To the 2025 Kodiak Sciences Investor R&D Day. I'm John Borgeson, Kodiak's Chief Financial Officer. Thank you all very much for joining us. We're excited to host this virtual investor event today. Our event is packed with a lot of content, so will likely go about two hours. This is truly an exciting time at Kodiak, and we are thrilled to walk you through today's program covering each of our three late-stage clinical assets, tarcocimab, KSI-501, and KSI-101. I would like to remind you that remarks made today include forward-looking statements about Kodiak that are subject to risks and uncertainties. A more complete description of these and other material risks can be found in Kodiak's filings with the SEC. We have key members of Kodiak's management team in attendance and participating today: Dr. Victor Perlroth, Chairman and CEO; Dr. Dolly Chang, Chief Scientific Officer; and Dr. Pablo Velazquez- Martin, Chief Medical Officer. We are also thankful to have distinguished industry experts Dr. Charles Wykoff and Dr. Sumit Sharma presenting today. Charlie Wykoff of Retinal Consultants of America, or RCA, is well acquainted with Kodiak, having enrolled more than 100 patients across our studies. Charlie is a highly regarded thought leader in the field and recently joined the American Society of Retinal Specialists Board of Directors and has a lot of impact on safety decisions in the community, as well as being very active in translational research and clinical trial design. Sumit Sharma is on the leadership at the Cleveland Clinic and is a well-known uveitis specialist, retina specialist, and researcher. Sumit is a world expert in uveitis, so we are very excited to have him present KSI-101 today.
Charlie and Sumit bring their own perspectives and to talk about Kodiak Sciences and put us in the context of the broader field. Looking at our agenda today, Victor will kick off our program by taking us through key messages that you can expect to hear today, as well as provide his thoughts on the contents to be presented next. Dr. Wykoff will describe how Kodiak's promising late-stage bioconjugates, tarcocimab and KSI-501, are designed to fill the best of both worlds. A science of high immediacy and high durability at the same time in a single biologic, which is a gap still not solved with today's approved medicines. We will shift our attention to KSI-101 with Dr. Sharma will provide some background on MESI, its causes, and the unmet need for the fourth leading cause of blindness and how KSI-101 is poised to address the need.
Importantly, and what many are waiting to hear, Sumit will also be presenting new KSI-101 phase I-B data from our APEX study in both DME and MESI. Continuing the discussion of KSI-101, Charlie will then present an overview of our pivotal program for KSI-101 and how we have applied our learning so far with KSI-101 into our new phase III trial designs, PEAK and PINNACLE. To help put MESI further into context, Dolly Chang will walk us through our patient journey, which we think typifies the current landscape for patients with MESI. And Victor will present an in-depth view of the commercial landscape and opportunity for KSI-101 as a first-in-class biologic for MESI. We will then conclude our program with a Q&A. Now I would like to welcome our CEO, Dr. Victor Perlroth, with key messages that you can expect to hear from today's event. Victor.
Thank you, John. Thanks, everybody, for attending. It takes a full team to make an event like this happen. I wanted just to take a quick moment to acknowledge the many contributors, the Kodiak team, our advisors, and of course, the AV and IT team. Thank you very much. I'm glad John also mentioned the forward-looking statements and an important reference to the many risk factors in our 10-K and 10-Q filings. We have a full agenda today, and I want to start by saying I have never been as optimistic about Kodiak as I am in this moment. I know that's a big statement to make as Kodiak is more than 15 years old, and we've had many big ups and downs.
As I see it, though, there is wisdom to be had from those experiences, and that wisdom is why I have never been as optimistic about Kodiak . Let's start with the KSI-101 program. Dr. Sharma will be presenting the 12-week data today. They are strong, strong enough to suggest a new unifying molecule in macular edema secondary to inflammation, a leading cause of blindness in the working-age population in the developed world. The simplest message I can impart today to all of you at this R&D Day: KSI-101 is outperforming and is a strong reason to believe in Kodiak . on its own. With our market cap at $250 million, there's tremendous room to run. For example, if the expectation for today's KSI-101 data from APEX is north of 7 to 8 letters mean gain, we're seeing 10 + with this phase I-B data.
If the expectation is north of 50% of patients dry on intraretinal fluid by week 12, we're seeing nearly all dry on IRF and the same on subretinal fluid. Also, our asset is doing really well. Wow. That's what we hear from the physicians when they call, by the way. We are observing these responses across diverse MESI patient types, supporting the bispecific broad-spectrum mechanism of action that KSI-101 is a new unifier across macular edema secondary to inflammation. This is reminiscent of the early anti-VEGF space. Wet AMD used to be divided into subgroups: predominantly classic, minimally classic, occult categorizations loosely tied to poorly understood mechanistic ideas and defined more by treatments available at that time, for example, PDT. Once anti-VEGF came around and it worked in all of the subgroups, the complexity of the etiology, the alphabet soup, was washed away. Another historical analogy here.
MACUGEN was the first anti-VEGF but was narrow spectrum, only hitting VEGF 165, and it was soon effaced by the broad spectrum anti-VEGF agents. That's the promise here for 101 in MESI the ability to shift patients to a safe, potent, high dose bispecific broad spectrum therapy early in their disease journey and to set the patient up for preservation of vision over the chronic course of the disease rather than a complicated and frustrating trajectory towards vision loss, which is today's reality. The longer the patients are exposed to the swelling of the photoreceptors, the macular edema, the less likely the patient will regain their starting vision. A simple unifying therapy will likely also mean earlier therapy. One of my closest friends growing up, her mother is battling MESI for years now. She ended up with cataracts in each eye from the inflammation, and the doctors couldn't repair them.
They couldn't operate because of the active inflammation. That was three years ago. She's now legally and functionally blind despite having had access to the best doctors, and she still has persistent macular edema. It turns out she had a systemic cancer, but the diagnosis was missed. Anyway, through the critical early ocular phase, the eye smoldered. The potential with 101 here is clear: a new unifying medicine that lets the ophthalmologist focus on and actually treat the eye. John Borgeson, the other day, his Uber driver, the driver's wife actually, she had been a scientist at Gilead and she had to leave her job due to MESI. Despite being on numerous standard of care therapies and doctors have found no known etiology, she still has recurrent disease and she's not getting any better.
A third person, actually a founder of a small fund that owns [KOD stock], has anterior uveitis, in this case tied to underlying immune HLA- B27 predisposition. He has no macular edema yet, but he's been treated during different flare episodes and at different times with steroid drops, systemic immunosuppressants, intraocular steroids. He doesn't have viral or any macular edema so far. The point is it's all around us and it's serious. Today we also present the beginnings of a commercial opportunity analysis for KSI-101 suggesting north of 450,000 MESI patient prevalence in the United States, of which 300,000 are the trial eligible patients for APEX and PEAK and PINNACLE and of which more than 150,000 are the initial KSI-101 addressable population of severe chronic and refractory patients here in the U.S.
In physician interviews, the KSI-101 profile was generally considered early second line after topical therapy and first choice for intraocular injection. It may be first line in patients with more severe disease or contraindications to steroids. We are continuing to advance this landscape analysis of KSI-101 in the United States to go deeper. We are also seeing nice tolerability with KSI-101 in APEX and we have been able to select our two top doses, so 5 mg and 10 mg, to progress into the registrational clinical program. As you will hear and I'm happy to report, the phase III PEAK and PINNACLE studies are already live and screening patients. I'm proud of our team and the timeline to get these registrational studies active. By the way, both PEAK and PINNACLE are being operationalized in parallel. They are enrolling at the same sites at the same time.
This is a testament to the fact that at Kodiak , we run our own in-house CRO, our Kodiak Cares CRO, which brings time and cost efficiencies and brings us closer to the physician and indirectly to the patient community. The designs of PEAK and PINNACLE, they are all well informed from our APEX interim clinical data and Dr. Wykoff will talk us through that later. We are pleased to share with you the 101 update and we have a full module for you. Shifting gears, let's remember that Kodiak is also poised in the larger retinal vascular diseases market, the anti-VEGF market. With our ABC Platform science we bring a strong immediacy, a full pharmacologic dose of unconjugated antibody to the strong durability of the conjugated antibody. We apply this, our ABC science, as you know, to both tarcocimab and to KSI-501.
The DAYBREAK study will show all of us exactly what tarcocimab and KSI-501 can do against EYLEA. We'll see the immediacy in the matched loading phase and we'll see the no gimmicks real world durability through the 48 week primary endpoint and then through the two year study duration in DAYBREAK. As you may remember, for tarcocimab we allow monthly dosing and all the way down to every six month dosing. For KSI-501, we will see additionally what the broad spectrum bispecific mechanism of action can bring to wet AMD patients. Do not forget that we already saw tremendous safety with our conjugates in the one-year monthly dose DAYLIGHT phase III study in wet AMD, the retinal vascular diseases market. It is still open season. Roche's VABYSMO shows that with its commercial success, a mainstay biologic with immediacy and incremental durability.
Imagine what a mainstay biologic can achieve if it has a science both of strong immediacy and strong durability. As Charlie will remind us, VABYSMO and EYLEA are both seven to eight day mean ocular half-life medicines in patients. With our ABC Platform science, and as Dr. Dave Brown presented at our last R&D Day in September, our conjugates are mean ocular half-life of 20 days in each of wet AMD, RVO, and DME patients. That is a very important result. It is unprecedented in patients. The commercial complexity of the anti-VEGF market is overstated. All of the biologics today and their biosimilars, their data cards are on the table. Today, they are battling it out in the efficacy zone of immediacy. This is a framework that Dr. Wykoff will be exploring with you in a few minutes. The physicians are clear.
Yes, these new agents, VABYSMO and EYLEA HD, have a strong immediacy but add minimal new durability. They are incrementally useful but not solving the problem. Of the new technologies being evaluated in the clinic, the implantables and the gene therapies are battling it out to demonstrate durability TBD, and in all cases we are aware of, these new agents are being tested on top of mainstay biologics, with LUCENTIS or EYLEA being given during the loading phase and then LUCENTIS or EYLEA being given as supplemental injections during the efficacy phase. That seems strange to me because what are you measuring actually? In any case, the real prize and the real unmet need is a mainstay biologic therapy with strong immediacy and strong durability in the same therapy.
This is what durability means to me. That is the hard learning. It is what the patients and the physicians need, and it is what the field has been searching for for the last 20 years. In many ways, the field has given u p. This is our ABC science and it's not relevant at this point what happened yesterday. It's about when we turn the data cards over for tarcocimab and KSI-501, what do they show? We agree with the enthusiasm we're hearing from the community on KSI-101. We remain excited about tarcocimab and 501 for all of the reasons I mentioned and also based on how the GLOW2 and DAYBREAK studies are prosecuting. Yes, and shortly we will put all the data cards on the table for you.
Three molecules today in four phase III registrational studies reading out in approximately seven months for GLOW2, 13 or so months for DAYBREAK, and approximately 18 months for PEAK and PINNACLE, and a BLA expected for tarcocimab shortly after DAYBREAK readout, and planning for a second registrational study with 501 towards a BLA filing in 2027 in wet AMD, and for KSI-101, also the potential for a BLA filing in 2027. There are steps to our story behind the science and clinical data of these late phase molecules. Our products are wholly owned and our science is homegrown and proprietary. We bring our own differentiation to the party, our own patent lives, our own design and manufacturing expertise, our own retinal commercial scale manufacturing, and nobody and no country can disintermediate us. As I mentioned, we have our own commercial manufacturing facility specialized for retina and partnered with Lonza.
Further, we continue to deepen our technology leadership in retina in our ABC Platform extension, our duet pipeline programs that will take our ABC science to tens of millions of additional high unmet need patients in glaucoma and geographic atrophy, and even our hardcore technology leadership being in Silicon Valley as we are with our VETi program, which is an underappreciated asset of value to Kodiak, an AI headset designed and built for scale. I suspect we will be hearing more about VETi in the coming months. Retina is this space with tremendous depth and tremendous opportunity. Blindness and cancer, those two vie for the top spot of most feared health problems across surveys. There are many commercial biopharma franchises in, for example, oncology R&D, but there really are only two major biopharma franchises in retina: Roche and Regeneron.
Everybody has two retinas and the disease burden is only increasing across the population. You don't have to take our word for the value of retina. Look at what a big value driver retina is to Roche and Regeneron in different ways actually. For Roche, it's all about VABYSMO driving the profitability growth for Roche as a corporation. For Regeneron, the EYLEA franchise continues to drive their current profitability. Back to Kodiak. All of this poised opportunity in a specialty sector where it's a very doable spend concept to access and sell into Retina, not like oncology or obesity, for example, where it's billions to commercialize. Retina is totally different. It doesn't cost hundreds of millions of dollars to run our clinical trials, more like tens of millions of dollars. It's a $20+ billion market globally where you can have an 80 person commercial team in the U.S. and saturate that market. While Retina is technically tricky and we have technical depth, it is commercially attractive if you enter the market with the right product designs and the right data. Not to mention the attractiveness of Retina to pharma at risk of their massive loss of exclusivity over the next three, five, seven years. Pharma who see the potential attractiveness of Retina but have no de novo way in in their time frame. Here at little Kodiak, we have three products, investigational therapies ongoing, a diversified portfolio and each one with something special to offer. Tarcocimab, the mainstay biologic with a full pharmacologic dose of immediacy and the best durability. 501, the opportunity to have better efficacy and all the immediacy and durability of our ABC Platform, and KSI-101, a new broad spectrum intraocular biologic with a greenfield market opportunity.
They are in four registrational studies today reading out over the next approximate 6, 12, and 18 months and BLAs that we anticipate can follow in quick succession as the registrational studies read out their clinical top line data. We are a pre-commercial stage ophthalmology medicines company with technology, product, clinical, manufacturing, and overall retina R&D leadership. Last September, we laid out the roadmap and today we are in motion and we are accelerating. Please enjoy the next 90 minutes or so as the Kodiak team, together with accomplished industry experts, walk you through the details and don't forget to save for the Q&A at the end. The presentation and the webcast after the R&D day is complete will be posted on the Kodiak events and presentations webpage. Now it'll be on to Charlie.
Be here virtually with all of you. I'm getting a little bit of feedback but I will move forward. Quite a few data points to unpack over the next, I don't know, 10 or 15 slides and I'll go efficiently through some of it that you've seen a lot of before. I'll slow down on some of the key points that I think are important to make. You know, it's an exciting time in Retina. There's a lot of ongoing clinical development programs. I'm personally excited about many of them and we'll talk about a few of the relevant development programs also as we go forward. Next slide please. This section is meant to unpack tarcocimab. This is a molecule that we have been studying now for a long time.
I remember being in the first in human trial I think back in 2018 and we have learned a tremendous amount about the opportunity of this treatment through many extra-disease states that we'll talk about and many different trials. I think that those learnings have been well applied to the ongoing current clinical trials that are positioning this molecule well to, I hope, be FDA approved in the near future and available for routine clinical use. 501 in my opinion is a build on tarcocimab with the addition of IL-6 inhibition and a great opportunity there building on pure anti-VEGF with tarcocimab. Next slide please. This framework is worth unpacking for a second, right? The concept here is that the current biologics that are available, faricimab and aflibercept and aflibercept 8 mg and ranibizumab, are quite useful.
They've of course dramatically changed the landscape of how we manage these retinal diseases now for nearly 20 years. I think the adoption of 8 mg aflibercept and faricimab has shown that there is a strong interest and a strong need for patients in our space in general for more durable agents that maintain that rapid and consistent drying capacity. We'll look at what that increased durability with those newer generation anti-VEGF biologics has been in a couple slides. The other box here on the bottom right is that there are a lot of ongoing clinical trials looking at implants, in particular tyrosine kinase inhibitors and gene therapies. There are two programs in phase III looking at tyrosine kinase inhibitors and three programs looking at gene therapies, one given by subretinal and two given by intravitreal, all in phase III late-stage clinical trials.
I am personally supportive of all of those programs. I think there is a need and a role for agents that are able to provide consistent long-term durability for a segment of our patients with exacerbated retinal diseases. We will talk about those options in a few slides in a little more detail. I do see an opportunity here and I think the opportunity exists for a lot of reasons. One is this is a tremendously large space, right? There are a lot of patients with exacerbated retinal diseases, most commonly of course wet AMD, but DME, RVO, and diabetic retinopathy as well. I think that there is a huge heterogeneity among the responsiveness of those patients who are given an anti-VEGF and the half-life of that given anti-VEGF, in other words, the efficacy effect and the durability effects. I think there still is a need for more of both.
There is clearly a need for bolus injections that are able to have a more durable profile. I think that there is a role for those durable products to have a greater immediacy, if you will, which in my opinion really means ability to dry the retinas rapidly. That is where I am hopeful that the newest formulation of tarcocimab with a combination of the biopolymer and the free antibody will be able to fill a part of that unmet need. You can go forward. I do not mean to dive into the details here a lot, but I do think it is fascinating talking to my partners and my colleagues and my friends across the U.S. about, look, what is your adoption to what we think of as next-generation biologics for wet AMD in particular, right? What is your adoption of faricimab and 8 mg aflibercept?
I have seen good adoption across many of my colleagues because there is an added benefit, I truly believe that there is in many patients. That benefit in most cases from what I have seen and experienced with my friends and colleagues has been increased durability. If you listen to the direct-to-consumer advertising out there for some of these molecules, you might interpret that durability to be one thing, but in the real world, that increased durability I think has been more modest than what the direct-to-consumer advertising would suggest. That said, I do think it is real. I think many of these patients that transition from a previous generation anti-VEGF to again faricimab or 8 mg of aflibercept are seeing an incremental benefit in durability. I think that's why you're seeing uptake of both of these next generation therapies substantially, I think, across the U.S.
I think this will only grow and that highlights the potential role for new therapeutics that are able to extend that durability further. You can go to the next slide. What is that increased durability with faricimab or 8 mg of aflibercept? I think the details here of this particular slide are less important than what doctors and patients' experiences are. I do think that there is an increase in the durability for many patients, not all patients with these therapies, but oftentimes that's on the order of a few days to a couple weeks, I think, in the high need patients. You're seeing that in some of the real world data sets. There have been quite a few of these presented on podium now and fewer of them that have been published.
It does appear that the majority of patients are still on approximately every eight to maybe up to 12 week intervals in the second year of dosing with these next generation biologics. You can go forward one slide. I think that the other angle here to talk about in a little more detail is these are these plays on durability and I am very supportive of these. Just to be clear, gene therapy has a very real potential role. Two phase III trials given by intravitreal are ongoing and a phase III program with subretinal delivery also ongoing across the U.S. Similarly, for the tyrosine kinase inhibitor implants, two ongoing phase III programs, again very supportive of these. I think there is a role here.
What is interesting though is if you look at the protocol design for all of these programs, there's one consistent theme which is that these are being given in combination with our standard on-label anti-VEGF therapies that we currently use today, meaning that there needs to be, we believe, some additional drying capacity given before these implants and gene therapies are then going to maintain a durable state long term. I think that there's value in this. I support these programs. There does therefore leave open the opportunity for something that is able to both dry the retina as well as increase durability beyond our current biologic bolus injections that we have access to today and go forward. Thank you. This brings up again that sort of upper right quadrant, if you will, if you graph this on efficacy and durability.
Could this be a tarcocimab opportunity where you, now that we have in particular the improved formulation with both the free antibody combined with the bioconjugate form, can you have both? Can you have this rapid drying capacity and an increased durability in the same bilaterally injected biologic? You can go forward. This brings up the bioconjugate and the combined free antibody concept here of tarcocimab. In particular, using this ABC Platform that Kodiak has been working on for many years, you can go forward. This slide summarizes some of those key points. Remember, the bioconjugate is a phosphocholine-based biopolymer that, on a couple slides from now, you'll see how that changes the intraocular half-life. There's good data from animals that by attaching this bioconjugate to the protein, you meaningfully increase the ocular half-life by about threefold.
More importantly, there's meaningful data from humans based on aqueous humor sampling. There's meaningful data from humans showing with aqueous humor sampling after tarcocimab injections that half-life can be meaningfully extended with the bioconjugate form as well. What we learned over the early pivotal trials with tarcocimab is that we probably would benefit from a combination of free protein. This is the darker blue section on the right, giving an immediate drying capacity equivalent to the current on-label anti-VEGFs in combination with a bioconjugated form that provides that durability advantage. That low tail on the right, you can go forward. Thanks.
This is a fascinating slide to digest for a moment. On the x-axis here is molecular size, essentially the size or weight of the combined molecule. On the left are all of the biologics that you're familiar with, with the addition of KSI-501 on the bottom right and tarcocimab on the top. Some interesting points. Tarcocimab is almost identically the same size as faricimab, the bispecific listed just below it. Those are, that's the free protein of tarcocimab at the top there at 149 kDa. By having an injection which has free protein in it, the concept is that you're going to have an immediacy effect that will hopefully be very similar if not identical to the current on-label anti-VEGF biologics.
On the right of the slide you see this durability play where this biopolymer has been covalently linked to the biologic, which allows that increased half-life based on the molecular size. You can see a dramatic shift in the molecular size on the left side of this graph to the right side with the addition of that biopolymer to tarcocimab as well as to KSI-501. The goal being for rapid drying with sustained durability. I think that we have seen a consistent signal for this in previous trials where a meaningful number of patients truly can build a substantial interval without having recurrence of disease. You can go to the next slide. Thank you.
This just summarizes that point where right here, by taking both free protein on the left and combining that with a proportion of the treatment that's going to be bioconjugated, you can hopefully have both, which is immediate drying capacity for the anti-VEGF dependent diseases as well as then a durability signal with the bioconjugate. On the top is the example of tarcocimab and on the bottom is KSI-501. You can go forward. These next few slides dive into some detail and numbers which are fascinating to think about. I think one of the caveats here is that there is great heterogeneity across humans for all human diseases, right? Not everybody presents with the same phenotype of wet AMD and not everyone responds the same to each anti-VEGF. That's why I think it's useful for this space to have multiple options.
If you look now at the mean ocular half-life, the little blue dots represent that average half-life, sorry, the half-life for each individual patient. The blue callout box is the mean average half-life, which is 19.8 days for tarcocimab. What's fascinating to me is the spread, right? You have some patients with a very rapid clearance set. The 10th percentile is 8.3 days and the 90th percentile is up there at 31.8 days. Quite variable.
This tells me that the ideal clinical trial is not to lump patients and to force them into long durability intervals. If they're going to be a rapid clearance patient, they're not going to do optimally. You want to give patients the opportunity to get more frequent treatment when they need it and allow them to have less frequent treatment if their disease is well controlled. I think that's really what this shred of dots tells me. Importantly, if you compare that to the public data for faricimab, for which the mean intraocular half-life is approximately 7.5 days, that suggests a meaningful difference between these two molecules. Again, with the caveat that these are different trials, different assets, different assays. There does appear to be a substantial difference in the mean intraocular half-life.
We believe this is being driven by that bioconjugate intentionally incorporated into a substantial proportion of the treatment in tarcocimab to allow that extended durability. You can go forward one slide. One of the values of having performed so many trials now with tarcocimab is that we've seen the effect of this molecule in many different disease states. In the original 1-B trial, we incorporated multiple different diseases and you can see that the intraocular half-life appeared consistent across wet AMD, DME, and RVO, again with an approximate 20 day intraocular half-life across each of these disease states. A nice consistency across these different exudative retinal phenotypes. Go forward. This is the busiest slide in this section, but it's worth digesting this for a second, because this tries to put it at a patient level.
I emphasized this before and I think this is really important, that this is a heterogeneous disease and the clearance in a given patient, in a given eye, can be quite variable from a different patient with a different eye and a different disease state.
If you look first of all i n that faricimab line, let's take the average patient, that sort of middle blue patient. If they're on a six to eight week interval with faricimab and if they go longer than that, they have recurrence of disease. Based on the half-life calculations I just showed you on the previous slides, you might anticipate that these patients are able to go a week to two, maybe three weeks longer with tarcocimab. Importantly, I'm not saying that this patient's going to go from six weeks to 16 weeks. That would be unlikely given that this patient is sort of a medium clearance patient where they're still going to clear a different biologic. Because that other biologic now has a unique bioconjugate on it, could they have increased durability? I think the expectation there is that yes, they could. Would a one or two or three week biology interval extension be meaningful?
I think all you need to do is ask a couple patients that question and you'll quickly see the answer is yes. The goal, in my opinion, is not to get the 16 weeks or 20 weeks or 12 weeks or whatever your favorite number is for every patient. The goal is to get as long as possible safely for each patient. I think that that's the shift that's important to consider. If you then look at the patient doing really well with faricimab, they're out to every 12 week injection. That's the lighter blue on the right. If we switch that now to tarcocimab modeling with the potential intravitreal half-life difference, you see that they may be able to go two to four weeks longer with tarcocimab, increasing their interval again meaningfully for that patient.
If you look at the highest need patients for the far left there, that darkest blue patient, someone that really requires monthly dosing, these patients tend to be the ones that we think of early in discussions as retina specialists. A, because we see these patients a lot, we're seeing them every month, and B, these are the ones at highest risk of visual function, visual loss, and anatomic changes when they are not able to get the frequency of dosing that they need. For patients like this requiring monthly dosing with our current anti-VEGF pharmacotherapies, I would strongly argue that even a small incremental change in increased durability can be quite meaningful for these patients. What you would expect by transitioning them to that longer half-life, maybe an extra four to 10 days on their interval.
Again, I'm clearly not trying to overstate this that they're going to be able to go 16 weeks. I don't think they will, but an extra week for those patients can be quite meaningful in their quality of life and their need to return to the doctor and also gives them a little bit more of a buffer. Unfortunately, patients develop other problems and sometimes they can't get back at exactly that one month visit. To have a little interval grace period can be quite useful to optimize long-term outcomes for patients. I think we've seen in the commercial success of both faricimab and 8 mg aflibercept there is a desire for increased durability. I think every incremental step forward is meaningful for patients in the space. You can go forward.
This is really sort of summarizing what we just talked about in that by ideally combining the unconjugated and the bioconjugate form in both tarcocimab and KSI-501 molecules, we can hopefully achieve that early drying and increased durability for a meaningful number of patients. You can go forward. Right, this then lays out the structure of what's ongoing and what's coming and what it's going to take to get tarcocimab across the line to get it FDA approved and into clinicians' hands. Also for KSI-501, and Victor reviewed this before, but we will go in detail in a little bit here into GLOW2 and DAYBREAK, both of which I think are well-designed trials which have a high probability of success. You can go forward. Great, DAYBREAK. I would love to take a deep dive here.
I think this is a fascinating trial and has actually meaningfully moved our space forward for multiple reasons and I'll tell you why. First of all, when I think of a clinical trial design, the first thing I think about is the control arm. Everybody wants to jump straight to the investigational product that's going to be better than the current standard of care and that's great, but to me the most important thing is actually the control arm because I want to make sure every patient knows the trial is getting optimal treatment and I'm not leaving anyone behind. I like this control arm. It's aflibercept gold standard every eight week dosing after three monthly doses. That is the gold standard for patients, so you know you're going to have a very robust control arm.
The second thing that I look at that is quite differentiated in this trial is that I think it's the first pivotal trial in Retina to incorporate two different investigational products. I like that because it's efficient from a company perspective and also from a patient perspective, right. Instead of having to do two different clinical trials that are pivotal for these different molecules, we can combine them all into one.
The third reason this is q uite differentiated and the most important actually is the use of a locally deployed AI algorithm to determine retreatment. One of the biggest discussions that will come out of pivotal trial designs when you're looking at durability is what are your supplemental retreatment criteria, what are your rescue criteria, how are you defining durability? What's nice here is that this is not investigator determined. This is purely based on a well understood validated algorithm that is commercially available across in many countries to determine a fluid volume status. This has been tuned so that patients are able to get treatment as frequently as they need. A point that we brought up earlier where I believe strongly for wet AMD that forcing patients into a given interval despite persistent significant fluid is not optimal for long term outcomes. I think there's quite a bit of data to support that.
If you look at the individual arms now in tarcocimab, the blue boxes at the top, they get four monthly loading doses and then those patients are going to be evaluated for retreatment every single month through the two year follow up, meaning that they can get monthly dosing if they need it. I think that that's great because we know that some patients will probably need monthly dosing for any of the biologics given their rapid clearance. However, if patients do not need monthly dosing, they're not going to be forced to get it. The safety net will be once every six month dosing during the two year trial, which I think is very consistent with previous data that we've seen with tarcocimab, where a meaningful number of patients will be able to go extended intervals while maintaining a dry retina.
Again, we're not forcing patients to go longer and waiting for them to lose vision. The retreatment here is based on pure fluid not requiring vision loss to get treatment, which I think is very patient centric and a strong trial design. The last arm there, the green on four monthly doses of KSI-501 with every other month dosing from there, but again with the caveat, we're not forcing patients to get every other month dosing. If they have activity the intervening injection visits, they can certainly receive those extra injections to maximize the chances of outcome, a strong efficacy outcome. I think that the screening here is planning to be closed probably in August and then data to follow next year. You can go forward. That's the ongoing DAYBREAK program which will round out the wet AMD package. GLOW2 is also a strong trial design.
The GLOW1 results are highlighted in gray at the top there. Remember, there was a strong signal on DRSS improvements. 41% of the patients treated tarcocimab in GLOW1 had a two-step or more improvement on the DRSS, which is the FDA approvable endpoint, compared to 1.4% in sham. More relevant to clinical practice, on the right we saw a 90% risk reduction in development of PDR or center-involved DME. The goal in clinical practice when you're treating diabetic retinopathy is actually not DRSS improvement. That's really not clinically relevant. It's very relevant from a regulatory perspective. What is clinically relevant is to prevent the development of a vision-threatening complication, which I think of as proliferative disease or center-involved DME with visual acuity loss. One of the other strengths of the Glow program, both GLOW1 and GLOW2, I would point out, is actually the inclusion not only of patients with DR.
They all had a diabetic retinopathy severity level of a very specific range, 47- 53. They also allow patients with DME, and this is critical, they allow patients with DME with good visual acuity. I refer to as sort of the Protocol V population defined beautifully by the DRCR network. That allows us to see the effect in these eyes with preserved visual function with mild to moderate DME. We saw that those eyes did quite well. GLOW2 has a nearly identical trial design except one additional injection at week four that's highlighted with the purple box there on the bottom left. That is to allow increased dosing flexibility in the real world, which I think is very useful in optimizing patient treatments. You can go forward. Last couple slides in this. This just talks about the concept of, great, you have GLOW1, let's say GLOW2 is positive. Is this really going to be used to treat diabetic retinopathy in the real world? We know that very few patients with pure diabetic retinopathy without DME are actively receiving treatment across the United States.
I think that this is a challenge for the space and I think we have to demonstrate the value here. One of the frustrations about diabetic retinopathy is that most patients that go blind from this disease process should not go blind. This is a disease that is readily treatable and in most cases preventable if we catch these patients early enough in the disease process. These high risk, what I think of as high risk NPDRs with moderate or early DME with good vision, I think that with a therapy that could be given as infrequently as a couple times a year, that may begin to change the paradigm for treatment for some patients with some physicians. I'm hopeful that we could therefore lean towards preventing more of the needless vision loss from this disease state over time.
You can go forward and then finally rounding out the exudative retinal diseases with the data we have for tarcocimab. This is the RVO data, this was very strong data from Beacon showing very good disease control. Remember, in the second six months of the trial, 75% of patients needed zero or one retreatment in that second six months after the fifth dosing in the first six months, suggesting again a significant durability signal. Not included on this slide was a direct head to head comparison of aflibercept with tarcocimab in that second six months. Indeed, there were fewer retreatments meaningfully given in a tarcocimab population compared to aflibercept. Again, what we think of as validating this increased durability signal in what I think of as the highest anti-VEGF need population, which are the eyes with retinal vein occlusion, you can go forward.
I think this is my last slide for this section and just bringing back the original core concept. I'm not here to disparage any of the other molecules on the market or in development. There are a lot of exciting things ongoing in excess of retinal diseases. We use aflibercept, we use faricimab a lot in clinical practice and they are incredibly valuable. There do remain unmet needs and I think that the TKIs, the gene therapies can all provide value. I do think there's also a significant unmet need for a molecule that has the immediacy of an aflibercept or a faricimab with increased durability beyond those molecules themselves. Go to the next slide. With that I'll pass it over, I think to John and then to Sumit. Thank you.
Thank you, Charlie, that was great. Sumit, can you hear me? Are you ready to get started?
Great. Next slide, please. We go to the next slide, please. Thank you. I'm going to be talking about macular edema secondary to inflammation and the cardiac program here. I'm happy to be a part of this. As mentioned, I'm both a retina and uveitis specialist and one of the things that I have always noticed and seen is that we have for a very, very long time distinguished between the cause of macular edema or uveitis. A lot of the other studies that are out there that have been done have really focused on defining macular edema by the underlying etiology. The reality is that it's really a spectrum of disease and there's a wide overlap in terms of the underlying etiology of what's driving the macular edema.
What I mean by that is you have pure uveitis, which is almost all inflammation driven, and then you have pure VEGF driven diseases such as myopic CMV, but the rest of these diseases fall somewhere in between. They realistically have components of both inflammation and VEGF driven diseases. With both systemic autoimmune diseases with post-surgical inflammatory CMV, they're mostly inflammation driven. However, there is still a large component that is VEGF driven. We see that and we'll talk about that in some of the data that I'll show later on. You have your retinal vascular diseases and neovascular AMD that are majority VEGF driven. We know that there is a large inflammation component as well. Next slide, please.
When we talk about macular edema secondary to inflammation, we're talking about a heterogeneous group of diseases that are driven by a combination that eventually leads to disruption of the blood retinal barrier and it's a combination of inflammation and angiogenesis that's causing it. You get macular edema, which we know leads to visual impairment and we know leads to morbidity for patients. We have a potential common therapy that Kodiak is developing in KSI-101. Next slide, please. We know that this is a very heterogeneous group of diseases. You can define uveitis by either the location of inflammation, so anterior, intermediate, posterior, pan-uveitis, all of which can present with macular edema. It probably happens at different rates with the different anatomic locations, but we see it with every single type and then many, many underlying etiologies.
It can be idiopathic, which it often is, or despite extensive workup, you can have it in juvenile idiopathic arthritis, in children as young as age 2 or even younger. Sometimes you can get focal chorioretinal Inflammation.
Because often they present with a combination of both the macular edema from the inflammation, but also with macular edema secondary to CMV. You can actually see that in this slide that this patient has both, they have both macular edema from inflammation as well as macular edema from their CMV. Next slide please. Regardless, we know that macular edema is a large portion or large contributor to the causes of vision loss in ocular inflammation. Overall, ocular inflammation is the fourth leading cause of vision loss in working age adults in the developed world. A third of the patients with inflammation develop macular edema in the U.S. according to our most recent data.
The symptoms that it presents with can be a wide variety of things including distorted central vision, reduced visual acuity, decreased color and contrast sensitivity, but eventually it leads to photoreceptor damage and can lead to permanent loss of vision as well. It is important to catch and treat these patients early on. Next slide please. What causes MESI or macular edema secondary to inflammation? At the end of the day, it's all related to breakdown of the blood retinal barrier and breakdown of that blood retinal barrier is mediated by a number of different cytokines. However, we know that VEGF and IL-6 play a huge role in this and they're co-inducing in that they promote each other's activity where VEGF promotes vascular leakage and neovascularization, while IL-6 really sustains the inflammation and upregulates that VEGF production. That combination feeds on itself.
We have really good preclinical data that shows that early on in preclinical, in animal models and in cell models, that combination of both IL-6 and VEGF has a greater effect than either molecule itself. Next slide please. We also know that both IL-6 and VEGF levels are elevated in patients who have both ocular inflammation and macular edema. We see that in various different levels. On the left hand side of this slide you see that patients with intermediate uveitis and measuring their aqueous humor levels of IL-6, we see there's a wide variety of levels of IL-6 elevation, whereas in controls we don't see very much IL-6 at all. On the right we see that those eyes that have CME have higher levels of VEGF in their aqueous humor when they have uveitis versus when they have uveitis without CME.
But interestingly, often these uveitis patients, when they're actively inflamed, will have VEGF, sometimes in the absence of CME, and the inflammation itself is causing that VEGF level to rise. Because they're often younger, they have a really strong RPE pump and they don't see overt CME, but they're still inflamed. Next slide, please. This is what I was alluding to earlier. This is a HUVEC cell model. What we see on the top in the blue is a high barrier resistance, intact tight junctions. We're looking at the integrity, using this model to look at the integrity of the blood retinal barrier by measuring the electrical resistance in HUVECs that are cultured. We see that when you supply VEGF in the purple, you get an increase in permeability.
When you supply IL-6 in the light purple, you see a similar but greater immediate reduction in the resistance, and then it kind of levels out to the same level as VEGF. When you provide both together, you get a greater loss of that barrier resistance than either of those two molecules alone. This lends credence to the thought of blocking both molecules in order to see an improvement in macular edema and inflammatory diseases. Next slide, please. What is really the unmet need and how do we look at this? My clinical experience is that we have a significant unmet need. Right now we really only use corticosteroids as our mainstay of therapy. The vast majority of our patients are either getting immunosuppression, so that's that other biologic section, or most often we treat with steroids.
Often I find that my patients aren't going to fully respond to intraocular steroids. It's really interesting that that happens. We see it not infrequently and very frequently. At least in the U.S., we see a resistance to using intraocular steroids, especially in the pediatric population and even in adults, because the really high rate of cataract formation will eventually happen with repeated steroid injections in almost everyone, and intraocular pressure rise, leading to uveitic glaucoma and glaucoma is damage from the steroid response in these patients. There are many docs who actually will not use steroids and end up under treating our patients because of that. We have to be very aggressive. I'm fortunate to have very good glaucoma specialists, but I also say to them I cause a lot of glaucoma because I use a lot of steroids right now because they really are the mainstay of therapy.
Next slide, please. My own clinical experience with topical steroids for macular edema secondary inflammation has been kind of mixed. If we look at it in different etiologies, I find pretty much across the board, and those data that'll be shown later that matches my own clinical experience, is that about a third of patients will be good responders, about a third of patients will be non-responders or refractory to topical steroids, and about a third of them will get elevated intraocular pressure, limiting the use of the topical steroids. Almost two thirds of these patients require either additional or alternative therapies after topical steroid use. It's a fairly large population that has a very high unmet need overall. Next slide, please. We cause a lot of complications.
I was alluding to having very close relationships with a number of glaucoma specialists, and I really do, because we have to be really cautious in these patients. In these patients who have inflammation, you can't proceed with cataract surgery when they're actively inflamed because it's really contraindicated. It can lead to permanent vision loss because of runaway cascading inflammation post cataract surgery. It's not as simple as saying, oh, you caused cataract with the steroids. Go ahead and just take the cataract out. Often these patients have to be significantly immunosuppressed or put on very high doses for long periods of systemic corticosteroids, which also has significant morbidity and sometimes even mortality, in order to allow them to get their cataract taken care of. A treatment that doesn't cause cataract is desperately needed in these inflammatory eyes.
The other part is a large portion of these eyes will develop IOP elevation when they treat with corticosteroids, either locally or even sometimes systemically. Concerns about IOP really limit the use of corticosteroids in multiple patients. We often will add topical drops to control the IOP, but it's often insufficient. These eyes often need surgery. We know with the registered fluocinolone intravitreal implant that 60% of patients require chronic IOP lowering medications. Nearly 40%, or 4 out of 10, need a glaucoma surgical procedure to control their intraocular pressure. Nearly everybody needs cataract surgery. This pretty much fits with my experience with local steroid use, as while they work in many patients, they do not work perfectly. They have a high rate of morbidity and mortality that limits their use and often leads to undertreatment of these patients across not just the U.S. but across the world.
Next slide, please. This is a patient of mine that presented in 2023 with a 12-year history of pan uveitis in both eyes with multiple failed treatments. We can see on the fluorescein angiogram that there is quite a bit of leakiness in the vessels, and it is in a fairly interesting pattern where it is following more along those inferior arcade vessels with some chorioretinal scarring. She continues to worsen with any type of local steroid. She gets elevation of a pressure to 40. She has a surgery to try to control both the cataract and the intraocular pressure, which is a combined cataract surgery and a canaloplasty. The pressure keeps rising despite surgery, so we consider alternative immunosuppression. She has already failed multiple immunosuppressant medications, but I refer to one of my rheumatologists who specializes in this, and her insurance will not approve any additional.
We go back to using local therapy, and local therapy is not working so well. She is continuing to get worse. Eventually, because her pressure is in the high 30s despite maximal topical drops and oral DIAMOX, she ends up getting a tube shunt, which is not a benign surgery. Tube shunt surgery is really associated with high rates of complications and even higher rates of complication in eyes that are inflamed. We often end up significantly hitting these patients with systemic corticosteroids in order to allow the glaucoma surgery to happen safely. Fortunately, she is now doing much better after a fluocinolone peritoneal injection. This poor lady has undergone multiple surgeries per eye, and this is just her right eye. Her left eye has had a very similar story.
She has now undergone multiple surgeries in order to try to get this inflammation under control that really is limited to her eyes. She has also taken multiple different immunosuppressive medications that have systemic comorbidities. If we had a local therapy that could avoid the side effects of cataract and intraocular pressure rise while controlling her inflammation, it would have been transformative for her. Next slide, please. There is really a core unmet need in MESI for a potent, high strength, locally administered therapy that is safe. We really have a few different things. We have intravitreal anti-VEGF monotherapy that's pretty safe but doesn't have much efficacy. We'll talk about some of the data in uveitis and uveitic macular edema and in MESI for intravitreal VEGF monotherapy. We have systemic immunosuppressants that are okay efficacy, somewhat okay safety sometimes depending on which one.
We have intraocular and systemic corticosteroids that have high efficacy in controlling the inflammation but often have a lot of safety concerns. What we would love is a therapy that gives us both high efficacy and fewer complications and a biologic therapy that could target both IL-6 and VEGF disease drivers. At the same time, while treating the macular edema, potentially being disease modifying would be fantastic. It would be good for it to have high strength, be potent, and have an excellent safety profile, and that would be transformative in the field. Next slide, please. The merit study was a randomized clinical trial that randomized patients to either the OZURDEX implant, intravitreal ranibizumab, or intravitreal methotrexate in patients who had uveitic macular edema. We looked to see what happened.
On the left-hand side, you're looking to see what proportion of eyes normalize their OCT based on a central subfield thickness. We see only about half of the eyes that we get. My own clinical experience and the clinical experience of pretty much everyone who uses the OZURDEX implant is that even though it is labeled as a six-month drug, it really is an eight to ten week drug because by week 12 we're already seeing waning of the effect in the vast majority of patients. By week 16 it's completely gone. We see recurrence of inflammation in many and the improvement in visual acuity isn't very significant. Overall, the visual acuity gains are best at week 8 and then wane off by week 12. Next slide. When you look at ranibizumab you see. Yeah, there's some efficacy.
It can actually provide a meaningful fluid response in a subset of these MESI patients. There is some biological plausibility to using an anti-VEGF or the addition of an anti-VEGF to anti-IL-6 for treating macular edema secondary to inflammation. Methotrexate overall doesn't seem to do much in terms of normalizing it, but over time, as you continue to inject it, you do see a little reversion and reduction in the overall edema. Next slide, please. DOVETAIL is a phase I study by Roche looking at intravitreal anti-IL-6 monotherapy with vamikibart. DOVETAIL was a multiple ascending dose study of intravitreal vamikibart given at day one, week four, and week eight at three different doses: 0.25 mg, 1 mg, or 2.5 mg. All patients got treated. All patients had a non-infectious uveitis and concurrent macular edema of at least 325 µm, in adult patients only, and about 12 patients per arm.
He then treated them at baseline, week four, and week eight, and then followed them in an off-treatment observation period to either week 20 for the 2.5 mg dose or week 36 for the other two doses. Next slide, please. What we saw was a very meaningful increase in visual acuity and a meaningful reduction in OCT central subfield thickness across the board. If we look at the overall numbers, we see that there's probably a slightly greater effect on the right-hand side for the orange and black lines, which are the 1 mg and the 2.5 mg, compared to the lightish green, which is the 0.25 mg, interestingly on OCT. Interestingly, in terms of best corrected visual acuity, we see pretty similar gains across the board and we see that that effect is sustained at least out through week 20.
There is a clear dose response seen in terms of treatment with patients with inflammatory macular edema. Next slide, please. When we really dial down and we look and see how many patients have resolution of intraretinal fluid, only about half at the end of the treatment period have a resolution out there for retinal fluid. That means half of these patients still have intraretinal fluid. When you look at the absence of subretinal fluid, yes, we've resolved that very successfully. Persistent intraretinal fluid is what's more dangerous and it's what's known to cause greater effects from visual acuity. When we look at the 15 letter gainers, we see across the board, only about a quarter to a third of the patients gain 15 letters at week 12 with vamikibart after three monthly doses. Next slide, please. How can we meet this unmet need?
There are a number of ways you could do that. One that Kodiak is pursuing is KSI-101, which is the high strength dual specific intravitreal biologic designed to target both IL-6 and VEGF mediated disease. It has a potent anti-inflammatory effect through the anti-IL-6 core, shaped by being able to block up to two IL-6 molecules to try to normalize the blood-retinal barrier. On the VEGF side, it's more like a VEGF trap, broad VEGF inhibition that binds multiple targets including VEGF-A, B, and central vertigo derived growth factor. We know the VEGF trap is probably the strongest way and the best way that we have out currently in blocking VEGF. This dual pathway inhibition would allow us to target both of these drivers of macular edema.
KSI-101 also has a high formulation strength at 100 mg per milliliter and a modified Fc region that's immunologically inert to reduce the risk of causing inflammation with this therapy. Next slide, please.
It does really well at blocking all of this. When we look at its ability to inhibit both IL-6 signaling as well as IL-6 receptor mediated signaling, we see that there is a strong inhibition with very good IC50s in the picomolar or nanomolar range. For VEGF signaling, we see that the IC50s are in the picomolar range, very similar to what you see for aflibercept. Next slide, please. This is a really interesting slide. This is looking at the ability of each of these molecules to be able to improve tight junctions. What we're looking at is on the very left-hand side you have normal, and you have what the RPE cells should look like when you apply exogenous VEGF and IL-6. On the second from the left, where there's no inhibitors, you see a significant breakdown of those RPE cells and loss of those tight junctions.
When you give VEGF monotherapy, you see some reduction, some restoration back to normal. When you give anti-IL-6 monotherapy, you see some restoration back to normal. When you inhibit both, as with KSI-101, you see a significant restoration back to normal, and it's superior to either of the anti-VEGF or anti-IL-6 monotherapy. This is great because this shows the synergistic effect of anti-IL-6 and VEGF dual inhibition. If we go to the next slide, we'll circle back to that HUVEC model that we showed earlier in blue. Again, you have at the very top the no exposure. In pink at the bottom, we have the eyes, the HUVECs that are getting both VEGF and IL-6 applied exogenously. At 20 hours in the three different curves, we see either VEGF plus IL-6 and application of KSI-101.
Interestingly, it restores the barrier integrity back to what you see with the no exposure, which is fantastic because when you look at each of them alone, you don't get anywhere near that type of barrier integrity restoration. Anti-VEGF gives some restoration, anti-IL-6 gives some restoration, but the combination effect is greater than just the summative effect of each of those two alone. This is very interesting because it fits in with the mechanistic view that this is a synergistic effect on each other. Next slide, please. KSI-101 is really designed to meet that core unmet need that I talked about earlier. It's a dual anti-IL-6 and anti-VEGF inhibitor that has the potential for a disease modifying effect based on its synergistic inhibition of both IL-6 and VEGF. It has a very high strength formulation with very high potency. It's given with local intravitreal administration.
The safety profile, as you see in the phase I study, is in line with other intravitreally administered biologics, which is fantastic. That's that need that I was addressing earlier: barrier, a local therapy that can very nicely restore the barrier function and get rid of the macular edema, irrespective of the underlying presumed etiology. One of the problems we've had in the field in prior studies has been that we have focused so much on the underlying etiology that we've kind of lost sight of the fact that, yeah, this is a heterogeneous group of diseases, but the treatment may be the same and the treatment could be really well done with a combination antioxidant anti-VEGF. What does that look like? As we go to the next slide, we'll go back and circle back to all of those eyes with edema.
A single dose resolves the edema in a large portion of these patients, irrespective of the location of the inflammation or the underlying etiology. This is fantastic because we desperately need this kind of therapy. If we go to the next slide, we'll kind of dive into some of these results. These are all patients that I showed you are from the APEX study. The APEX study was a phase I-B. As we go to the next slide, in both diabetic macular edema and macular edema secondary to inflammation. It's an ongoing study and I'm going to show you some of the data that we have so far. It's an open-label, multicenter study to look at the safety, tolerability, bioactivity, and pharmacokinetics of the KSI-101 at multiple doses in both diabetic macular edema, where it was first in human, and macular edema secondary to inflammation.
On the left-hand side under diabetic macular edema, 12 patients were treated and enrollment is completed. Ten patients have completed the study. One patient is still ongoing in the study and one patient has discontinued treatment because they were lost to follow. In the macular edema secondary to inflammation arm, 41 patients were completed and again enrollment is complete. Ten patients have completed the study while 29 patients are ongoing and 2 patients have discontinued their treatment. One was because of an adverse event of a uveitis flare-up that was consistent with their underlying disease.
I want to really focus on this because I think we have seen with other biologic therapies uveitis or inflammation or retinal vasculitis and really concerningly occlusive retinal vasculitis from these disease from the, from the therapies. This is a top of mind, really high concern for retina specialists and uveitis specialists. I'm always very, very cautious now with any new biologics. We were very, very fortunate with our first three. We were incredibly lucky that AVASTIN didn't cause inflammation because it was never really tested in the eye before it was put in. We were also fortunate that neither LUCENTIS or EYLEA caused inflammation. Since then we've seen inflammation with multiple different drugs that have been out on the market, including brolucizumab which was approved but we've not used very much because of its complications and abicipar which did not get approval because of how much inflammation it caused.
Here this patient did not have inflammation from the drug. Their inflammation was a flare up of their underlying disease. This is going to be challenging to differentiate dates of times, but we'll talk through it as we get to the safety side. I'm presenting the preliminary data here. If we go to the next slide, one more please. In DME we looked at three ascending doses, 2.5 mg, 5 mg or 10 mg. Every patient was treated in this study, regardless of which dose they got at baseline, week 4, week 8, week 12 and week 16 and the end of the study was at week 24. Patients were included if they had treatment naive center involving DME of at least 400 µm and less than 650 µm and a best corrected visual acuity between 20/32 and 20/320. Next slide. Overall, the baseline characteristics were fairly well matched.
For a small study you can't always do great, but you see that there's not massive differences in a small study like this, but there are going to be some. We see that visual acuity can be a little different. What's interesting is the CST overall is pretty close. 442- 485 is the range. One out of the four in the first three doses in each of the three doses were pseudophakic, but the others were not. They were phakic.
Next slide, please. We see that there is a clear dose response here in that the 10 mg dose had the greatest reduction in OCT CST compared to the 2.5 mg and the 5 mg doses. We see that it's rapid. After that first injection, we see a significant reduction, but we continue to see improvement out through week 16. With all of these injections, we do see some improvement in both the 2.5 mg and the 5 mg arms, but not nearly as much as we see in the 10 mg dose. If we combine those and look across the board, we see that after that last injection we're seeing about 160 µm reduction overall. Next slide, please.
If we look at best corrected visual acuity level change and improvement over time, we see that there is a rapid and sustained increase up to about anywhere from 10- 15 letters at week 20 in the first visit after the dosing period. On average, it's about 12.5 letters. Next slide, please. Most importantly, this was well tolerated. Very few rates of complications. There was one patient who had a somatic cataract from their aqueous humor routine sampling as part of the study. We didn't think the drug caused it. We think the actual aqueous humor sample caused the cataract formation in that patient. Otherwise, no other AEs were reported and no study discontinuation, no signs of retinal vasculitis or other cataract formation, and really very clean safety data.
Switching gears as we go to the next slide, you can do one more, and looking at the KSI-101 in MESI, very similar design. Three multiple ascending doses: 2.5 mg, 5 mg, and 10 mg. More subjects, we have a total of 41, and dosing was slightly different in that patients did not get that 16 dosing, but we still followed them out to week 24. They had to have macular edema secondary to inflammation and a diagnosis of active or inactive non-infectious intraocular inflammation that could be acute or chronic. They had to have active leakage on a fluorescein angiogram with a CST of at least 320 µm. Insane 20/32-20/320, Snellen and baseline acuity equivalent. Next slide. Enrollment is completed and overall the baseline characteristics we can see here, it's a little bit of a female preponderance, which we see overall in uveitis or MESI-type studies.
Across the board, we see a mix of etiologies, so anterior, intermediate, posterior, and pan uveitis. We see a mix of active versus inactive and a mix of unilateral versus bilateral disease. Overall best corrective visual acuity is about 20/50- 20/60, and overall CST is really a bit of a different range between 460 and 528. Here, a larger proportion of these eyes are pseudophakic. Next slide please. When we look at what happens with the OCT data, we see again an improvement but less of a dose response. Here, we see that all three doses give you an improvement overall in OCT CST. When we look at the three different doses, it's 2.5 mg and the 10 mg are very similar, but the 5 mg dose has a greater reduction.
When we look at it in the lens of dryness, so getting under 325 µm on OCT, we see that all three arms give you an equivalent amount of drying as time goes on, and we see that it's very rapid. Unlike in DME, where we saw continued improvement throughout, we see that the majority of the improvement is happening as early as week four. Next slide please. Interestingly, we do see meaningful visual acuity gains, and I'll reference back to this and we'll compare some of this data. It's always you have to be cautious when you compare data across studies because they're heterogeneous patient populations, and the patients enrolled in one study are not necessarily the same as another study. We do see that there is a significant visual acuity gain and that we see it across the board with all of the dose levels.
We go to the next slide, and looking at the proportion of eyes that are 15 letter gainers in those patients completing week 12, we see that about half of the patients gained 15 letters. I'll reference back to the vamikibart data. Again, two different studies, two different study designs, looking at things different. All those caveats apply. What's most powerful, I think, is the next slide, which looks at the proportion of patients achieving absence of intraretinal fluid, and over 90% after the dosing period have no intraretinal fluid or subretinal fluid, which is just absolutely fantastic. What's really, really fantastic is by week four, almost 80% of the eyes had no intraretinal fluid and 90% had no subretinal fluid. That is a massive improvement on the line of what we often will see clinically with intraocular steroids.
As we go to the next slide and look at the safety data, what we don't see is the complications of intraocular steroids. We did not see elevated IOP in a single patient. We did not see cataract formation in any patients, which is absolutely fantastic. There was an episode of a recurrent uveitis flare up in one patient in each arm, and it was consistent with the underlying disease. There was a patient who had a vitreous hemorrhage secondary to their aqueous tumor sample. Aqueous humor sampling in eyes with uveitis can be dangerous because when they're inflamed and you stick a needle in that eye, it can lead to complications. That is what I was alluding to with cataract surgery. When an eye is inflamed, doing cataract surgery can lead to complications. That is what we saw in one of the two patients that had a flare up.
The other was thought to be related to their underlying. This is fantastic.
Now we have a therapy that's giving us improvement in macular edema in uveitis and inflamed eyes that is as powerful, maybe more powerful than some of the intraocular steroids we use, but it doesn't have that side effect profile of cataract or elevated IOP. This is just incredibly powerful. As we go to the next slide and look at where this fits in, I want to reference back to the vamikibart data that I was referring to and go to the next slide, please.
Like I mentioned before, with vamikibart, in terms of three line gainers, and again, I will caveat this that you can't compare across studies directly. Just to give an idea for where things sit, with vamikibart, a quarter to a third of patients gained three lines. With KSI-101, on the next slide, we see about half of patients, depending on the dose level, gained that three lines of visual acuity. Go to the next slide, please. When we look at proportion of patients with resolution of intraretinal fluid, we see it's about 50% after the three doses of vamikibart. This is different. With KSI-101, again, nearly every patient had complete resolution of their intraretinal and subretinal fluid after four doses. This is just actually after the three doses still, because the week 12 data is when they got injected again, but this was after their third dose.
This is just a very, very strong signal of effect. If we put this into context on the next slide, we can see that it rapidly dries the retina after a single injection. This is a little bit of a busy slide. You have DOVETAIL with the three dose levels and the baseline CST and the reduction in CST. We have the PEACHTREE study, which looked at suprachoroidal injection of XIPERE. We have the MERIT study, which I mentioned earlier, that folks had OZURDEX injection versus methotrexate injection versus ranibizumab injection. We look at how these different meds do, and we see that KSI-101 does have a stronger effect than all of them. Caveats for different populations, different study designs and all of that. This really is just to kind of give an idea for this.
If we go to the next slide, we see that dual inhibition really provided somewhat of a synergistic effect and gave us better anatomical benefits than any really of these monotherapies, except for potentially steroids. As I mentioned, we're getting the drying effect of steroids while avoiding all the complications of steroids. We'll go to the next slide. After the three monthly doses, we're seeing a drying effect that's on par with or even better than the intraocular steroid injection with OZURDEX. We are actually seeing none of those side effects. This is just absolutely a fantastic effect and it could significantly change how we treat these patients overall.
In summary, I will close with just some of my thoughts on the next slide, which is that I think that this is fantastic data that's very promising and if this holds up in phase III studies and we see that the safety is really, really good, then we really have the opportunity for a paradigm changing therapy in macular edema secondary to inflammation. Thank you.
Great. Thank you so much, Sumit. Next up, leveraging off what Sumit was telling us on that strong data, Charlie will walk us through the peak and PINNACLE trial designs, taking into account all the learnings we've had from KSI-101 to this point. Charlie.
T hanks Sumit. Great job summarizing very impressive data and interesting, exciting for the field MESI . Okay, I'm going to now try to apply some of those learnings that we've had from APEX into the design of the phase three program. I think that you can go to next slide. This is a lot to think about in the trial design here and I think this is again unique in the field for a few key reasons and I'll point that out. First of all, here's the overall structure of the trial PEAK and PINNACLE. After I go through the general structure, we'll answer sort of what I think of as the six most common questions about this trial design and we'll try to answer each of them sequentially. The key inclusion on the left side here, so MESI, what Sumit just described beautifully, macular edema secondary to inflammation.
Second, a diagnosis of active or inactive non-infectious intraocular inflammation, acute or chronic active leakage on fluorescein angiography, CST of 320 µm or greater and visual acuity is 20/25-20/320. All patients are going to receive monthly dosing of KSI-101, either 5 mg or 10 mg for the first six months. That's through week 20. The primary endpoint is the average of weeks 20 + 24. In the second six months of the trial, patients will be seen for six monthly visits and be retreated on an as needed basis. The retreatment criteria here are OCT-based CST of 50 µm increase compared to the lowest previous measurements or a CST simply greater than 320 µm, which again was the enrollment threshold to begin with. Importantly to me, patients are not being forced to lose vision before they get retreated.
This is an anatomic decision, which is often and most commonly what we would do in clinical practice when the swelling is coming back. One of the key inclusion criteria, the patient will be retreated again even if the vision has not decreased, which is optimal from a patient perspective. You can go forward and then critically, this brings in the control arm. Now, because remember, as I said before, when I think about a clinical trial, the very first thing I think about is the control arm. In this clinical trial, it's actually sham treatment, which means that patients will get sham injections at each of the first six visits and then sham as needed injections for the next six months. This is where rescue criteria are critical because our job as investigators is to make sure that we're protecting, again, all patients in each of the treatment arms.
What are those rescue criteria? The first one is visual acuity loss of 15 letters and CST worsening of 100 µm from day one. That would be quite a bit of vision loss. The second one is worsening of inflammation by two grades in the anterior chamber cells and/or vitreous haze or progression to grade four. The third is intraocular inflammation complications in the study eye that did not improve and require rescue treatment to prevent irreversible loss of vision per the investigator's judgment. I think this is a great addition because it shows that the sponsor here is aware that all the patients enrolling here are trusting their physician to do what's right for them. They're hopeful that they get the optimal treatment arms, which in my opinion would be the 5 mg or 10 mg arm.
They understand that they may be in the sham arm because we're doing this trial program to try to get approval. If they're in the sham arm, we don't want them deteriorating. If there's anything that is not improving, which is what that third bullet point is, then the patients will be eligible for rescue, which I think is absolutely the right thing to do for patients. You can go forward. Thank you. The next study design question is, what are the key endpoints here? The primary endpoint is the same for both PEAK and PINNACLE, which is best corrected visual acuity mean change from baseline to the average of weeks 24 and 20, the primary endpoint being there at a combination of months 5 and 6.
Key secondary endpoints, time to 15 letter gain is shared between PEAK and PINNACLE, with an additional key secondary endpoint of time to 15 letter loss, also in PINNACLE. We'll talk about why that subtle difference. You can go to the next slide. The next six or seven slides are the six most frequently asked questions about these trials with a clear answer to each one. The first one: are these trials identical? I think the short answer there is that, yes, they essentially are, but there are some subtle key differences. How they are identical is that there's one master protocol under which patients can be enrolled. What this means is that study sites will have the opportunity to be in both trials automatically. It's one master protocol. Patients with MESI with CST of 320 µm or greater and visual acuity of 25 to 78 letters will be eligible.
At enrollment, it will be determined if they're eligible for PEAK and PINNACLE. This is not a subjective decision. This is based entirely on anatomy, what we think of as disease severity as well as visual acuity. If there's moderate to severe macular edema, you go left on this flowchart, in other words, CST of 400 µm or greater. If they also have moderate, moderate severe visual impairments, they will go into PEAK. PEAK is selecting for the worst eyes from a visual acuity perspective and an edema perspective. However, if they have moderate to severe edema with mild visual impairments, they will be enrolled into PINNACLE and then on the top of the flowchart again to the right. If they have mild macular edema, which is less than 400 µm with any visual acuity, then they will go into PINNACLE.
Overall, PINNACLE is enrolling what we think of as slightly more mild to moderate disease, whereas PEAK is enrolling more of the moderate to severe edema with moderate to severe visual impairment. You can go forward. Next question. Why are the APEX top two dose levels selected? Why did we not choose the lowest dose of 2.5 mg? This answer is quite simple. Sumit described this beautifully. This is based on efficacy. We saw the best efficacy signals there with both the 5 mg and 10 mg dose. We saw the same safety profile. Therefore, it makes sense if we're trying to achieve optimal patient outcomes, to select the two highest doses. You can go forward. The next key question is why is mean change in best corrected visual acuity the primary endpoint and not 15 letter gainers or losers? I think this has a couple different answers.
The most obvious is that it increases the probability of success.
I think it's pretty clear that we expect to be successful with 15 letter gainers and loser analysis compared to sham, but best practical acuity, mean change probably have the highest probability of success. I think more relevant to a clinician and patient perspective is that I think every letter of visual acuity gain counts. If you gain 14 letters versus 16 letters, it's hard for me to tell a patient in clinical practice the 14 letter gainer is not a success, but the 16 letter patient is a success.
If they've gained one, two, or three lines, those are all directionally positive for patients. I think it's important to capture that at a patient population level. I think best practical acuity does that the best, even if regulators are focused again on a three-line change versus best practice visual acuity. If you look at what that data might look like, on the right there are the APEX patients. I'm sorry, yeah, on the run, the APEX patients in the 5 mg and 10 mg populations combined showing a mean gain of over 10 letters. On the left, for possible comparison, is a sham-treated population with in PEACHTREE . If you go forward, thank you. Now we're dividing out the APEX population into what we think of as the PEAK eligible versus PINNACLE eligible patients, again based on the baseline CST and visual acuity combination.
You can see that mean visual acuity change is still quite meaningful in both populations, although greater in the peak population because you're enrolling an enriched population for more visual acuity loss in that patient population. We know from many trials over many disease states that the worse your vision at baseline, the greater probability you have of gaining more vision. You can go forward. The next key question is why are the key secondary endpoints different between PEAK and PINNACLE? The first point I would make is that they actually are the same with the addition of one in PINNACLE. The key secondary endpoint of a 15-letter gain is the same and is shared between PEAK and PINNACLE, with the addition of 15-letter losers in PINNACLE. The reason for that is again the baseline enrollment criteria.
Remember that in PEAK we have selected intentionally for patients with more severe disease, more severe vision loss, and therefore they're going to have a higher probability of being able to achieve 15-letter gainers. Whereas on the right here in PINNACLE, you can see some patients may hit their ceiling where they are unable to improve 15 letters because we're allowing better visual acuity in the patients within PINNACLE. However, some patients will still certainly gain 15 letters of vision. From an anatomic perspective, remember, we're selecting for the more mild to moderate macular edema, the case evidenced in the gray scale there on the right, the Heidelberg imaging, you can see that that's really more mild edema. While they will probably improve visual acuity wise, you see, this patient does improve six letters.
It would be unlikely to expect a 15 letter gainer in a patient with an anatomy such as this. You can go forward. The next key question is how do the APEX data educate the probability of success for PEAK and PINNACLE? I think I can, Sumit described this well. If you first look on the left here, the signal for visual improvement was strong in both PEAK eligible and PINNACLE eligible patients. You can see at 80% of PEAK patients improved 15 letters or more, and that was 25% with the PINNACLE eligible. You would expect this difference because the PINNACLE population has been intentionally enriched for more mild to moderate visual acuity loss. What could the control arm look like? A good surrogate here is the PEACHTREE data, again the gray on the left side of the box here.
If you look at all comers in PEACHTREE, 16% of patients had a 15 letter gain or more. If you look at just the PEACHTREE patients that we think will be most similar to the patients being enrolled in PEAK and PINNACLE, that was patients from Israel or the U.S., just 5% of patients improved 15 letters or more with sham treatment. On the flip side, with prevention of visual acuity loss, you can see that no patients in APEX that met criteria for PINNACLE experienced 15 letters of loss. In comparison, in PEACHTREE we know that 72% of patients received rescue medication, suggesting that they had lost vision or they were on the way to losing vision at that time. You can go forward. I think my nearly my last slide here is right.
Why are the primary and key secondary endpoints being evaluated at month six, at week 24 and not at week 16? If the regulators would allow an earlier endpoint, why not take that exit and just get done sooner? I think the answer here is that we saw in APEX a potential time effect where when more patients were dosed for longer, there appeared to be improving efficacy over time. Certainly there are examples. I'll show you one on the next slide in a second where there was essentially normalization of the OCT after just one injection. Sumit described beautifully how the percentage of patients was quite dramatic after one injection and of dramatic reduction in fluids, but there were some patients that continued to improve over time.
The hope here is that we can optimize outcomes for patients both anatomically and functionally with more monthly doses up through the six month primary endpoint. Again, the primary and secondary endpoints will be evaluated on the average of week 20 to 24 for mean visual acuity, and the categorical endpoints will be assessed at week 24. You can go forward. My very last slide, just bringing this back to what Dr. Sharma had described, right. MESI is a new way of thinking about a common pathophysiology of blood retinal barrier disruption associated with inflammation and VEGF driven disease. We have lots of examples of this in clinical practice, and it is hopeful that combined anti-VEGF and anti-IL-6 treatments may provide a new opportunity for visual improvement and anatomic stabilization in these patients. With that, you can go forward. I'll pass this over to Dolly to take us forward. Thank you.
Thank you, Charlie. As a practicing glaucoma specialist today, I want to take you through a brief journal of two patients that I am living with. Matthew, we know that this is an incredibly difficult type of disease to handle. This story, I hope, will highlight two things. One thing is why do we need something better? The second thing is how KSI-101 might help us rethink the entire diagnostic and treatment journey. The first story is from a fellow physician who became a patient for success. She shared this patient with me and showed the staggering number of eye drops she used every day. She was telling me that her macular edema flared up often even though the result works, but it also caused significant eye pressure rises. That is probably one of the reasons why she was never treated with intraocular steroids because of the fear of glaucoma.
This is a list of, you know, the picture of the eye drops that she's taking. She is managing her eye pressure, managing her MESI with a cocktail of eye drops. You can look at it. She is managing with Durezol, depending on multiple times a day, depending on how her MESI flares up. She's also taking an NSAIDs eye drop called Ketorolac. She's also taking dilating eye drops to prevent scarring and multiple IOP-lowering eye drops as well. This case actually reflects a broader issue. There are many patients who are undertreated just like her because of the fear of steroid complications. As Dr. Sharma mentioned about his clinical experience, we can see that from this study, MESI patients, about 60% of the MESI patients are not responding well to eye drops alone.
At the same time, about 32% of the patients will experience IOP elevation when treated with chronic Durezol. These are not rare complications. This is a daily dilemma that our patients and today's physicians are facing. Now we are walking through the second patient. This is a 52-year-old healthy woman who presented with bilateral blurry vision and floaters. On clinical exam, we saw mild anterior segment inflammation, some vitritis, and scattered yellowish white retinal lesions at presentation on OCT. There was no macular edema at that time. As part of the standard uveitis workup, you can see that she underwent a number of diagnostic workups that include blood testing, imaging testing, and a panel of autoimmune and infectious workup. All came back negative except HLA- A29. In combination with the clinical presentation that led to a diagnosis which we call first shot chorioretinopathy, which is a chronic bilateral posterior uveitis.
Initially, she was treated with multiple systemic drugs including oral prednisolone and later on transitioned to methotrexate, and she is doing pretty well in terms of controlling her ocular inflammation. However, at about month six, even though with well-controlled intraocular inflammation, she developed macular edema. At that time, she underwent three cycles of IV SOLU-MEDROL and then started anti-TNF inhibitor, but she wasn't able to tolerate it because of the cutaneous reaction. She was switched to CELLCEPT oral immunosuppression, but her MESI still proceeds, and that's the time that she started to receive intravitreal OZURDEX, which is a steroid treatment for MESI . She actually temporarily responded pretty well to the first OZURDEX, but then the effect went after two to three months, getting the second OZURDEX injection and then the third one as well.
Unfortunately, after the third injection, she developed cataract and also glaucoma, leading to a combined cataract and glaucoma surgery.
Even that this wasn't the end, as similar to the patient that Dr. Sharma just presented, after the surgery, the patient developed fulminant intraocular inflammation that required more steroids to control her inflammation, and that's also causing her eye pressure to continue to rise. Eventually, this patient unfortunately has vision loss from not just the MESI and inflammation but also the complication from taking the medicine steroids. Where does that leave us? Both cases show the complexity of diagnosing and treating MESI, where the treatment itself can also become the problem. We can see that we have to weigh multiple factors to determine what kind of steroids we are going to treat with the patients, depending on the underlying diagnosis. How was the response previously to steroids?
What are the risk factors for glaucoma development, whether the patient has cataract surgery or not, already phakic, pseudophakic, and multiple risk factors to determine on the steroids. What if there is a local therapy that is highly potent and safe that we can just treat MESI from day one and focus on that to avoid the potential surgical complication and the IOP rise and the cataract that we are talking about? Imagine this: if this is KSI-101 and being approved in the market, if it demonstrates safe and efficacious, we are hoping that this could potentially really transform the way that we treat MESI patients. These patients really need a simplistic, safety and strength, highly potent drug to help with their visual outcome. Now with that, I'll just turn it over to Victor, who will walk us through the commercial opportunity for KSI-101. Thank you.
Thanks. Thanks. We'll work quickly to wrap up and move into the Q and A. Before we do that, we'll jump into a little bit of an introduction. First, a repeat of the problem statement. Ocular inflammation is the fourth leading cause of blindness among the working age population in the developed world. MESI is a serious complication of ocular inflammation and is the primary contributor to the vision loss and blindness in this important group of people. We remind ourselves with MESI, a serious vision threatening disease. It's chronic and has to do with disruption of the blood retinal barrier, creating the edema and leading to the serious risk of vision loss. It's triggered by a variety of underlying systemic and local autoimmune conditions.
As you'll see, it represents a prevalence of approximately 500,000 patients in the United States, of which 300,000 are trial eligible and fall within the inclusion exclusion criteria for the PEAK and PINNACLE studies by and large. Within that 300,000, we defined, together with physician interviews, an initial KSI-101 addressable MESI population in the U.S. of greater than 150,000 patients. Those represent patients in the U.S. who are contraindicated for intraocular steroid injections, are at risk of glaucoma or cataract development due to chronic steroid treatment, or are refractory from chronic steroid treatment. Over time, avoiding. Over time. Over time.
Can you hear me? Yeah. Over time, avoiding the consequences of longer-term steroid use together with standard of care matched efficacy can support a first-line therapeutic of choice profile for KSI-101. In other words, even within 150,000, there's headroom up towards the 300,000 trial elements or even deeper into the 450,000 patients who may have a MESI population preference prevalence. We're working to build a profile with a differentiated, potent, high-strength, broad-spectrum, dual MOA biologic, and we hope through the data that we generated today and the breadth of the patients, as Sumit and the team and Charlie and everybody demonstrated, that there's the potential for a simplified, safer, and earlier MESI patient journey with historically physicians treating patients based on the presumed etiology resulting in a lengthy trial and error patient journey.
We offer the promise, the early promise based on the 12-week data in the APEX study and the studies we're going to perform in the PEAK and PINNACLE registrational program of simplifying the MESI diagnostic inpatient journey and fundamentally upgrading the ophthalmologist as the primary ocular caregiver and improving patient outcome across the etiology. I think there's, based on early physician interviews, which is quite early in our landscape analysis, quite a lot of excitement from physicians. They're impressed by the safety and the efficacy profile. They note that it lacks to date the serious negative consequences of chronic steroid use including glaucoma and cataract, but it has strong efficacy across etiologies on par with current ocular intraocular steroids. Just very quickly looking at the U.S. MESI epidemiology, what we did is we used two separate methods to estimate the population.
The first one is a top-down approach where we took all the patients with macular edema and subtracted out wet AMD, DME, and RVO as well as other known etiologies such as epiretinal membranes and retinitis pigmentosa, leaving approximately half a million patient prevalence who are MESI patients. The second approach we did to verify that was a bottoms-up approach where we took the epidemiologic data and added the patients who we know have the etiologies of MESI. For example, we estimate the proportion of patients with uveitis will develop macular edema. That would be those with known autoimmune related causes, those with ocular inflammation without a known etiology, and we call them the idiopathic no known etiology group and the post procedural inflammation group. Adding those together is also approximately 450,000 patients.
The confluence of these two methods, that's what we mean, that lends confidence and credence to the MESI patient prevalence. We know that the post procedural, for example with MESI with macular edema, they can often resolve with topical eye drops during the acute post procedural period. These are not the patients we're targeting nor enrolling. We know the infectious macular edema patients, for example, although steroids are used in them, in any case we're excluding them in our trials. There are some other macular edema patients, those with epiretinal membranes I mentioned in the retinitis pigmentosa. Although they may benefit from KSI-101, again we're excluding them from our trials. It leaves us with approximately 300,000 or 298,000 patients who are KSI-101 trial eligible in the United States. These data, and they're also epidemiologic and they're supplemented and supported by practice pattern information.
Obviously not all the trial eligible patients will be treated with KSI-101 initially. While the safety and efficacy data are maturing in the community, in the payer landscape, what we see here is initially the 455,000 total MESI prevalence, removing the acute patients who are post procedural and infectious, leaving 298,000, then perhaps the 70,000 patients who would be well treated, as Sumit and Dolly mentioned, with topical steroids and perhaps the addition of some oral anti-suppress. From there, patients who will be perhaps treated with single intraocular injections of steroids.
Maybe in the future those could become first line patients for KSI-101, but for the time being, we exclude those and we end up with those patients in orange here on the right as the 101 initial addressable population for those patients contraindicated by intraocular steroids, those treated with multiple intraocular steroid injection and those who are refractory to intraocular steroids. All of those are good candidates for the 101, the initial addressable population. Again, as we say, it's north of 150,000 patients. This next slide quickly is an interesting and preliminary analysis of ophthalmology physician practices. It's another way of looking at the number of patients. In this case, it looks at the percent of macular edema patients, patients by patient subtypes across physician types, ophthalmology types in the United States. Essentially, what percent of the patient caseload for each type of ophthalmologist is a MESI patient?
Surprisingly, across the United States and all types of ophthalmology practices, the MESI indications represent about 8% of patients with macular edema from all causes. This is excluding again wet AMD, DME, RVO and other causes, which is quite a lot we felt actually and from a general ophthalmologist standpoint represents around 26% of their patient volume. Even for retina specialists, the data suggested that as many as 17% of their volume of patients represents the MESI indications. For uveitic specialists, uveitis, it represented around 40% of the caseload, which makes sense. Of course there aren't that many uveitis specialists in the United States. This is sort of the beginning of our landscape analysis, I think, just to remind ourselves. This was sort of an interesting quote.
Physicians were impressed with both the rapid response by week four that we were seeing with 101 and also the diversity of the etiologies that are responding to KSI-101. As we kind of said and assume it enough others, this is a very nice quote by a retina specialist. It's not much different than using anti-VEGF to treat DME, the AMDs and the RVOs. Those are very different diseases with very, very different pathophysiology. At the end of the day the medicine is the same and it works well in all three diseases. I didn't see that before, but seeing these pictures and seeing the data you showed me, I don't see a reason w hy I wouldn't want to use this.
Medicine as a unifying therapy across all of these different etiologies. These, what we call, we include in the deck that's on the website, some backup slides for landscape analysis and some physician interviews. In summary, I'm so proud of the portfolio of the opportunity that we have in front of us here at Kodiak . We talked about KSI-101 in MESI, we talked about tarcocimab and KSI-501 in the anti-VEGF market. Charlie articulated the very nice four quadrant analysis and our focus as a biologic in that upper right quadrant. We also talked about the pivotal studies across all three molecules, the four studies that are in progress, and the expected timelines for the top line data readouts for those studies. Kodiak as a company, we're in motion and we're accelerating.
That's why I've never been more excited and optimistic about what lies ahead for Kodiak. Thank you very much for participating in the R&D Day. We're now going to open it u p to Q&A and questions. Okay.
Our first question c omes from the line of Michael Yee of Jefferies, y our line is open.
Hey, thank you guys very much. Thank you for a very comprehensive overview. Thank you to the two doctors. Maybe just a question for the doctors. On the MESI plan, can you describe your expectation for the Roche results? I presume you think those will be positive. I think you were saying it was about 28%- 30% that get above 15 letters and that the [ODX] results will be significantly better than those results. Those would set the initial bar. Maybe talk about that and Roche coming first, and then on VEGF and tarcocimab. I know maybe that's still going on and of course, trying to finish execution there. Maybe for Dr. Wykoff, you could talk a little bit about how you expect those results to play out. I know that there's been some increasing questions we've gotten about the TKIs.
Do those matter at that point, at this point? Maybe just how do you compare and contrast. Thank you so much.
On the compartment, you know, as I caveat, it's very hard to say and compare across studies, but what we do see, and I think what really will drive some of this, is the rate of resolution of macular edema or the rate of resolution of retinal fluid in that 50% rate with the vamikibart molecule versus KSI-101 getting a stronger reduction in overall edema. I think that that synergistic effect really does play a role. I think that is a key differentiator here and would lean towards, at least on looking at the two phase I studies, that the effect would be much stronger for KSI-101. Charlie. Charlie, you're muted.
There you go.
Thanks. Yeah, I think that the tarcocimab question, both the TKI and then the trial readout, I think DAYBREAK really kind of puts it all on the line, if you will. I think that we're going to see how durable tarcocimab and this bioconjugate with the free protein really is. I think based on all the data that we have, we expect to see significant signals of durability. What's nice is that we're not shoehorning patients into certain buckets. You're not forcing patients to be Q12 when they have persistent fluid that might be getting worse, even though they haven't lost vision, which is what many other trials previously have done to kind of game the system, if you will, to show a signal of durability when it may not be accurate. This trial puts us all on the line that the threshold to retreat monthly is actually very low.
It's just above noise. If there's basically any significant fluid left in the retina and the central 3 mm, the patients will continue to receive monthly dosing. I think we're going to get really good feelings for true durability out of DAYBREAK. I'm impressed that the design is so patient centric in that regard. The question of how that is going to stack up against the TKIs, again, as I said before, I am supportive of both of those programs. We have two programs that are in phase III for tyrosine kinase inhibitors. I think there's a role in clinical practice for tyrosine kinase inhibitors. I think that each program has its strengths and weaknesses. From a TKI perspective, I think we have learned that while there is a durability signal, the immediacy of those drugs may not be as robust in many eyes as bolus anti-VEGF pharmacotherapy.
That's why those trials are designed with a series of anti-VEGF injections upfront before patients receive the tyrosine kinase inhibitors. That's quite a different paradigm than tarcocimab, which is a molecule that has both an immediacy effect and then a durability effect because of the bioconjugate. I think that there's a role in the space for both. I think that they are just different development programs looking at slightly different patient populations within AMD.
Very helpful. Thank you guys.
Thank you. Our next question comes from Michael DiFiore of Evercore ISI, please go ahead.
Please stand by. Take the next question.
Please stand by w e are having a technical issue. One moment.
Thank you for standing by. Our next question comes from the line of Michael DiFiore of Evercore ISI, please proceed.
Hi guys, can you hear me?
Yes, we can hear you.
Okay, great. Again, thanks for taking my question. Thanks for putting on such a terrific and c omprehensive event here. Just thinking about phase III for KSI-101, when we think about just the baseline characteristics, to what extent may having active flares or inflammation at baseline influence outcomes in a much larger set of patients compared to phase I? I mean, are these predefined subgroups that you plan to look at and just kind of want your thoughts on how we should think about risk here in terms of just confounding factors? Thank you.
Sumit, do you want to take the question first?
Sure, yeah. I think one of the interesting things about the phase one design is that we see there was a mix of active and inactive patients, and there was quite a range of patients throughout the study. I think in terms of baseline activity, you'll see a similar mix in the phase III. I don't think it's going to be all that different because we had about a little more than half that were inactive, so about 40% across the board that were active, and we saw improvements across the board. There is always some risk that when there's active inflammation, something else happens. I don't think we've seen that, and we didn't see that with the [MART] studies either, which had a similar setup. I think overall, I would actually say a low risk overall.
Yeah. Just to add to Sumit's answer. If you focus, Sumit talked about the safety of the KSI-101 model in MESI patients. If you look at the footnote on that slide, that one patient that had recurrent inflammation that had the vitreous hemorrhage, it's a patient that had very significant inflammation at baseline, I think plus three anterior chamber cells and haze. Very significant and active inflammation, anger i nflammation, as we call it.
If you look at the footnote as well, that patient did really well. I think it's at + 24 letters currently and no inflammation. As Sumit was mentioning, we don't see any difference in treatment response in active versus inactive in this small subset of patients. This kind of individual patient level data helps to support that, and we didn't expect any difference in a larger set.
Maybe just add on top of Pablo. If you're looking at the trial inclusion and exclusion criteria, we did require patient to be on stable immunosuppression or regimen that patient doesn't anticipate to add additional escalate additional therapy for uveitis. In other words, generally patients are relatively well controlled. They may have active inflammation but not in a fulminant active inflammation at baseline when they enter the clinical trial.
Got it. Thank you.
Thank you.
Next caller.
Thank you.
Our next question comes from the line of Anupam Rama of JP Morgan.
Please go ahead.
Hi guys, this is Billy on for Anupam.
Thanks for taking a question and for the detailed overview today.
One for the calls in the call. For us, if that's okay, is just looking between 101 and vamikibart. How are you seeing relevant patient populations for each of these drugs? Of the 150,000 patients, how do you think that split kind of works?
I think for tarcocimab you don't have the post-operative patients and you don't have some of the other categories that are included in MESI. I think the patient population is much broader for KSI-101 because of this new definition of macular edema secondary to inflammation. I think that broadens that overall patient population here, and I think that the overall group is maybe even larger than that 150,000 number gets at because, as I was explaining, there are a large number of these patients who get under-treated because of the concerns of intraocular pressure elevation.
Thanks. I got a question.
Thank you.
Our next question comes from the line of Gena Wang of Barclays.
Please go ahead.
Hi, this is Justin on behalf of Gena Wang. Looking at slide 68 and 69, it seems like in DME KSI-101 shows a dose response and CST change, but not for the change in BCVA letters. Then in slide 94 there does seem to be a better dose response in the MESI patients, but the 5 mg group still had a greater proportion of 15 letter gainers than the 10 mg group. How do you guys interpret this and are you still confident that we will see a dose response in the primary endpoint for PEAK and PINNACLE? Also, if you don't mind, I have a second question just switching gears briefly. Can you also comment on any specific indications you're targeting first with KSI-102 and 103 and overall, how do you see them complementing your existing pipeline? Thank you.
Sumit, do you want to start and I can continue?
Yeah. I think, you know, as I mentioned, the DME population is a little different and DME patients tend to respond a little slower and that's not unusual to see that difference. I think it's hard to compare between the two groups. What's the more interesting portion for me is when you go over to the percentage of eyes that are really dry or getting under that 325 µm threshold, that proportion is greater across the board and it's for the UME group or the MESI group where you see almost every eye is getting underneath there. We don't see as clear of f a dose response, it's also a much more heterogeneous population. If you look at the baseline characteristics, they are slightly different between the groups. That total amount of edema is different between the groups. I think it's really hard to compare there. I think what is interesting on the vaso acuity side is we are seeing a difference that fits with there being still some level of a dose response.
If we can go to slide 74, please. There you go.
Yeah. This is what Sumit was talking about. What is important? You can interpret the DME data in that way, and it's quite evident it's a four patient cohort for each dose level, right? It's a smaller sample here, it's larger. What Sumit was saying, that what is important is where you get to, right? The magnitude of the gain has to do with the baseline CST. What is nice to see is that level of dryness at 325 or below is achieved with all of them. Basically, some of these, like 325, is like the threshold, and it depends o n how you measure it.
Some of these patients with chronic inflammation, with chronic therapy, they can go atrophic a bit. Their normal could be 250. That band of dryness is the sweet spot, and all of them get to the same level. That is what is nice to see. We don't think that there's a dose response. What we see is that all those levels are quite bioactive.
You want to talk a little bit about the DME data for 101, Pablo.
I think that Sumit summarizes it. If we go to slide 68, this was a first in human. This was more towards the safety, and Sumit was showing that safety slide is as good a safety slide as you will get. That is the check that we wanted. Here you can interpret that the difference of magnitude of the 10 mg dose being superior or having superior dryness, but the reality is that the curve o n the right is a bit more informative.
Right. It's by activating all of them. Here, what you can say in a four patient cohort per dose level, 10 seems to be better and actually kind of quite supports our decision to go with the 5 and 10 if you like. If you want to see it that way for the PEAK and PINNACLE phase III program, I think that supports it well. We don't think that this, there's a like that difference in magnitude is real.
That's why we show both curves.
Sumit, you mentioned you may have to run in a moment.
Sorry. Thank you.
Yeah, we appreciate all your contribution. Thank you so much. We're still available for a couple of questions to us.
I show no further questions in queue at this time.
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