Thank you for joining the Kodiak Sciences DAYBREAK Top Line Data Results Conference Call. I'm Victor Perlroth, Kodiak's Chairman and CEO. The webcast portion of this call contains a slide presentation that we will refer to during the call. Those following along on the phone who wish to access the slide portion of this presentation may do so on the investor relations section of the Kodiak website. An archive of the webcast will be available on our website. Let's turn to slide number two. I would also like to remind you that remarks made on this call today include forward-looking statements about Kodiak. A more complete description of these and other material risks can be found in Kodiak's filings with the Securities and Exchange Commission, including its Form 10-Q for the quarterly period ended June 30th, 2026, which has been filed with the SEC.
Kodiak does not undertake any obligation to update publicly any forward-looking statements, whether as a result of new information, future events, or otherwise. Turning to slide number three. It's with pleasure that I welcome all of you to our DAYBREAK primary endpoint results webcast. Turning very briefly to the slide number four, where we can take a moment to reflect on the length and also the importance of the journey that we have been traveling together with our Kodiak stakeholders of employees, patients, physicians, financiers, family, and friends. In particular, we like to refer to this four-quadrant plot here on slide four. As Dr. Brown said it nicely in his quote in our press release, "20 years after Lucentis was approved for wet AMD, the holy grail remains the same. Robust anatomic disease control and maximal visual acuity gains, i.e. immediacy/efficacy, sustained with less frequent dosing, i.e. durability."
Before DAYBREAK, and in particular Zenkuda in DAYBREAK, durability always came with great sacrifice. And despite best efforts over these 20 years, our results as a community have been incremental. But today and together, we describe a tremendous step forward, a step that builds on Kodiak's 17-year history, following what I like to call the gentle arrows of science and the harmony of company-building and retinal medicines development. On this plot, the upper-right quadrant has always been our target zone. I think we've hit the target directly in the middle, in the upper-right quadrant. On that note, we'd like the data to speak for itself. Turning to slide number five. Joining me today from Kodiak is Pablo Velazquez-Martin, Kodiak's Chief Medical Officer. And joining us today also are Dr. Charles Wykoff and Dr. David Brown. Both are distinguished physician-scientists with an important history of retinal drug development.
After our prepared remarks, we will open the call for Q&A. Turning to slide number six. I'm now pleased to turn the call over to Dr. Velazquez-Martin. Pablo?
Thank you, Victor. I would like to take a minute to bring us all the way back two years ago, and we can move to slide seven. Almost to this date of Investor R&D Day for Kodiak in September 2024 in New York City, to remind us how we got here to this moment. At that time, we emphasized our focus to be a learning organization and strengthen our commitment to the journey from data, to insights, to learning, to action. At that time, we made a variety of critical course correction decisions that led us here. In slide seven, continue this intentional journey got us here today. It is my privilege, in slide eight, to introduce this presentation.
The primary endpoint results of the DAYBREAK Phase III study in treatment-naïve with wet age-related macular degeneration, exploring both of our Antibody Biopolymer Conjugate investigational therapies, Zenkuda and tabirafusp, also tedromer, which will also be called during this presentation as tabirafusp-ted. One important reminder in slide nine. The DAYBREAK innovative design enabled an independent evaluation of Zenkuda and of tabirafusp-ted at full clinical and statistical significance. This is important because each molecule had a different objective in this trial. Aligned with this principle, Dr. Wykoff will present the DAYBREAK results for each molecule compared to aflibercept separately in independent sections. We move to slide 10, please.
With that, I am happy to pass the presentation to Dr. Wykoff, who will present the efficacy and safety results for Zenkuda first. Charlie?
Good morning. Can you hear me?
We can hear you, sir. Please proceed.
Thank you. Good morning. Great to be here with you. It's an exciting time in retina. A lot of ongoing clinical trial programs. Always enjoyable to digest new data, particularly when it's as positive as I think you will see that this is. You can go forward to the next slide. DAYBREAK, fascinating phase III clinical trial for many reasons. First is that it compared two different therapeutics to the same control arm, so a very efficient trial design to digest a tremendous amount of data. We'll first unpack the tarcocimab data and then dive into the tabirafusp data. With tarcocimab, the comparator here was aflibercept fixed Q8 week dosing, 2 mg every eight weeks after three monthly loading doses, 225 patients, really the gold standard Eylea control arm. Always important to think about the control arm first.
Secondly, the tarcocimab arm was four monthly loading doses up front, 225 patients, and then a highly differentiated trial design here, and we'll go into detail about that on the next slide in just a moment. These patients were then evaluated every four weeks and could receive dosing as frequently as every four weeks, but could also be observed at those visits, depending on their disease activity. We've talked a lot about disease activity criteria in this space for the last many years, and this trial was extremely strict on when patients were retreated, and we'll dive into that. The primary endpoint was change in visual acuity there across three of the time points, weeks 40, 44, and 48, again, comparing tarcocimab with aflibercept, ultimately, though, a two-year trial. Again, all of these were treatment-naive wet AMD patients. You can go forward.
In many ways, this may be the most important slide. Can you go to slide 12, please? Thank you. The retreatment criteria in any clinical trial trying to look at durability are critically important, and most clinical trials use a retreatment threshold of increased CST of a certain threshold, 50, 75, 100 microns, for example, associated with visual acuity loss, usually five, 10, even 15 letters of visual acuity loss. This trial was highly unique and none of those requirements were necessary. Specifically, we did not wait for patients to experience visual acuity loss, and there was no CST threshold that would drive retreatment. Instead, we used an AI-based fluidics analysis to look for the smallest amount of intraretinal and/or subretinal fluid to initiate a therapy. We were trying to use practical criteria.
In the real world, when we see fluid, we reinject, and we don't go longer in between injections. That's what we tried to recapitulate in this clinical trial using a point-of-care deployed AI algorithm. On this slide, you can see examples of what this looks like. On the left is an eye that was dry, that did not have significant intraretinal or subretinal fluid. In fact, you see no fluid on that central B-scan. On the right, you see those small intraretinal cystic spaces highlighted in red, which is an indication of recurrent disease activity that would not have met any of the other retreatment criteria that I'm aware of in any advanced clinical trial used in retina previously.
It did cross the threshold for volumetric increase, and therefore that eye was retreated at that time point before there was vision loss and before there was a meaningful increase in CST. You can go forward one slide. Baseline characteristics for the tarcocimab versus aflibercept comparison were balanced. Visual acuity was about 20/60, and there was balance in the BCVA category, the low limits visual acuity deficit, and CST was about 350 microns in both arms. About 40% of all patients were phakic. You can go forward one slide. This slide demonstrates mean visual acuity change over time. Absolute visual acuity actually plotted here on the y-axis between both of the arms. Importantly, you can see the primary endpoint was met with high statistical significance, demonstrating not only non-inferiority, but equivalence of tarcocimab versus aflibercept.
You can see at the end there, the aflibercept arm had gained 7.6 mean letters compared to 7.2 with tarcocimab, and you see numerical fluctuations across the year. Of interest, you see actually slightly higher numerical visual acuity gains through the loading phase there with tarcocimab compared to aflibercept. Again, the key message here is really overlapping visual acuity curves from baseline through the end of one year at the primary endpoint. You can go forward one slide. Looking at the similar trajectory here with absolute CST, again, you see overlapping trajectories. This may be the most important data point for tarcocimab for me. If you look at the loading phases there through eight, 12 weeks, you see overlapping CST curves.
No indication of a separation between these curves, meaning that we have achieved that immediacy result, or we have achieved complete drying relative to the aflibercept gold standard monthly dosed control arm there in that loading phase. After that, you see that characteristic sawtooth pattern in gray when you switch to the aflibercept every eight week, 2 mg dosing pattern. Again, you see minor fluctuation with tarcocimab. Again, these values are overlapping, demonstrating equivalence of anatomic outcomes from a CST perspective through the week 48 endpoint. You can go forward. What does this look like from a durability perspective? Because remember, the goal here was to achieve a completely dry retina and then maintain that retina at a dry state, right? We were not allowing significant recurrence of fluid before these eyes got retreated.
That is very differentiated from most of the other programs, and I think is a much clearer reflection of how we manage these patients in our routine clinical practice. Despite that strict treat to dry and maintain dry approach, we still had a very large number of patients at an every 24-week or six-month interval. 54%, majority of patients achieved that, again, within that 48-week time window. Another approximately 30% of patients achieved Q12, Q16, or Q20. Reflecting the real-world nature of these treatment-naive patients, about 15%-17% were in every four or eight-week interval. I really like looking at that because it shows me that, yeah, this is a representative patient population for what we expect in the real world.
Some patients do need very frequent dosing, and I am glad that we have included that population of patients in this clinical trial, and yet the large majority are at every 24-week dosing without recurrence of fluid. You can go forward. From a safety perspective, we saw no cases of intraocular inflammation here in the tarcocimab or aflibercept arms, no occlusive retinal vasculitis, no endophthalmitis. There were three cataracts, one in the tarcocimab arm for 0.5% and two in the aflibercept arm at 0.9%. You can go forward one slide. This slide summarizes that tarcocimab comparison with aflibercept, Zenkuda as it is also known. Again, the primary endpoint here was met, showing equivalence through the loading phases and through the extended dosing phases through week 48 from both an anatomic and visual outcome perspective, while a majority of patients were at every six months dosing intervals.
Importantly, from a clinician's perspective, a multi-indication BLA is planned by Kodiak across five positive phase III clinical trials involving DR, RVO, and of course, wet AMD with this DAYBREAK trial. You can go forward. You can go two slides, actually. Go to slide 20, please. Now we are going to switch over and look at the comparison with tabirafusp. This is a comparison using the same fixed Eylea control arm there, aflibercept 2 mg every eight weeks. Again, that same 225 patients. Now we are comparing that with a separate statistical analysis plan with tabirafusp. This drug was given, again, 5 mg doses. David will go into details about what these drugs look like in the dosing. This was four monthly doses through week 12, followed by fixed every eight-week dosing. That is that solid green boxes there at 20, 28, 36, and 44 weeks.
Importantly, in between, patients could also receive additional monthly doses if there was presence of disease activity using that same AI algorithm I discussed before, and David will go into more details. Again, the objective here was to give patients what they need on a very individualized, patient-specific basis on an ongoing basis. If patients had disease activity, we did not want to extend them. We wanted to be very aggressive and treat them as they deserve to be treated. But if there is no fluid, we did want them to be able to go every eight-week dosing. Again, the goal here with this trial was to really look at patients within the treatment-naive population and see if there could be a population that could do better with IL-6 inhibition. You can go forward. Baseline characteristics were similarly balanced here.
We saw baseline visual acuity about 20/60, BCVA categorical, and a low luminance deficit. Ranges were again balanced. CST was about 355 microns in both populations, and again, 40% phakic. You can go forward. The primary endpoint in this trial comparison was also met with equivalence demonstrated between tabirafusp as well as aflibercept. You can see at the end of the 40-week period, gain of 7.6 versus 6.3 mean letters, and again, non-inferiority was demonstrated with high statistical significance. The P value at the bottom there, 0.0036, with minor visual acuity fluctuation across the duration of that one year endpoint. You can go forward. Slide 23 here demonstrates CST outcomes. Again, this was actually an alpha-protected P value in this comparison. This anatomic endpoint also demonstrated non-inferiority and actual equivalence between tabirafusp as well as aflibercept every eight-week dosing. Again, you can see minor CST fluctuations.
Again, that classic sawtooth pattern in the gray population of aflibercept Q8-week dosing, as well as some minor fluctuations with the tabirafusp arm, and then nearly identical CST improvements in both populations at week 48. You can go forward. From a safety perspective, similar to the tarcocimab comparison here, no cases of occlusive retinal vasculitis, no cases of endophthalmitis. There was one intraocular inflammatory event in the tabirafusp arm at 0.4%. Again, there were two cataracts in this comparison, none in the tabirafusp arm and two in the aflibercept population. You can go forward. Slide 26, my last slide here is just summarizing this tarcocimab analysis. You can see that tabirafusp met the primary endpoint of wet AMD, demonstrating equivalence with both visual acuity and CST outcomes in a comparison with fixed gold standard 2 mg aflibercept arms.
Looking forward, this drug is being studied in ongoing DME program ALTO, trying to understand who the patients are that may be able to benefit from additional IL-6 inhibition.
With that, I'll pass it over to my friend and colleague, Dr. David Brown. Thank you. [audio distortion].
Ladies and gentlemen, please stand by.
I keep getting muted. Can you hear me now?
We can hear you, sir. You may continue.
All right, great. Technology, you got to love it. All right, next slide. The biggest problem we have, we have great drugs. We have great drugs that solve blindness. The biggest problem is all our current drugs require frequent injections, especially for a population that has fast drug clearance. Even though a treatment-naive population, it's only 5% or 10% that need monthly dosing. In our clinics, it's 30% to 40%, because those patients have to come every month, and we know their kids, we know their families. We'd love to have a drug that maintains visual acuity, and we see these great patients a little less often. Next slide. What Zenkuda is interesting, they have a conjugated ABC protein, which is very high molecular weight. We know from all kinds of pharmacology studies that the larger the molecular weight, the slower the drug clearance.
You actually have about a 20-day drug clearance of this big ABC conjugated protein. In the previous studies with Zenkuda, it was only the conjugated protein. While you saw longer dosing, you didn't see an immediate improvement in anatomy and visual acuity like we see with our standard of care great drugs like aflibercept, Eylea. What this is a two-in-one formulation. It's 20% unconjugated protein and then 80% conjugated protein. You're basically getting a rapid response from your unconjugated protein, while your conjugated protein provides long-lasting and longer-acting durability. Next slide. Again, like I talked about, you have strong immediacy. What that really means is just disease control. You want the OCT curve, or you want the fluid to go away. Correspondingly, you want improved visual acuity that comes with that.
The durability or the ability to last without having injections all the time, I think comes from this conjugated platform, exactly as it's been designed by Kodiak. It's a phosphorylcholine-based polymer that's conjugated to the antibody. Again, the half-life is approximately 20 days. Our current drug's half-life is seven-nine days or so, but that's in the average patient. There's good data that with faricimab, 10% to 20% of the population has a half-life about half that. That's probably the same with all of our drugs. Some people have a longer half-life, some people have a shorter half-life. Next slide. Both of the conjugated and unconjugated have a high binding affinity. The binding affinity with maximum inhibition is really good numbers, very comparable to aflibercept. The inhibition of a cell culture media, same thing, very similar to aflibercept.
The difference is one of them is available immediately, the unconjugated, and then one is more sustained release, or you can look at it as sustained release, which gives you that long-acting end of this curve. Next slide. I love this slide. We pushed for Kodiak to really look at their mean ocular half-life in humans. This isn't done in many drugs. It's in faricimab in the FDA filing, and so that's where this data comes from. The mean half-life in faricimab is 7.5 days, and again, that comes from their FDA filing. Zenkuda is 19.8 days. I think it really is the main reason why you're seeing the more than 50% getting out to six months, like Charlie showed. Next slide. This was calculated in the aqueous humor fluid of the patients in the phase I-B study. I applaud Kodiak for doing this.
I beat on them and said, "Boy, this is super important." It really shows us what you're looking for in a drug if you're trying to get extended durability. It doesn't mean that you're going to get six-month dosing in everybody. If you look at this study, 10% or so percent needed monthly dosing. That being said, the majority of patients had a very long duration between treatment intervals. Next slide. Just showing you more of that phase I-B study. Again, this is the fully conjugated protein. Here you have the half-life varies from 6.1 days to 39.8 days. Very similar to what we see in the faricimab filing data, and I'm sure it's the same with aflibercept and ranibizumab. Some patients just clear drug fast. That's a function of pseudophakia, how much the vitreous is syneretic, how long the eye is, et cetera.
But it just shows you we're very different. I love the design of this trial, because it's not one size fits all. It's trying to figure out how do we get each patient the maximum effect within the realms of their biologic clearance. Next slide. State of the art today is faricimab and Eylea HD, even though in the clinical trials, which were a little artificial. They were artificial because they required some vision loss and substantial fluid before you could get retreated. You had 77% and 79% and 70% of the faricimab trials go out to 16-week interval. A recent study by Bill Freeman shows that in real world, it's about 25% with Eylea HD and about 21% with faricimab. Next study. Next slide.
Discrepancies, two things. One, real world different. We know from the CATT trials that a certain percentage of patients, three shots and you're done, and so those all go away in a treatment-naive trial. However, in a real world trial, the patients that stay in our clinic that need ongoing injections probably have a faster clearance if you test them all. Very few of these patients can switch and go to these lengths that you see on the TV commercials of three and four months. Next slide. I do applaud Kodiak for this retreatment criteria. It is PRN, and so it's not going to be quite as good in real life as you see in this trial, but it was a very tight PRN.
The AI reading read just very small amounts of fluid, which is much better than what you saw as retreatment criteria in our phase III pivotal trials of faricimab in aflibercept 8 mg. Next slide. Here you got treatment of retinal fluid monthly, individualized treatment. Again, it treated very small amounts of fluid. It is PRN, which I'm not happy about in the clinic, but I think it's the best you can do in a clinical trial, and I think it's very good to not allow much fluid. That's why you have maintenance of the visual acuity curves. A lot of the other trials out there for TKIs and gene therapy have a very lenient, you have to have a lot of fluid before they let you retreat, and that's why you see those visual acuity curves dropping off, which is, in my mind, not acceptable.
Next slide. 54% of patients got six-month dosing interval. That is super impressive. If this is anywhere near this in clinical practice, it certainly will set a new standard of care for durability. Next slide. In conclusion, we really are excited to be able to see what this clinic can do in the clinic, right? They are impressive. This is where the field needs to go. I love the clinical trial design because with it, they can go to the FDA and say they can get monthly dosing. A certain number of patients are going to need that. The strong fluid and vision gains in the loading phase and then the maintenance of both the OCT curve and the vision curve are super exciting. The safety is consistent with our existing anti-VEGFs. I applaud the development team and Victor and Kodiak for helping us move the game forward.
With that, I am going to pass it off to Victor for Kodiak's next frontier.
Well, thank you, Pablo, and thank you, Charlie and Dave, for walking us through the results, the exciting results both for Zenkuda and for tabirafusp-ted. Thank you, Dave, for putting a bit of the results into the historical context and into the context of your clinics. Let us turn to slide 41 for a very quick conclusion, and then we will move into a few Q&A. I just wanted everybody to take a moment to think after the 17 years of development, it takes a long time to try to move innovation in drug development. I think we have achieved a definitive milestone here in the field of retina.
We are proud to have been part of that, and we are poised as a company for upcoming regulatory in terms of BLA filing that we are planning to do this year for Zenkuda in wet AMD in diabetic retinopathy, following our GLOW 1 and GLOW 2 studies, and in RVO, following our successful BEACON study. We are excited to do the work to file the BLA and hopefully move from a pre-commercial stage company into a commercial stage company. We are excited from the tabirafusp-ted standpoint. We are very pleased that our KSI-501 molecule met the primary endpoint in DAYBREAK, and we will continue to evaluate different subgroups of patients within the wet AMD populations to identify which populations there really can benefit from that dual mechanism and the anti-inflammatory action of the 501 molecule.
Of course, we already are enrolling and randomizing patients in the ALTO of phase III DME study. We're continuing to accelerate site activations and randomizations. We're powering in that study for superiority, and we're very excited to see where we can take the 501 molecule into these inflammatory vascular diseases. We think that can be a good partner for Zenkuda commercially. Of course, with our KSI-101 molecule, where we have ongoing clinical trials in the PEAK and PINNACLE pivotal program, we remain extremely excited about what we're seeing. With KSI-101, obviously, we had very strong data in the APEX study and have moved APEX into the PEAK and PINNACLE program. We remain on track to release top-line data for KSI-101 in PEAK before Christmas. We're looking forward to that milestone as well.
Following from that, we'll have the top-line data from the second pivotal analysis for the PEAK and PINNACLE program. That'll be expected in the second quarter of 2027, and hopefully, we can follow that with a quick BLA for KSI-101 as well. As you look and think about Kodiak, and you think about year-end 2027, and we think about hopefully approval for Zenkuda, and potentially as we look, probably not the end of 2027, but let's say early 2028 approval for KSI-101, and also, of course, continued progress and acceleration of the tabirafusp-ted program in the background in DME. We think about Kodiak as a three-product company. That's very exciting.
Led by the science and I think the validation that we see on the ABC Platform, also validating some of our pipeline and development work, looking at future retinal diseases such as glaucoma, geographic atrophy, and additional bispecific work in ocular inflammation. We have had also very exciting work on our VETi retinal analyzers and engagement tools, and that's something that we can talk about a different day.
I think I'll stop here, and we'll begin to take a few questions. Thank you.
Thank you so much. As a reminder to ask a question, simply press star one one to get in the queue and wait for your name to be announced. To withdraw your question, press star one one . [audio distortion] One moment for our first question, please. It comes from Anupam Rama with J.P. Morgan. Please proceed.
Hey, guys. Thanks so much for taking the question and congrats on the data. Really great to see. I was wondering if I could ask two quick questions of the KOLs on the line. The first one is with the profile of tarcocimab or Zenkuda in wet AMD, where do you see the product fitting into what is a fairly competitive treatment landscape? Which types of patients do you think would be best for therapy given the emerging profile that we're seeing here? The second question for the KOLs, what percent of patients are super difficult to treat in wet AMD and maybe have some sort of inflammatory component from which they may benefit from an IL-6 mechanism when thinking about KSI-501 or [audio distortion] tabirafusp? Thanks so much. [audio distortion].
Yeah. Charles Wykoff here. I don't know if you can hear me, but happy to take that question first. I appreciate the perspective that you're taking, which I completely agree with, that we need to start thinking about wet AMD patients as more of a heterogeneous disease population than we have historically. Historically, we have a one size fits all, and I think we're getting to a place in retina where we can be more nuanced. To take the second part of the question first, the tabirafusp, I do think that there are some patients with an inflammatory component. I think we still have to dive into the data to understand who those patients might be in this particular clinical trial. On average, we're seeing that we've met equivalence here, non-inferiority with the aflibercept. But are there subpopulations that may be doing even better with IL-6 inhibition?
I think those analyses still need to come. I do think there will be those patients, and we'll see. On the other side, I think that tarcocimab could be useful for a broad range of patients with wet AMD. The value of this clinical trial program is that we're showing that we can dry equivalent to fixed Eylea monthly dosing during the loading phase, and that a very large number of patients can go longer in between injections than what we're used to with our current biologics. From that perspective, I think this could be broadly useful for a large proportion of patients with wet AMD, both the patients with high need dosing frequencies and also those patients that are already on extended intervals because we can hopefully go longer based on the half-life data that Dave beautifully unpacked.
This biopolymer conjugate looks like it's meaningfully extending the intraocular half-life for this anti-VEGF component in these patients, which I think would be quite clinically meaningful for a large number of patients.
Yeah, I agree with Charlie. There's lots of patients out there that to answer the first question, it's in a busy tertiary care clinic like Charlie and I have. It's probably 30% of the waiting room needs monthly treatment with faricimab or Eylea HD. So that population is really out there. Will this molecule move that population? I don't know. We'll have to see. In terms of the IL-6 question, I think it's much more likely that with diabetes, we're going to see an IL-6 responder group. AMD, there's less evidence of IL-6 or inflammation. But in the DME population, certainly that's why steroids have persisted all these years is there's a certain part of the population that really has inflammatory components.
Thanks so much for taking the question, and congrats again on the data, guys.
Thank you. Our next question comes from Maury Raycroft with Jefferies. Please proceed.
Hi. This is Amin on for Maury. Thank you for taking our questions, and congrats on the data. Couple of questions. First, for Dr. Brown and Dr. Wykoff. How do the treatment criteria compare with your real-world practice? Would you expect durability to change outside the trial? Then I have a follow-up.
Yeah. In the real world, most of us don't allow any fluid. In the real world, we figure out a dosing interval, and we stay at that interval. The difference in this trial, and you had to do it in a clinical trial, is here you're actually waiting for fluid to occur, even though it's a very tiny amount of fluid. In the clinic, you're going to use this a little less than what you see in this trial. How much less, you really won't be able to tell until you get it out there. But unlike previous trials that wanted 50 microns of fluid or 100 microns of fluid and commensurate vision loss, this is much more real world. This is very small amounts of fluid.
Any appreciable amount, essentially, with the AI read. This is as close as you're going to get to the way we treat in the clinic. Given the trial constraints, you can't do treat and extend in a clinical trial and get a drug approved.
Yeah. Agree with those comments. I think the biggest differentiator of this clinical trial program, DAYBREAK, is that retreatment algorithm that Dave described, and we showed the images for. Most other clinical trial programs that are showing extended dosing intervals between treatments or gene therapy or TKIs are using a combination of increased CST and vision loss to drive retreatment or to determine your treatment interval. No one in clinical practice does that. We do not wait for visual acuity loss and meaningful change in CST. CST is a number that most retina specialists are not routinely using to drive retreatment in wet AMD.
We use the presence or absence of fluid to determine what that interval is going to be, and this is really the first pivotal trial to use an AI algorithm, and I applaud them for doing that. This is sort of a first of its kind, and I really think this is where future trials need to go to try to find these recurrences and disease activity before there is vision loss and before there is significant architectural distortion of that central foveal zone.
Thank you. Sounds good. For tabirafusp, what do you think explains the numerically lower letter gain with this drug versus aflibercept? Is there any reason to believe it is mechanism related? Does it change your view on the ALTO trial?
Yeah. This is Pablo Velazquez-Martin. Thank you for the question. I think this is a positive study, and both BCVA and drying met statistical significance. I think that that is important to remind ourselves. I think that the comment from Dr. Wykoff and Dr. Brown about finding which patients benefited the most from the IL-6 inhibition in this treatment-naive patient population, it is our next task. To understand the data better, of course. As Dr. Brown was mentioning, wet AMD and particularly treatment naive overall broad population is not probably the best place to shine for an IL-6 inhibition or inflammatory inhibition to shine. That is what basically validates our development path, which we are moving to DME. That would be my take on the results.
Charlie, do you want to add anything else?
Yeah. It's a good question. I don't know the answer to that. I can tell you statistically, not only has non-inferiority been demonstrated, but my understanding is that equivalence here has also been demonstrated. I do think from a statistical perspective, these are overlapping, at least the way the trial statistical analysis plan was defined. I think that that's critically important. Beyond that, these subpopulations will be really interesting, right? I think we're learning so much about new biologies in retina, and it's fantastic for patients, right? We have Ang- 2 biology that we've learned about now for a while. We're going to get a lot more data on direct TIE2 activation, Wnt activation, and in this case, IL-6 inhibition.
There's a lot more that we're learning about these different disease states, and I believe strongly that we are going to migrate more to an oncology approach here, where we're being more specific about patient subpopulations that could benefit from additional modulation of different biologic pathways beyond VEGF inhibition.
Sounds good. Thanks.
Thank you. One moment for our next question. It comes from the line of Umer Raffat with Evercore ISI. Please proceed.
Hi, guys. Thanks for taking my question. First of all, congrats to the whole Kodiak team for persevering through this over the last five years. I have three questions, if I may. First, perhaps for Charlie. Charlie, do you think this is standard of care based on all the data we're looking at? Number one. Second, maybe for David. David, can you speak to how the AI could be implemented in practice? Or that little bit of fluid method that retina practices do use will effectively mimic that? I'm just trying to think about how to implement and find that first one-third of the patients that do need the additional supplementation.
The last one, Victor, for you and maybe for your staff team. There's something I was looking at, which may be a labeling thing. On the OCT graph that Charlie leaned into, it shows 133 micron drop for aflibercept in the table, the least squared means when the tarcocimab analysis shown, but it shows 138.8 when that aflibercept arm is shown again for the 501. Similarly, I felt like in the tarcocimab OCT disclosure, maybe the gray versus blues flip, the way the OCT is shown, it looks higher even though the numbers are deeper. I just wanted to clarify that. Thank you very much.
I'll take the first of those. Thanks. Is the standard of care. It's interesting. Whenever you do a prospective clinical trial, there's a lot of bias there. Every single trial is different than routine clinical practice patients for a lot of reasons. I think the biggest disconnect that we've had as retina specialists, as practicing doctors over the last few years, has been this disconnect between what we do in clinical practice, which is treat to dry and then go as long as we can in between those doses based on anatomic recurrence of disease and/or patient symptomatic of recurrence of symptoms.
The disconnect has been in clinical trials, because clinical trials have sort of instituted these thresholds which are more than that, where they've required visual acuity loss and anatomic worsening beyond what we would allow in clinical practice before retreatment or before determining what that longest acceptable interval is. That's been a disconnect because we look at these clinical trials that require, for example, 15 letter loss, and that's just not standard of care in any of these diseases and especially wet AMD. Even 10 letter loss is a lot of visual acuity to require a patient to lose before you retreat them. The five or greater letter loss is, I think, a little more acceptable for some of those clinical trials. But again, that's not what we do in routine clinical practice.
I think this is the closest pivotal trial that we've ever seen in the modern era for wet AMD management, getting at how doctors actually think about managing these patients in the real world. I think this will be more closely aligned with treatment intervals that are achievable in the real world for a broad treatment-naive population. If this is approved and we used previously treated patients in the real world, that's going to be a different outcome than, again, a broad population like this that's treatment-naive. Because those patients a priori are going to need more frequent dosing.
Umer, David Brown. Good to talk to you again. In terms of AI, it's fascinating. AI is rapidly getting into our imaging. I think AI will be useful in the clinics to help doctors find small amounts of fluid that if you're looking at a 94 volume scan, it takes a while to scroll through all that and kind of like a radiology read where it shows you sort of where to look. I think that's going to help. In the clinics, though, the real-world story is that with step therapies, most insurance companies make you either step through Avastin and/or probably an aflibercept biosimilar at some point. You're going to have a much tougher population that moves on to these advanced drugs.
And so you've already weeded out the easy ones with that step therapy. I think you're not going to see these kind of results because unless an insurance company figures out that, boy, it's cheaper to give two or three doses of this drug than to make the doctors go through Avastin and aflibercept biosims, I think the real world is we're going to be, in the United States, stuck with that paradigm.
Thank you, Umer. Pablo here for the third question. The numbers are not flipped. In the OCT graph, just looking at tarcocimab sarcolizumab as an example in slide 15, it's observed CST. If you look at the baseline of the aflibercept arm, it is slightly higher, and that's why it doesn't fully represent the change at the end. The numbers are correct. It's -138 and -132 for aflibercept and tarcocimab respectively at week 48. Regarding your second comment, the difference between those numbers and the numbers in the table below is the numbers in the table below use the MMRM model. That's the square means numbers, whereas the number on the right on the graph is the mean change observed. That's the difference.
The one on the bottom of the table is the statistical number, which is the one that is used for statistical testing.
Okay. But because the Eylea looked different between the two tables when the analysis on OCT was shown.
Go ahead and take a look. Yep. As we referenced it at the beginning of the study, the two studies are independent. The analysis and the models and everything are independent. I do think that they're identical. We can double-check for that, but I'm pretty sure that they're the same.
Thank you very much.
Thank you. One moment for our next question that comes from Michael Yee with UBS. Please proceed.
Hi. Thank you. Good morning, and congrats again, Victor and the team. Maybe a question on 501. I think there is not really any debate on the AMD stuff. I think you guys wrote in the slides the new benchmark. Just thinking about the read-through then for DME and the ALTO study, maybe the doctors, Charlie and David, could comment. Do they seek or would they be pleased to see better BCVA, higher BCVA, superior BCVA, or would greater dosing be attractive? Maybe just comment about where you could see significant opportunity here in DME, given AMD is not such an inflammatory-driven disease. The second question is, beyond DME, how does the data today change any of your thinking about your confidence on MESI, which of course is reading out in a couple of months? Thank you.
Yeah, I am happy to jump in there first. Thanks for the question. I agree with your premise and other comments here by many that DME historically is looked at as more of an inflammatory disease state. I certainly agree with that. I do think there is broad heterogeneity in both wet AMD and DME that has been underappreciated historically, mostly because we did not have the tools to address these different subpopulations in unique ways. I think we need to get more sophisticated as a specialty at understanding who these subpopulations of patients are. Credit to groups that have been looking at things like intraretinal hyperreflective foci and the amount of DRIL and retinal non-perfusion. There is a lot of imaging biomarkers that can be leveraged in the DME and DR populations to try to identify who those subpopulations of patients are.
I think we have a lot more to learn there. Specifically to your question, sure. I would love to see improved mean visual acuity outcomes across the entire population of patients and better anatomic drying. I am not sure if that will be achieved. I certainly hope it will be. But what I expect will be achieved will be very similar outcomes to aflibercept 2 mg, with the potential for some subpopulations of patients to be doing meaningfully better from a clinical perspective.
Thank you, Mike. This is Pablo again. Just to remind the audience, so tabirafusp-tedromer and KSI-101 share the same protein. That is where the relevance of the question comes from. How do we think about MESI? I think that it is two different compounds and two different patient populations and two different everything. That is why we are doing them separately. They are a full development plan. We are extremely excited about what the results will be for MESI and for 101. As you mentioned, it is coming up very soon. About the patient population and the response and the validation, Charlie, you want to comment? You are an investigator in the PEAK and PINNACLE trials.
PEAK and PINNACLE. Fascinating study population, where clearly that is an inflammatory-driven group of diagnosis. I really like the approach that Kodiak has taken, and I hope others take it also, where they are broadening that potential funnel for patients with inflammatory-associated macular edema. We are certainly aware of the core uveitis-associated diagnosis that are associated with inflammation, but there are many other categories of disease that are being studied in there as well. It will be fascinating to look at those different subpopulations of patients based on their entering diagnosis to get a feeling for how that IL-6 inhibition can benefit them clinically.
Well, thanks everybody for joining us for the DAYBREAK primary top line data Webex and results discussion. I think it is a very good discussion. We were privileged to have Doctors Wykoff and Brown participate. Thanks also to Pablo. I think we have achieved something very important within the wet AMD field with Zenkuda. I think, in summary on these different retreatment criteria, what we tried to accomplish in DAYBREAK was something as close as possible to what the retina doctors do in their clinic. They might print out the OCT, the B-scan of the OCT image. If there is any fluid present, the physician would treat that patient. The application of our tool was only to provide a consistency across the study and to accomplish the same thing.
We set the thresholds for treating based on intraretinal or subretinal fluid. If fluid was present at the limit of detection reproducibly of the machine, then it would trigger retreatment for the patient in DAYBREAK. Having said that, we were able to bring a majority of the patients coming out of the loading phase and at the endpoint, through the endpoint, a majority of them on six-month dosing. As dave says, and Charlie says, the population in the real world may be a little bit different. But the point is, as we showed, Dave showed the curves of the aqueous TAVs and the ocular half-lives, that every patient has a different ocular half-life.
Now with the combination of the free protein and the conjugated protein, the two in one, our concept is to provide the best possible immediacy and the best possible durability for each patient, and to have the retina physicians do their job and to have the best drug to be able to provide the best journey for that patient. We had a clinical trial that best approximated what they do every day in their clinic. That is very exciting to see that together with the safety that we have also witnessed in this study so far. With the 501, very excited to accelerate it in DME. We are glad to have a positive study in wet AMD. Very exciting, I think, because of the strength of the Zenkuda data in DAYBREAK. Then you are asking questions about the tabirafusp-ted or the 501.
I think we are very excited about these results in DAYBREAK and very excited about the potential for our superiority study design for 501 in DME. KSI-101 in MESI is a very different animal. Very excited to be in macular edema, secondary to inflammation, which represents a very broad population with a very high unmet need, and excited in the development of Kodiak in my own career to be able to bring KSI-101 as a career medicine into the commercial setting for patients. Thanks for joining us. We look forward to the next steps of the journey together. With that, we will sign off.
Ladies and gentlemen, thank you for participating in today's conference. You may now disconnect.