimab drug substance, and that will take place in the first half of this year. So that is a unique asset that positions Kodiak well as a commercial player if we're that lucky and successful. Now, this is something that we haven't shared before, exactly. And this is what we call our VETI or our visual engagement technology and imager. And this, we believe, can form part of Kodiak's commercial franchise, for example, tied into the launch of Tarcocimab. Essentially being in Silicon Valley as we are, we're located in Palo Alto and having access to important technology talent from whether it's Apple's Face ID team, or the Google X team, or other high-tech groups, Kodiak has built over the last several years a goggles-based imager that delivers an OCT, that's a two-dimensional OCT for the patient. That can be translated into a tool that could be bundled in some fashion together with Tarcocimab and our other ABC medicines through their commercialization. There's an element of bringing the AI and bringing a series of different apps and AI potential. We mention this because we're now using some of that more modern AI in the execution of the DAYBREAK study when we look at the presence of the intraretinal and subretinal fluid in the DAYBREAK design. So as we think about DAYBREAK being a study that generates data for how the molecule truly will perform, okay? And then the ability for it to also predict how the molecule can be used once it's in the market. Kodiak's VETI tool is something that we think can form part of our interesting commercial potential. So what is the Kodiak opportunity? So in Kodiak's fifteen-year history, we've made missteps, mistakes, and the three clinical programs in our pipeline utilize the learnings from these mistakes to increase the probability of rebuilding significant value over the next several years. So our two ABC investigational medicines built with our proprietary science of durability and of our new science of the enhanced formulation, both being developed as mainstay intravitreal biologics, along with the other majors, to address unmet need for high efficacy and high durability. With 90% of Tarcocimab's clinical and manufacturing costs, they're behind us, and we anticipate a high probability of success in our late-phase clinical trials, with the potential to launch in two and a half years. We have significant flexibility in commercialization to support adoption, as well as the ability to enter into partnerships if desired, as a full-fledged retina franchise R&D company today. In an area or a market where incremental market share gain translates into meaningful revenue potential into a $14 billion-plus growing market, with built-in life cycle management with KSI-501 to fast follow Tarcocimab and an uncorrelated bispecific KSI-101 product in a greenfield market with near-term data readout early in 2025, where we may and are exploring the ability for accelerated development and approval options. So today represents an exciting investment opportunity, we believe, for Kodiak, and we think that the science is what needs to take us there. So rather than moving into the roundtable discussion, in the interest of time, we're going to have Dolly Chang now come and present on some of our deeper pipeline. Can we do the Q&A now with Dave and Charlie, because they need to leave, maybe? What do you think? What time do you guys have to go? We're okay. Yeah. Okay. Great. Okay, thanks. So I'm very thrilled to be here as part of the Kodiak team. As Victor mentioned before, that I was at Kodiak, I was at Genentech and Roche, responsible for the early clinical development portfolio. And what drove me to Kodiak is a very exciting and tremendous potential of the portfolio that you heard before, and also the strong commitment to environment. And over the next couple minutes, I'm going to walk you through some rapid advances of the ABCD platform, as mentioned by Victor, and also some of our early pipeline as well, which I think that it provides tremendous potential, you know, to change the way that we treat complex disease in ophthalmology and even beyond. So, you know, if you just review the current drug development landscape, it's pretty much most of the drugs follow the one drug, one target approach. It works in many patients, but it also brings some limitations. It's oversimplified for the complex biology and may miss some of the potential synergistic effects. And there are some breakthrough in the field that we know, but they all come in with their key limitations. So just take a couple, for example, if you look at RNAi therapy, there's tremendous breakthrough, but it is still limited to the liver, to the muscle, and also has very limited cellular uptake. If you look at the oncology field, the ADC field still has a limit of DAR, which is the drug loading to one to eight ratio. If you just imagine if there's a foundational platform that can address multiple disease and multiple targets all at one time, and then the best thing is, if this new drug concept is designable, it is manufacturable and it's being safe to the patient, that will really change the way that we treat patients. As Victor mentioned earlier on, for the ABCD Platform, it, we think that this could potentially bring this kind of vision to life. It comes in with, you know, I would say, four main advances and advantages. First of all, it allows us to conjugate a wide variety of payloads, including small molecules, peptides, proteins. In terms of the second benefit, it accepts high DAR, which is the high drug loading ratio, up to a 1100, and we are going to walk you through a little bit more of how to achieve that. Number three is we can tailor the release profile of the payload by customized linker. Number four is the drug can be embedded in the glycolic backbone, that it has been proved to be, you know, biocompatible and in many different tissues and, you know, with our focus in the eye. How does the ABCD platform work? It's highly modular, and each component can be customized, designed, and developed. Let's start with the A, which is the antibody and the biologics. Within Kodiak, there are very strong protein engineering team that can create different proteins that are targeted toward different tissues, specific tissues or modulating the pathway. For the biopolymer, it is highly customizable, and we can customize different sites and loading with different drugs. Let me just take a quick example of ocular application. Let's say we can choose a 750 kilodalton, the larger biopolymer, with a 10% of drug loading, and that can achieve a DAR of 250. That's pretty incredible. Let's say for sustained application, we can take a smaller biopolymer and for example, 250 kilodalton with a drug loading of 3%, that can achieve a DAR of drug loading, let's say 25, and that has not been achievable with the ABCD field or an RNAi therapy. And lastly, to talk about this drug cargo. We have talked about it, that it has highlighted the capability that we can work with different types of property of the drug cargo, so by including different size, different solubility, and different charge as well. And with the customized linker, we can have varying release half-life as well. So let's just, you know, put a couple of the design concepts into what we mean by these kind of ABCD Platform. So first, we can take a look at the small molecule and the peptides, that we can conjugate a lot of them with high DAR up to, let's say, 250 into the biopolymer. And we are able to improve the solubility and then carry the durability in the eye. And with the releasable linker, we can also tailor the release profile as well. These two are the foundation for the dry AMD an d the glaucoma NLRP3 pipeline that I'm going to talk about in the next couple minutes. Just, you know, just the flavor of the potential of the ABCD platform. If you're looking at RNA-based therapy, we can conjugate with the antibody to target specific target tissue, paired with a small biopolymer to carry multiple copies of the RNAi therapy to overcome the limitation of the cellular uptake. If you look at lastly, you know, we can also potentially create an oncology field, a second generation ABCD, that increase in the dose, so then we can choose different payloads with less toxicity and with a higher number to overcome the safety and efficacy issue. Now, let's just go into the two early pipeline that we have, one in glaucoma and one in dry AMD. As my background as a glaucoma surgeon, I do want to highlight the unmet need in the glaucoma field. We know that most of the medicines are targeting for lowering the eye pressure in the eye, because that's the only modifiable risk factor that we can, you know, tackle with. We know that patients either cannot do the eye drops, cannot tolerate the eye drops, or they don't adhere to the eye drops, or they may still have high eye pressure despite multiple drugs and multiple surgeries. At the same time, even with controlled eye pressure, the disease can still progress. That's probably why glaucoma remains the number one cause of irreversible blindness worldwide, and that demonstrates a tremendous unmet medical need in this field. So we are. I'm really excited that with the BCD component of the ABCD platform, we are combining two mechanism of action of two different small molecules. Number one is the neuroprotective agent, NLRP3, to, and the second small molecule with IOP lowering, to achieve one intravitreal injection with two mechanism of action, and only require one injection every couple of months. And the reason why we choose NLRP3 as a target is because the NLRP3 inflammasome play a key role in glaucoma progression. The inflammasome complex is the intracellular complex that drives inflammation and cell death. It is actually a very exciting target for many of the disease area. Many pharmaceutical companies are targeting for this pathway, but it has been very challenging for the eye because of the fast clearance of the small molecule and also the solubility issue. But I'm very proud that our team were able to develop a novel NLRP3 inhibitor, specifically designed to work with the ABCD platform, so that we're able to bring this to the glaucoma patient. And then to Victor's point that, you know, how can we know that without the antibody, the biopolymer still works in the eye with extended durability? So from the rabbit PK study, we can see that, if we look at the ocular half-life and the biodistribution of the biopolymer alone compared to KSI-301, which is the biopolymer with antibody, the half-life is very similar. So for the glaucoma program, we are going to take a biopolymer that is very similar to what we have used in KSI-301, and so we are anticipating a long-acting delivery in the eye. And so there are a couple, you know, key insights that when we work with the ABCD platform for the glaucoma duet program. First of all, we already talked about how we pick the biopolymer, and we also have shown that we're able to, you know, incorporate two different small molecules in a single biopolymer. We also have seen consistent relief simultaneously for the two different small molecules. We think that this will be a very exciting, you know, a tremendous opportunity for the glaucoma patients, that we can bring neuroprotection and in lowering the eye pressure, both in one. Next, I'm going to talk a little bit about the dry AMD program. What we mean by dry AMD is that the advanced form is geographic atrophy that we are quite familiar with, and also the earlier disease, which we call intermediate AMD. We know that there are some treatment options for those geographic atrophy patients, but the outcomes are pretty limited. It moderately slow down the GA progression, and there is no therapy for the earlier disease, like intermediate AMD. Our approach is to combine a macrocyclic peptide or complement inhibition, and also incorporate the novel NLRP3 inhibitor, which we know that inflammasome also play an important role in AMD. So by combining the two, we think that we can achieve better clinical outcome because we think that by dual mechanism of inhibition, better tissue penetration, and we are able to achieve dose higher with the ABCD platform, so that we potentially can improve the efficacy for the treatment of geographic atrophy. And secondly, because of the extended durability, hopefully, we'll be able to provide a gentler treatment, just like the DR scenario, that we're able to treat patients earlier and prevent the progression into late-stage diseases. So those are the two programs that I just want to provide a high-level overview of what we are working on and addressing two very important unmet medical needs and, you know, very poorly addressed markets. Now, I'm going to turn it back to Victor. Thank you. Thanks, Dolly, so just as a quick summary before we move into the Q&A, a summary of the three clinical programs that we're advancing, that we've talked about. A nice introduction, thank you, Dolly, to the ABCD Platform, which brings fifteen years of development and also brings our commercial facility in line, where we can build these conjugates, in the future in commercial scale. We'll bring our timelines up on the screen perhaps while we go through the audience Q&A, to remind everybody that our focus as a company is on late-stage clinical execution on the tarcocimab program, the KSI-501 program, and the KSI-101 program, with GLOW2 actively enrolling. We're trying to target completion of enrollment towards the end of this year or early 2025, and DAYBREAK also actively enrolling as a two-year study and looking towards a completion of enrollment, let's say, towards the end of Q1 of next year, if we can achieve that. So 48-week endpoints and top-line data very close to last patient, last visit, taking us into very early 2026. And then exciting data we hope from KSI-101, both DOVETAIL-type data we hope open label, early 2025. The decision of which two dose levels to move into the PEAK and PINNACLE pivotals, driving the initiation of target enrollment start for PEAK and PINNACLE, and then target enrollment complete, with the 16-week primary endpoint. So looking at an exciting execution 2025 and a large number of really important readouts for us and hopefully the field in early 2026. Thanks very much. Good. Let's do some Q&A. Justin. Okay, great. This is Michael Yee from Jefferies. Maybe for the doctors, I appreciate all the clarity and commentary. Maybe just taking a step back, assuming the data for Tarcocimab play out as you expect into the enhancements and improvements for the study design, maybe Dr. Brown and Dr. Wykoff, how could pontificate about how you would expect to use these types of drugs in the first few years, what types of patients? It's obviously a complicated field, so that would be helpful if you could kind of explain how one might use that type of drug profile. And then if an IL-6 compound is also promising, where does that fit in and how would you use that type of drug? Thanks. Yeah, I'll start with the first one. You know, if you're looking at a situation where you're probably gonna have a bunch of aflibercept biosims, and so I assume that there's gonna be step therapies from insurers, et cetera, that step through that. Depending on where they market it and price it, you know, the-- If you indeed can go one or two weeks longer with this drug, or even three or four weeks longer, there's gonna be a big push for all those that can't go eight to ten weeks with two milligram of aflibercept. So I think the devil's in the details. It all depends on how long people can go. With this trial design, you'll be able to see it because you can get up to monthly, and, you know, it's capped at twelve. If you can really get most people close to 12, I think it's going to be very commercially successful. IL-6, I don't treat you guys, so Yeah. Me neither, either. Yeah. Yeah, I think that the perspective there is that most retina specialists tend to look at their high-need patients as the first one to transition, so to switch. Like you saw that with the Vabysmo or Eylea HD. And, you know, those high-need patients that you're seeing every month in front of the DAZZLE reference, that are constantly asking, and are remarkably well informed in many cases about what's next, what's next? I want something better than what I've got now. And so those are the ones that are the lowest hanging fruit to transition. I think, you know, if the half-life data bears out in the DAYBREAK study, and we see a meaningful proportion of patients that are, beyond eight to 12 weeks, I think that will confirm what we've seen so far with the PK data, and that would be meaningful for patients. Look, yes, we think we can get you meaningfully further. It doesn't have to be four months longer. As Dave said, you know, an extra few weeks for patients is highly meaningful from a quality of life perspective. Incremental benefit is incredibly valuable for our patients. Then where I see the KSI-501. A lot of feedback up here. I don't know if that's a me thing or something else. But you know, the 501, to me, is not a durability play. It'd be great if it did have that durability angle. It should, given the structure of the molecule, but for me, I'm most interested in can we do better with the additional MOA. For me, that's why I was excited about Ang-2 for a long time. That's why I'm excited about many other molecules in development, is I truly believe that we can and will do better than VEGF monotherapy in addition, but we're not quite there yet as a field, and maybe IL-6 will move us meaningfully forward. I don't know. Sorry, so that would be on BCVA and other endpoints, or how would you think about it? It's all of it. When I see-a nd it's a good question, right? There's a nuanced discussion there about what do we really mean about efficacy. But ideally, from a patient perspective, it's vision, right? That's sort of the holy grail. Can you see better than we can do with the gold standard anti-VEGF therapy? And that would be ideal. Because usually, if it's not vision and it's anatomy, that's a durability play versus an efficacy play. So really, when you talk about efficacy, you're talking about visual function. And there's complex ways of looking at visual function that we don't get into, contrast, sensitivity, visual field, all these other things which we have not, you know, been able to quantify well in our phase three trials to show benefit. But patients talk about all these other additional benefits when a fluid goes away. Good. Yeah. Hi, Mike, [Jefferies]. I first of all thank you for putting up with, you know, it's a comprehensive and informative event here. Just want to pivot back. I have two questions. Number one, I just want to pivot back to the formulation. In current coverage, I recall that a while ago, when you were just announcing this new formulation at phase III, it was 70/30 conjugated versus unconjugated mixture, now it's 80/20. And my question is, what gives you confidence that you've struck the right balance or ratio? Is this built on actual experimentation, or is it built on modeling? And I have a follow-up question. Thanks, Mike. Well, the formulation- for the Tarcocimab go-to-market is a 20%, 80%, or one plus four. And the formulation, as I say, go-to-market for the KSI-501, is a 30%, 70%, or a 1.5, 3.5. And the reason we did that is we believe the one plus four for Tarcocimab is the right strength. Okay? And Dave went through a little bit of some of the molar comparisons for the anti-VEGF, right? That the one plus four, right, the one is equivalent from a VEGF binding to a 1.3 mg of Eylea, or a 0.7 mg of Lucentis, or a 2 mg of bevacizumab. Okay? Now, in KSI-501, that bispecific protein is slightly larger than the antibody is in Tarcocimab. In Tarcocimab, the antibody is, let's say, 150,000 molecular weight conjugated to the polymer. But for the KSI-501, that bispecific protein is, say, 190,000. And so because it's a little bit larger, we wanted there to be a little bit more room, right? Because to get the certain number of molar equivalent of stoichiometry, we've shifted up from one to about one and a half mgs of unconjugated to achieve a high molar amount of the unconjugated is of the conjugated. So that's the type of balance that we drove, and we believe in both cases that, you know, the objective is have this unique signature durability, the promised land of longer interval durability. In order for patients to be able to get there, to have the unconjugated so that we can try it on every patient and have that early strength needed to see where the patient can go as a mainstay biologic therapy for all patients. Okay, very helpful. My second follow-up question is on the DAYBREAK study. It's fully acknowledging that this is a non-inferiority trial versus Eylea. I guess, the risk here, if there is a risk, is that KSI-501 doesn't appear to be at least directly more efficacious than Tarcocimab. How do you think about that, and what are your expectations for 501 efficacy here? I assume it's, is that it would be a lot more or some degree of directly improved versus Tarcocimab, but any color you could add to this would be helpful. Sure. I think for the 501, the study design with an objective to try and really push for, trending better efficacy, it's very hard to achieve that when you look at the broad mean population. And so I think what's a nice model is to look a little bit at the vabysmo bispecific, where they went for superiority and did not show it. Okay? They showed non-inferiority. But now there's quite a lot of analysis to try to identify certain large subpopulations of patients within the broader population, to try to really identify, well, where actually this medicine, with its bispecific mechanism, actually may be able to achieve something special. So we may not need to look for the mean curve showing a superiority, although a trend would be nice. I don't think that's necessary at all, and we shouldn't set that as the standard. The objective is to explore, at a high intensive dosing, whether there are certain subpopulations of patients where we have a very different behavior. Certainly within the aflibercept control patients, and at Kodiak, we have many thousands of patients now. When we evaluate data, there is tremendous unmet need across the disease areas, you know, even with drugs like aflibercept, you know, where they have disease reactivation or significant increases in subretinal fluid across the diseases. And the question is, with the KSI-501, can we think there's a different pattern? It's hard to know. We could spend two to three years in phase II trying to figure it out. We're going to look now in a phase III setting, combined with tarcocimab in a very cost-effective manner, right? In enough patients over enough time, right, in a non-inferiority setting for the threshold for success, right? But hopefully to be able to find what Vabysmo is trying to do, large opportunities to describe differentiation in different ways. Along those lines, if you could comment at this moment, what the predefined subgroup analyses may be or predefined, again, subgroups might be in the study or the program? No, I mean, I think the nice thing is that the primary endpoint is set, and then we have some time to think a little bit about secondary. I mean, the one layer I would add to that is, right, the typical subpopulations are the larger lesions, more fluid, worse vision at baseline, the polypoidal patients. There's a subpopulation of patients in wet AMD that the field's pretty aware of, are typically a little more difficult to treat and have worse outcomes. Andrea? Yeah, Andrea Tan Goldman Sachs. Victor or John, just a question here on your cash runway. You mentioned $200 million ending 3Q, which gets you into 2026. Just curious if you can confirm that we will see some of these top-line data reads before that. And then how much does that account for any type of development or discovery work from the ABC platform? Yeah. I can take it first, and John can provide perhaps some more color. We don't, you know, make any promises about. I think what's going to be important in twenty twenty-five, say end of Q1 or early Q2 of twenty twenty-five, where will Kodiak be? We'll have data that I hope will be DOVETAIL equivalent data out of the KSI-101 program, and we'll be selecting dose levels to start the PEAK and PINNACLE pivotals for the KSI-101 program. We'll also hopefully have completed enrollment into the GLOW2 study, so we'll have visibility into the timeline and top-line data readout for GLOW2. I think also towards the end of Q1 or hopefully early Q2 in 2025, we'll have, completed enrollment in the DAYBREAK study. So we'll also have visibility into the timeline with the 48-week primary endpoint readout for top-line data for DAYBREAK. I think when you look at our cash position, we're not going to make any promises exactly whether or not we can take us all the way through, let's say, DAYBREAK top-line data. I mean, as a public company, you know, that's not what you do. I think our, you know, commitment is that we're going to be thoughtful about, you know, when we raise capital and how we raise capital. I think whether or not we could get to, you know, GLOW2 data or whether we get to DAYBREAK data is something that's beyond where we think we need to discuss today. What we're looking at is, you know, let's say in, you know, early Q1 or Q2 of next year, perhaps whether or not we have transparency and clarity about these timelines, and that will help us to determine what kind of capital we look for. Really, the type of capital we might look for really may only be two quarters, so it's really not a lot. Gena? Oh, sorry. Go Go ahead. I'm not Let me go back to durability quickly. Have you been able to flesh out yet any baseline characteristics of patients who have low durability? I think that's very challenging. And if you think about the level of expense that some of the other technology companies are doing to do run-ins, you know, of all subjects, whether treatment naive or previously treated, on the anti-VEGF biologics before they move into the port delivery system or to depots or gene therapies, I think that tells you that people don't believe there is a way today to really know. I've been looking at it forever. I don't think there's a way. You know, if we have an assay, like, Regeneron's got a very good assay for aflibercept. They could probably do it with an assay and multiple tests, right? You can tell if you're a fast clearer or slow clearer, but, you know, individual. Yeah, pseudophakic patients or myopic guys should be a faster clearer, but we've never been able to identify those, and so we treat an extended downtime. But, I mean, I will tell you that, for example, if you want to try and identify, well, what percentage of treatment-naive patients entering, weighing in these studies may meet criteria as well controlled? That may be in our analysis of, say, our data on historic studies. You're looking at around less than 25% of patients. So that's why when you look at what we're trying to achieve by going for 100% of patients, that's why we think we're developing a mainstay monotherapy. But it also shows you the challenges for other players, where they're selecting smaller groups and trying to, you know, generalize those results is very challenging. Maybe our ready tool will help to solve that conundrum, but that's going to be a few years down the road. Gena? Also follow the DAYBREAK data. So I think that Dr. Wykoff, you mentioned that you wanted to see higher percentage of patients were able to achieve, let's say, 8-12 weeks treatment frequency. So maybe wanted to know, like, what is the bar, you know, what percentage you are looking for? And also, now we use a different criteria, like this is a fluid volume versus, I think, in the Lucentis, all the other trials using ACV and LOP sickness. How do we do comparison, like the 45% in the current trial setting, how do we do that in this? Yeah, it's a good question, and I don't have a definitive quantitative answer to that. I think the important points I would make are that this is a highly differentiated trial, right? This is very different than every other durability trial that we've had in the space, because they're artificially set, and all the sponsors have done this, including Kodiak. You know, they've talked about this, you know, beautifully before, where they're set so that you're putting your best foot forward. I get that, and that makes sense, and that's been the standard in the space. And this trial really turns that on its head because really the first and foremost goal here is, let's make absolutely sure that we get non-inferiority and that we have really good drying. But let's make sure the efficacy is first and foremost. Built into that is the concept of our team really believes the durability signal or the trials have been slightly artificial, as they have across the entire space. We still believe in that signal, and therefore, in a trial that's designed to really treat any amount of fluid, if you believe in the durability message, then those patients will still rise to the top, and we'll still see a meaningful proportion of patients that are able to go on an extended interval. I'd say, if we're trying to get both in one design, focusing on dryness, which I really like, is how clinicians practice in most cases. That said, you asked a really good question, but what is that percentage? I don't know, and I can tell you that if 100% of patients are getting monthly dosing, that's not going to be great, and that's obvious. One, very extreme. I don't think it's going to be 59.4% of patients getting five months or longer, right? Some of the patients have some fluid. So where is that sweet spot? If you look at CAT and HARBOR and all these trials that were as needed after the first shot or a few shots, somewhere in the range of 5%-15% of patients may not need additional shots through one to two years of follow-up after you get dry to begin with. So the percentage would need to be meaningfully higher than that, right? We can assume 10%-15% of patients don't need any more shots, and therefore, they're definitely going to be every six-months intervals. So I'd love to see, you know, at three months and beyond intervals, that to be 30+%, because that to me would be a meaningful differentiation from the other anti-VEGF regimens. So if you'd like to add to that, if you look at VIEW, about 60% of treatment-naive patients are dry on the aflibercept Q8. Which means 40% aren't. If you can get more than 60% Q8 or longer, that's meaningfully different. The other thing is, and what I applaud them is, there is no biologic or scientific reason to require vision loss before you retreat. They only do that to decrease the number of injections to make their drug look better. Fluid is a pure biomarker. I mean, you can argue how much fluid. I don't like any fluid, but you know, the amount they're picking here makes way more sense than making you lose vision and have fluid. Right. We've tried to design the DAYBREAK, have GLOW two be very... We anticipate a very high probability of success for GLOW two. We like the addition of that third loading dose at the beginning, so that provides a lot of flexibility commercially for, you know, for reimbursement, to use, to be used broadly in the diabetic retinopathy population. So that's very great. And then in the DAYBREAK study, we've really tried, again, to think about skating to where the puck is going to be, to say, let's not, we, you know, think about how other people have designed their studies, but let's actually think about how the physicians are going to take our data, right? Because we think we can rapidly move the data into a BLA. We have our commercial facility with all the DPQs and rapidly move that into product, and we hope we can do that in the context of a pre-filled syringe. So we're thinking, where is the field going to be and what kind of data do we need to generate to educate the physicians about how the drug really works? Rather than trying to think about, you know, like, well, how do you understand really whether or not you've lost vision or 80% or 90% of the patients on 12 or 16 weeks? We're trying to do it a little bit differently, but importantly, have a very, very high probability of meeting the non-inferiority in the study for both molecules. Being a bit scarred from our experiences in the past has pushed us, I think, hopefully, to be more thoughtful. I have two on the formulation and two on the trial. Should I split them up or? Okay, let's talk two on the formulation, maybe. So the ratio of one to four, presumably could have been two to three, where there's more unconjugated in there, and that could theoretically have also obviated the need for having four induction shots versus three in the trial. What was the thought process, I guess, on your end, and I have two follow-ups. Well, one is we weren't completely free. We couldn't, you know, drive the change in a, you know, invert it, for example, because our historical data was predominantly conjugated, and we wanted to stay close to that. So that's, I would say, one element, but in reality, our conjugate did extremely well in the majority of the patients and the majority of the studies. And so what we're trying to do by bringing the unconjugated is to drive a bit more immediacy, let's say, in the higher-risk patients. And by looking at that percentage, right, at the molar equivalent and comparisons, we think, you know, we don't know exactly where we're going to need to go, but like I said, for me, it's arithmetic. We're going to definitively close the gap or narrow the gap. I don't think actually the field demands that we need, you know, exactly overlapped with Eylea, right, in the loading phase where that would be better. I think it was an amazing surprise when eight mg of aflibercept didn't drive better through the loading phase than two mg of aflibercept. I mean, from a science standpoint, that's a bit of an earthquake. I think what that tells you, you know, is that you're saturating earlier. So with our 1.3 mg equivalent of aflibercept, right, in the one plus four, we're going to definitively be a lot better. The goal is to get the patients to the promised land, so the majority of patients predominant, you know, very long or longer interval dosing, but to do well at the beginning, and then for the physicians to decide, like, "Oh, well, should really high-need patients be on, you know, on KSI-101, or should they be on Vabysmo, or, you know, can they actually be on Tarcocimab or KSI-501?" So we'll find out, but we're not gonna be weak, right? We're going to still have a very strong, differentiating and longer interval durability drug. With AMD, we hope we don't need four loading doses. All right, that's... Most AMD patients dry up with, you know, they're either gonna dry or not dry with that two doses, and that third dose is usually just bonus, but hopefully, we don't need four for AMD with this particular molecule. Got it. Maybe also, and I want to get to the trial in a second as well. Formulation changes, could you remind us what was changed in the formulation that goes from gel-like to fluid-like? Is there any prior data on that? I just want to understand maybe the probability for possible kind of formulation change. The main thing is that the T arcocimab old clinical formulation had 100% of the antibodies conjugated to a biopolymer. So you had a high amount of, let's say, biopolymer mass in that highly concentrated formulation. Okay, so for example, the biopolymer is five times larger than protein. Okay? So if you have 5 mg of protein, you know, you have north of 25 mg of polymer, so for a total of 30. But when you bring that down so that you only have four milligrams of conjugate, then you have, say, 20 s of polymer, right? The point is that it turned out that we were a bit on the steep part of the curve, okay, where we have biopolymer amount and the impact on different biophysical criteria like dose time, dose force, so that as we marginally decrease the amount of polymer from 100%- 80%, okay, you actually come down that steep part of the curve fairly quickly, and you can have dramatic impacts on the dynamics. In the end, you know, whereas we leaned into the changes in the formulation initially from a manufacturing standpoint, as we moved to commercial scale in our Ursus facility, because the drug substance was quite gelatinous and, you know, somewhat difficult to work with, and similarly led to some complexities in the clinic as they did dose preparation, right? And as we talked about the dosing-- But as you mildly decrease the biopolymer amount in the concentrated formulation, you do have a dramatic improvement in many different qualities. So it's going from the steeper part of the curve down into a flatter part. Got it. And maybe just to wrap it up, KSI-501, I think you've shown just about a hundred drop on the CST. I'm just trying to compare that versus Roche, whether we should or shouldn't make that comparison. As well as on DAYBREAK, it remind me, is the timing of primary endpoint measurement at week 48? And I ask because, the way I'm looking at the trial design, because of the, the way the opening structure, ideally, a last injection happens eight weeks before the primary endpoint measurement, whereas for 501, the last injection happened four weeks prior to the primary endpoint measurement. Could that make the regulator and/or a clinician ask whether one arm was just designed a little better than the other based on the timing of last injection? So I'm gonna answer your second question. So the primary endpoint is a combination of weeks forty, forty-four, and forty-eight in Daybreak, so there's. It's a mix. How does that work? So if I was a decision maker, how would I do that? Just take an average of all three? Yes, it's an average of the three visits, which is, so it's a more fair comparison. For all arms? For all arms. Correct. That's predicated, you know, the Vabysmo studies do the same thing. There's many other sponsors that have done it. We actually think it's more fair. It creates a more realistic comparison, as you say, like, if you, instead of, like, how long after the last visit is the primary endpoint, this is a combination of the three. Okay, got it. Sorry, could you repeat the first question about the 501? On 501, the CST, the depth of CST response versus what you saw on Roche option? I think it is impossible to compare between trials. Like, that's it. Yeah. What we see, like, what we see in the 501 phase I data is that there's clinically meaningful improvement in BCVA that corresponds to that response in CST. That's what you want to see. It's a small sample size, so it's directionally as good as you could get, but it's really hard to compare to something else. You can see it depends on the baseline characteristics and so on. Richard, I guess, how do you think about that? Because I feel like if there's one thing I got really wrong on Kodiak first time, it's exactly this issue. CST was weak last time, and it perfectly correlated with the phase three problems. I'm just kind of seeing that on the KSI-501, and I'm just trying to make sure I don't-- If that's clearly DAYBREAK, you've adjusted for a lot of that, but it does seem to the system. I'm just curious about- Don't forget that the 501 now has the enhanced formulation technology, and so therefore, you know, if there were an early weakness in OCT associated with 100% conjugate, now it's a 1.5, 3.5 for 501. So we're bringing a lot of power, and the protein itself is very potent, right? In fact, on the VEGF, it's now a VEGF trap on the 501 design rather than an anti-VEGF or antibody. Whether that's helpful in terms of early power or VEGF, you know, control is still up for debate. But I think, you know, we're, you know, we agree with that. That's why we brought the new technology. The other issue, and again, it's hard to cross-trial compare, but they're also different reading centers. Like, the Vienna Reading Center, Ursula, is very different than the reading center that we use. So that's closed now, and so now you're going to have some more. The new trials, I think, will be more, they're moving to Wisconsin, right? Okay. Well, great. I think that's, that's a bit of a tour de force of Kodiak R&D, and now we know as much as we need. We'll work hard on the clinical trial and the early pipeline. Thanks so much.