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

Welcome, everyone, to the 10th Annual and 2021 JPMorgan Napa Valley Biotech Forum. Our next presenting company here is Kodiak. And presenting on behalf of the company, we have CEO, Victor Perlroth. [Operator Instructions] Victor, if you want to introduce the broader team on the line here, we can get started.

Yes. Well, I'm Victor Perlroth, I'm the CEO of Kodiak. Thanks a lot, Anupam. We're glad to be part of the conference. And then we also have Jason Ehrlich, our Chief Medical and Development Officer on the line as well. So we'll look forward to chatting with you for the 45 minutes.

Yes. So related to the KSI-301 ongoing Phase III studies, with DAZZLE enrollment and wet AMD complete, how are you thinking about the enrollment curves of GLEAM, GLIMMER and DME and BEACON and RVO? How are these tracking sort of to start 2021 relative to your expectations, given these are global trials and the pandemic is ongoing and different regions are impacted differently here?

Right. Yes, that's a great question. We have our clinical development strategy that has essentially the wet AMD DAZZLE study, the 2 pivotals in DME, GLEAM and GLIMMER and then the pivotal in RVO BEACON. And so the objective is to bring all of those study readouts together right into a single BLA. So DAZZLE, as you mentioned, is fully enrolled as of last year with the 1-year primary endpoint. So the last patient, last visit for the DAZZLE primary endpoint will be towards the end of this year. And then our objective would be that, that study would read out top line data in the first quarter of next year. And our objective would be for BEACON to read out a quarter after that and for GLEAM and GLIMMER to read out yet 1 quarter after that. So I think BEACON is enrolling very well. GLEAM and GLIMMER, a little bit more slowly perhaps than our upfront expectations. RVO is very acute, right? DME, while acute, sort of an acute-on-chronic, I guess, treatment, and DME patients perhaps showing up in the clinics a little bit less than we might have thought. That may be opening up a little bit. At the same time, with those studies, our full suite of studies being global, essentially in the U.S. and Europe, and with some of the pandemic especially in Europe and Eastern Europe, we're also a little bit cautious. So I would say at a very high level, we're pleased overall with site activations with the support from the retina community and the retina doctors in the clinics on a global basis. DAZZLE enrolled very quickly at the end once we had all sites activated. I think we're also very optimistic about GLEAM and GLIMMER once we have full site activation. We've been a little bit cautious on that. I still think we're on track for multiple -- for all of the studies to read out in 2022. Whether GLEAM and GLIMMER reads out in the third quarter or a little bit later, that will depend a little bit on the recruitment time line. BEACON, however, with its 6-month primary endpoint, is well positioned. And I'll say at a higher level, as we think about KSI-301 as a medicine in retina, we really want to and are thinking about it internally as a medicine for every patient, potentially. And so we think a lot about the label that we want to have and that we can have based on the existing suite of pivotals across the 3 diseases, right, and the different dose kind of duration and regimens that we're going to have coming out of the pivotal. So we're also doing more broad thinking around do we have all of the right suites of studies that we want to enable a really broad label so that KSI, when it is approved in all of those indications, let's hope in parallel, that it can also be used in all patients.

Understood. And so most recently, the KSI-301 Phase Ib results were presented at the Angiogenesis meeting just last month. What was the physician feedback at the conference in terms of the compelling points, the strengths within the data? And what were the potential pushbacks that you heard at the conference on the data?

Right. Well, there's a lot of different ways to answer the question. The 1-year data for KSI-301 presented at Angiogenesis was data and treatment-naive patients in wet AMD, DME and RVO. And the vision curves were exciting and strong in all 3 indications. And the changes in the retinal anatomy or OCT, also strong and appropriate and consistent across the 3 diseases. And the durability data, really even beyond our own expectations, where we took 2/3 of the patients or more to 6 months in between doses or longer. It was capped at 6 months in the wet AMD cohort, and it was not capped in DME or RVO. So there were pushback or discussions around 2 areas in the wet AMD data. One of them was the question of whether the absolute gain in vision in terms of number of letters, right, on the best corrected visual acuity was strong enough, and then also whether the change in the OCT or the drying effect of the medicine in the wet AMD was also strong enough. And I think not like misinformation per se, but when -- what's important in looking at wet AMD in terms of vision and OCT is to think a little bit about, well, what should a good, strong drug show in terms of vision game in the population, the treatment-naive population that we had in wet AMD, right, and how much drying effect should also be expected. And when you go to just that next level, the vision gain that we had when you look at the baseline vision in the wet AMD treatment cohort, which was close to 64 letters, and you look at the north of 5-letter gain that we showed, that's a phenomenal level of benefit, which is well in line of all recent pivotal studies for anti-VEGF agents. So very simply put, the vision gain as very strong and appropriate. And then in terms of the OCT, when you run the analysis of looking at the complex retinal anatomies that are seen in wet AMD, and realizing when you get one more level of kind of technicality, that all of the sites that we ran in the Ib used a certain kind of OCT machine. And in that machine, a normal female retina is 305 microns, and the normal male retina is around 315 microns. And so we're bringing patients in that analysis to around 320. And a number of these patients are in their 80s or 90s in terms of how old they are. So bringing that cohort of patients essentially down to around like 320 is very strong in terms of the drying effect. So there was some discussion, I would say, around the absolute value of the vision gain, the absolute value of where we got to in terms of retinal thickness. But when you kind of scratch the surface, the data is very strong. And of course, we're not just exploring the drug in one indication, wet AMD, we're also looking at data in DME and RVO, which are also hard to dry, right? And we're seeing very strong vision gains and very strong and appropriate OCT changes. So the full data package is very solid, and that was well understood and, I think, recognized by the retina community. And we were very pleased with the data and at least with the response.

So your point basically is on the visual acuity and the OCT that you need to put it into context of some of the baseline demographics to understand the total benefit, right?

Yes. Like, for example, there were some folks saying, "Oh, well, in studies with EYLEA, EYLEA showed a 10-letter gain and Kodiak showing 5-point X letter gain. So it's half as good. That's really an inappropriate comparison because what you need to do is compare all the studies and look at the baseline vision of where you started. And there's kind of a ceiling. So the higher you start, the less room there is for you to actually have vision gain on average. So when you put the baseline vision out there, we actually have extremely high ceiling in our studies in terms of our data. So once you do that, then you can do a much more appropriate comparison and recognize that the drug is having a very powerful effect.

Yes. Here at JPMorgan, we recently published a global sort of physician survey with the global team here. And one of the things that came out, and this has been a point of discussion, is that the majority of physicians kind of didn't view the Phase I re-treatment criteria as materially shifting their view on the product, which was an interesting data point to me. Is this something that's in line with your market research? And what are like the push-pull levers for physicians when thinking about the re-treatment criteria in the Phase Ib?

Yes. I can maybe take a quick crack at it, and we can let Jason weigh in with a little bit more nuance. The re-treatment criteria is sort of a broader subject of how you run pivotal studies in retina. So you don't run a study exactly the same way that the medicine is used in the retina doctors' offices. So it's sort of a way to kind of bridge to the best we can, right, how a doctor may use it in practice versus how you run a pivotal study. So the pivotal studies that have re-treatment criteria in the modern era, DAZZLE is our study. But for faricimab, TENAYA and LUCERNE in wet AMD, for example, or from Novartis, the ranibizumab, HAWK and HARRIER study, all of them have different types of re-treatment criteria. And the criteria that we use are well in line with those. It's just one area of nuance in the study design. So we're very pleased with the choices that we made in terms of our re-treatment criteria in DAZZLE. And those decisions were educated by what we have in the 1b. So to go from the 1b to DAZZLE, we tighten slightly the criteria. We don't think it should have a material impact or even much impact, to be honest, in the results of DAZZLE. The bigger changes in DAZZLE are we're only using our top dose, which can only be helpful, and also, we don't even allow patients to go up to 6 months' duration. We cap it at 5 months. So the focus on the re-treatment, it's really a broader question around how we run pivotal studies, which is not how physicians practice, but that's how other people do it. And so we follow the same rules as they do. We use very similar re-treatment criteria. We've tightened them up a little bit, and we're pleased with them. You can't directly compare because in the Phase Ib study, although we have, say, a 75-micron criterium for re-treatment on OCT, for example, and in DAZZLE, it's 50, the reality is you can only really look in the Phase Ib at the time to the first re-treatment. If you wanted to try and do some direct comparison, well, how would the re-treatment of the Phase Ib translate into a DAZZLE population? It's actually not that useful because there are more opportunities to drop in DAZZLE. We have different dose level. We've pulled back so you don't take patients to 6 months. So there's a variety of differences. And really, it's just the point that we've designed DAZZLE, I think, with the high level of excellence overall, educated from the Phase Ib and in line with other agents that apply re-treatment criteria. I think just as a last point, Anupam, it's important to remember historically, that when EYLEA ran its pivotal, okay, it had a 4-week dose group and an 8-week dose group after 3 loading doses. And so actually, there were no re-treatment criteria at all for EYLEA, right? All patients were taken to 8 weeks. And even though patients were evaluated at 4 weeks, there was 0 opportunity, right, for patients to be dosed on the 4-week interval. So they basically dragged patients along, okay, even though they saw them at 4 weeks and knew that they really should be treated because even modern treat-and-extend studies, such as the RIVAL study, which we highlighted on the corporate website for Kodiak, show that in well controlled studies, EYLEA in almost -- in 50% of the patients is used on a 4-week interval. And so we use re-treatment criteria that let us push longer and allow us to drop patients, right, from 5 months to 4 months to 3 months. But actually, historically, with EYLEA, they sort of took a gamble. And they had a re-treatment criteria where they didn't allow the patients to be re-treated at all. So what we've provided is sort of a more modern version, following what Novartis has done and also what Roche did with ranibizumab. So that's kind of a broader dialogue in and around re-treatment. But the bottom line is we apply re-treatment criteria in DAZZLE for wet AMD. And we also apply re-treatment in GLEAM and GLIMMER for DME.

And there are no changes in the protocol from Phase I to GLEAM and GLIMMER for DME worth noting for re-treatment?

I mean there are small edits, okay, in a variety of different ways. We're extremely pleased with our drug in DME, and it should be really a disruptive medicine. There's really no doubt there, I would think, especially on top of the faricimab data that was presented, which in DME, for example, where they have a matched regimen with EYLEA on an every 8 week. And you can see exactly the same sawtooth or flutter pattern in the OCT as EYLEA. So there's no core durability advantage of that agent in DME. And then they have sort of re-treatment criteria in those Phase III studies for faricimab in DME. But if you actually look over the first year, right, the median number of doses in that sort of re-treatment arm, I think it's, what is it, 8 median doses in year 1 as opposed to their intensive treatment arm of 9 or 10 doses. And so whereas in our Ib, we had only 3 loading doses and then 1 additional dose through 52 weeks, so 4 doses in the first year. So the criteria are a little bit different in DME. But again, we're in a fundamentally different durability category with our biologic in retina, based on the science, right, that we've used to really design our medicine as a conjugate. So the bottom line is, I think, that the differences in the re-treatment criteria really are going to be swamped by the native capability of our conjugate in our molecule versus other biologics that are more naked and really not designed for durability, if that makes sense.

Understood. If you were to apply the DAZZLE re-treatment criteria to the Phase Ib results, what would the treatment interval be? And have you conducted this sort of analysis and appropriate DME and then RVO, if there are any differences in the re-treatment criteria?

Jason, do you want to kind of address that?

Yes. Sure. Thanks, Victor. Thanks, Anupam. So in terms of like doing that kind of like Phase Ib through into the Phase III design for DME, I think we look very carefully at the Phase Ib data when we were coming up with the final design and the final re-treatment criteria for GLEAM and GLIMMER, the DME studies, and for BEACON, the RVO study. And so we incorporated all of those learnings and observations into the study designs, right? And as Victor mentioned, we made some tweaks on the margin to the re-treatment criteria in DME in the GLEAM and GLIMMER designs. So I think that the durability that we see in DME in the Phase Ib study really should translate nicely into the Phase III. And remember, in those studies, we allow dosing every 2 to 6 months in DME versus EYLEA, which is just going to be on its 5 loading doses, and then every other month fixed interval dosing. One of the other innovations that we have in the DME program Phase III is we allow the visit window or the re-treatment interval to go both up and down, right? So not just shrinking it, but you can continue to extend the dosing interval in DME, even in the first year, if the patient is doing well. And the rationale for that is that anti-VEGF therapy can improve the severity of the underlying retinopathy, and you can get some disease regression even in the first year. So there's a potential if that benefit is realized early with the loading doses to extend the treatment intervals even from the beginning over a longer period -- increasingly longer periods of time. So I think that -- those data I think could be really exciting in DME. And then in RVO, actually, the first 6 months of the RVO study design is fixed interval dosing, right? So it's monthly EYLEA. And then our comparator is 2 loading doses of KSI, and then every 8 weeks through 24 weeks. That's the primary endpoint. It's a very short study. And then thereafter, it's a head-to-head dosing -- head-to-head same re-treatment criteria for both EYLEA and KSI-301. So that will be another interesting opportunity to showcase the differentiated features of KSI versus EYLEA.

We've got an e-mail question through the portal here, which is for the data presented most recently at Angiogenesis, looking at the swimmer plot, how durable are the longer treatment intervals. For example, if a patient achieves a longer interval, do they sustain there? Or do they sometimes need to drop to a more frequent dosing regimen? Why do they need to drop to a more frequent regimen, if possible?

Right. I mean one way to answer the question is that we've been very transparent, right? So the swimmer plot show all the patients and then all of the doses. So one answer to the question is you have all of the data available to calculate and to answer that question directly for every patient through 1 year. And actually, we include swimmer data for each of the patients well beyond 1 year. So that's one way to answer the question. Another way, I think, is to say I believe we've seen the durability intervals, actually, if anything, right, Jason, either be stable or get longer. Obviously, these are human beings, right? And so you have a lot of variability in the underlying disease and in the life of the patients. And so there is a lot of overall variability. So it's not really one size fits all. I think -- so one is we've shown all of the data. And so you can calculate that and come to your own conclusion. Another is I think that earlier on, people said, "Well, you're doing a loading phase where you're giving a lot of drug, 3 doses every 4 weeks." So you'll sort of get a durability boost that will then diminish over time as the level of drug in the eye falls as you leave and get further away from that loading phase. That actually is not something that we've seen. In fact, I think you often get further extension in many cases and the durability gets better. But that's caveated against the natural variability of these aren't animals, these are patients and they have their disease activities in their life. Jason, do you have any quick view on that?

Yes. Only just to add, I think building on your point about we've tried to be very transparent with the data. There are very few, if any, other studies of anti-VEGF in these common diseases, where people have presented all of the individual patient-level data on re-treatments, right? So for instance, if you look in the Roche faricimab studies, they have this personalized interval. And that's based on previous work that had been published from investigators looking at different treatment extended intervals. And I always present things as like the average or this percent of patients who are on durability proportion x 4 weeks, 8 weeks, 16 weeks at a certain time point. So the heterogeneity that you see in treatment intervals has never been presented before, right? But it definitely exists, right? A diabetic patient, if they end up in the hospital or they end up sick or they don't take their medicine for 4 months and their diabetes gets worse, you'd expect their DME to get worse, right? So there's like many reasons for heterogeneity, just as an example, right? So I think that the key point there, as Victor said, is we're showing what is, I believe, really the heterogeneity that exists in patient populations. There are some people whose disease becomes better controlled over time, and maybe it regresses or becomes less severe and the treatment intervals extend. There are some people who are very predictable. And there are some people whose disease gets worse over time, regardless of what treatment you give them. And then they might need more frequent tree for a while. And that's why I really like that we studied treatment-naive patients in this study. It's not a preselected group. We're not trying to bias the population for frequent flyers or for people who don't need very much treatment. It's an unselected patient population, and that's a little bit closer to the truth. So we're very pleased, actually, with those data.

We've got another e-mail question here, which is -- we've talked a lot about wet AMD, DME and RVO. But can you get the company's thoughts on the 2-year Protocol W results with EYLEA in diabetic retinopathy and whether this changes their view on the opportunity in DR?

Well, Jason knows the DR area very well from really being a pioneer with the approval of LUCENTIS in DME at Genentech as well as the label extension into non-proliferative DR for LUCENTIS based on the analysis that he and his team did. So Jason, maybe put that in the Protocol W data a little bit in a historical context. And then maybe in context of our NPDR study, GLOW, which is -- will begin enrolling shortly.

Yes. So Anupam, this is hot off of the press data that was just published late last night, actually, from the DRCR network. So this is, in some ways, a companion study a little bit to the PANORAMA study that Regeneron used to get approval of EYLEA in DR. But the Regeneron study, they looked at 8-week dosing and 16-week dosing. That study, the DRCR study looks primarily at 16-week dosing. And I think what we see there is a very consistent effect of anti-VEGF therapy on reduction in the rate of developing these sight-threatening complications, proliferative diabetic retinopathy, center-involved diabetic macular edema. The -- I think the key question for clinicians is you know that anti-VEGF therapy has the potential to reduce risk on a going-forward basis. How often do you need to dose it? And what's the sort of the benefit/risk of doing that, right? And that benefit/risk is different in different patients, right? So what I've always thought about diabetic retinopathy is you want to -- we're developing this medicine these medicines as preventive treatments, right? So the dosing interval needs to be practical and achievable in order to really justify that, right? There's procedure associated complications like endophthalmitis can occur and occurs maybe 1 in 1,000 or 1 in 5,000 injections or less, but that's like a risk. So what's the right dosing interval? So with LUCENTIS, we ended up with a monthly dosing interval for diabetic retinopathy. And that's, obviously, not practical for patients who haven't yet developed sight-threatening disease. With EYLEA, if you look at PANORAMA versus -- the 8-week versus the 16-week, and then you also look at the 16-week Protocol W data that were just published, it's pretty clear that the optimal treatment regimen for EYLEA is actually still fairly frequent dosing, right? Like the 8-week data are quite a bit better than the 16-week data and also probably better than the data that were observed in PANORAMA in terms of the approvable endpoint, which is retinopathy severity. So you can get a benefit with 4-month EYLEA, but not as much of a benefit as if you dose it every 8 weeks. So with KSI-301, just to bring it back around to that, we're going to study an interval that goes out to every 6 months, right? So if you're talking about a preventive therapy for patients who have not yet developed sight-threatening disease, I think an interval of longer than 4 months is going to be important to really make it clear to patients and to physicians that that's the dosing interval that I think where the benefit/risk starts to become really favorable or even more favorable. I think that depending on your point of view -- and there are 2 very nice editorials in the JAMA Ophthalmology published yesterday that took like some different points of view on this, right? What's the cost -- benefit cost analysis of this kind of a therapy with EYLEA? And also the other editorial pointing out what are a lot of the benefits, maybe the unappreciated benefits. There's significant reductions in quality of life associated with diabetic retinopathy severity. How do you think about that? And who are the right patients to treat? So looping back around, I think Protocol W generally consistent with the PANORAMA data. I think it reinforces that more frequent EYLEA dosing would result in better outcomes and, again, I think reemphasizes the potential value of a long-acting medicine like KSI in this disease, right? So if we can get 6-month dosing, that's the kind of thing where I think you can really say, "This could be a really important preventive medicine." 2- to 4-month dosing in DR, I think, has already proven itself to be difficult for patients and physicians to maybe accept.

The other interesting point, right, Jason, was the mortality over the short duration of the study.

Right. Yes, I think that's another good reminder, right? So if you look in those data, 7% of the patients with this level of diabetic retinopathy severity died over 2 years, right? It was -- there was no imbalance with the anti-VEGF, okay? That's one thing that's important to point out. But I think it reemphasizes, there's a lot of morbidity associated with diabetes -- with the complications of diabetes at this level of severity, right? So if we can help...

Which is an intermediate -- yes. It's kind of in immediate, right, that was chosen for these kind of preventive studies. So there's a tremendous need actually under the hood that's somehow underappreciated. Our GLOW study, which brings it out to 6 months may be able to really be the slipper that really fits the foot kind of thing.

Yes.

And the other thing that's interesting, Anupam, talking about diabetic eye disease. When we speak to clinicians and we talk about, well, what is the impact of a drug like KSI-301 on their retina practice and the types of patients so with a more durable agent that can basically extend their patients, so to what degree does it debulk, they call it, the practice and create open spaces? And is that a good thing or a bad thing? And what they often say is it's a good thing because there are many DME and diabetic patients actually in the community that just aren't really finding slots that are convenient for them to come in for anti-VEGF dosing. And so in the context of a more durable agent like KSI debulking practices to some level, it's actually opening up utilization windows and slots where diabetic patients that have high morbidity, actually, whether it's DME or proliferative diabetic retinopathy or this sort of early or sort of intermediate DR actually should be treated with an agent like KSI, like we say, a drug for everybody.

You guys keep saying PANORAMA study, which I'm trying to think of how many times my name in transcripts has been spelled PANORAMA, but I think it's more than one. Another question we have here is in wet AMD, the efficacy seems to peak around 16 weeks and then decline through week 40 but then ramps back up. What accounts for this? And in the real world with docs, not inject again with visual acuity are deteriorating from week 16?

Well, probably in a cohort size of 50, small changes or edits may result more from broader variability in patients. And DAZZLE obviously has many more patients and is going to be an active comparator study. And so we'll see the broader truth of the molecule and its capability in DAZZLE. That's kind of one way to approach the question. Another way would be to say, "Well, the design of the Phase Ib study was to allow disease to recur before you would re-treat." However, we don't believe that that's really the driver for the curve shape. That's a second way to answer the question. And the third way is sort of to look at the most recent study in retina, which was the faricimab Phase III studies in wet AMD, the TENAYA and LUCERNE studies. And basically, they have a curve shape there that is not that dissimilar from our Phase Ib curve shapes in terms of vision and OCT and is the most predicate or most proximal study. And we like the TENAYA study in the sense that it's the more predominant treatment-naive U.S. population and that TENAYA will be closest probably to DAZZLE in terms of its overall population. So those are sort of 3 different ways to think about the answer to that question.

And thinking about the DAZZLE results, what would be considered a clinically meaningful treatment interval here between, say, KSI-301 and EYLEA? Like -- and have your and physician views changed post the faricimab data at Angiogenesis?

Right. One, an important way to look at the results of the faricimab data is to think, do those data reflect clinical trial design? Or do they reflect a native capability of the molecule and its design? So in order to answer that, I think as I mentioned briefly earlier, for faricimab, it's really to look at the DME study, where they have a matched 8-week dose regimen. And when you do that, the flutter interval on the OCT is the same as EYLEA. And so what that tells you is that it doesn't have any kind of native durability. So faricimab despite that in the wet AMD study showed, I think, 45% of the wet AMD patients were on a 16-week regimen based on their study and design, okay? And the question is, well, what would EYLEA do in a similar kind of situation. Faricimab has a higher molar dose of anti-VEGF than does EYLEA. However, Regeneron will test their high-dose EYLEA and explore safety and whether they can marginally improve some of their durability. I think KSI is still in a differentiated category of its own in terms of the durability that we have shown and that we hope to show in DAZZLE. What is a meaningful delta, right, that creates sufficient white space between KSI and all of the other agents, right, with faricimab being sort of incremental on top of EYLEA. And I think we, in the Phase Ib showed 2/3 of patients going 6 months or longer, we definitely don't think that that's the right expectation to set. I think if we bring half the patients to 5 months or more with the same vision, that would be phenomenal. And then in the real world, probably you may see the utilization of KSI to be a little bit more similar perhaps even to what we see in the Phase Ib study, right, where physician discretion is allowed -- was allowed in the Phase Ib, right? Whenever a physician wanted to dose the patient, they would call and, of course, decide to dose the patient. In DAZZLE, of course, it's more prescribed, right? The dose decisions are driven by the computer IRT system based on vision and OCT. So what is a meaningful distinction? Faricimab achieved 45% at 4 months. And our hope will be to achieve 50% or more, a majority on the 5-month interval. And we think that, together with the design of the molecule and the durability that we also expect to show in the other diseases, will definitively position KSI-301 as a clear amount of white space between our agent's durability and the next closest agent.

And Victor, in the response, you also talked about sort of visual acuity being in the same range, right? But we also, earlier in the discussion, talked about how you think about baseline. So how should we be thinking about the baselines on visual acuity across -- in DAZZLE versus other studies? And then I guess what's the delta in visual acuity that would be considered to be sort of clinically insignificant, like...

Right. That's a really great question. Jason, do you want to take that? There's a lot there. It's a good question.

Sure. So let's talk about first the baseline and maybe expectations around that, right? So if you look at the baseline vision across the anti-VEGF studies in wet AMD, in particular, and also DME over the last like 10 to 15 years, baseline vision has been going up, right? And if you go back to like -- we have a nice slide about this in our corporate presentation on the website. And mainly, it's going up because patients are getting diagnosed earlier, right? They come in -- they're aware of treatment. They come in for treatment earlier. And so they're not waiting as long. So if you look in the HAWK and HARRIER, the Novartis studies that were run a few years ago, the faricimab wet AMD studies, the vision -- the baseline vision is somewhere on the order of like 60 letters, plus or minus, right? And that can -- that's quite a bit better than it was 10 or 15 years ago when the LUCENTIS studies and the view -- Regeneron pivotal studies were run. So that baseline vision sort of sets up what the incremental room is for further improvement and what the ceiling is. Like as Victor talked about, where -- you can look at like the final visual outcomes across these studies and see where patients are getting. So if you -- just take EYLEA for an example. If you look at the EYLEA comparator arms in the faricimab data that just read out, right, EYLEA is gaining 5-ish letters, right, as opposed to 10 letters that it was gaining in the VIEW studies back 10-plus years ago. And that's a result of this baseline vision and the ceiling effect. So I would say that our DAZZLE study, right, and our studies that are recruiting now are sort of contemporaneous with the faricimab data and, to some extent, the Novartis data from a few years ago. Most of our patients are coming from the United States. And I would expect, therefore, our baseline visions to be comparable to what we've seen in other large pivotal studies where most of the patients are being recently diagnosed. Okay, so there's that part. Then with regards to what differences between groups are meaningful, there's a couple of ways to look at that. The first is what's the noninferiority margin. So for DME and RVO with a comparison to EYLEA, it's 4.5 letters. And the reason for that is that 5 letters is 1 line on the eye chart. And I think most people would say that one line of vision difference on the average between groups, that's starting to be clinically meaningful. So they want the noninferiority margin to be less than that to exclude that potential difference. And for wet AMD, it's 4 letters, which is slightly tighter, but it's the same principle. You want to exclude a clinically relevant difference. Then how much noise is there within that measurement? So if you look at the EYLEA control arms of the recent studies, like, say, the faricimab studies, one of them, it was 5.1 letters. One of them, it was 6.6 letters, I think. Right now, it's the same -- it's just 2 groups of patients randomly assigned and treated the same way, right? If you look back to the VIEW studies, there was like a 2-letter, plus or minus, difference between groups of EYLEA when every one of the patients were just randomly assigned, 2 different groups of patients treated identically monthly with EYLEA. So somewhere on the order of like 2 letters is essentially noise, right, because if you just run the experiment several times, you're going to get that. So that's, I think, the brackets that you might think about. Fundamentally, like the most important thing is the noninferiority margin.

Post Angiogenesis, are there scientific forms we should be expecting additional Phase Ib updates in 2021? Any additional analyses that we should be considering? This morning, we ran some additional cuts of some of the survey data that we published a couple of weeks ago. And it kind of highlighted that physicians who are familiar with the product and have been educated on the product maybe view the product differently than those who are less familiar was kind of the takeaway of the note. Like -- so how should we be thinking about additional analyses, additional data and medical education this year?

Right. Well, we don't see ourselves in a branding phase of the company yet, maybe a light pre-commercial component. Our focus is still, broadly speaking, on acceleration of our execution in our clinical pivotal studies and in the manufacturing activities towards BLA and really preparing for top line data readouts. As I mentioned, that will be happening on a quarterly basis in 2022. That's a core data package. We're well capitalized, right, as a company from a cash standpoint with close to $1 billion cash to take us all the way through those top line data readouts. And our focus is, by and large, as a company on that execution. So in terms of additional specific analyses, we'll keep our eye on that. However, our main focus will be on top line data. We do want to engage as much as we can with clinicians and retina practices. And we're doing that as part of the broader escalation of our clinical program and also thinking about any other studies that we think are going to be important, right, for KSI-301. And of course, our pipeline is continuing to develop. And as we think about what are other areas within retina, right, where, like, for example, where -- what's the population where we want the KSI-501, fundamentally, right, to be tested? And how can that molecule also deepen our engagement, right, with the retina community, right, as we bring in another mechanism of action, right? That's an IL-6 VEGF dual inhibitor bioconjugate. Or, on a palm, really exploring more some of the tremendous and really exciting underlying science around the design of our ABC Platform and KSI-301's design because it won't just be -- I think what you're -- what we're hearing, and to a certain degree, what the survey highlights, there's still a lot of room for additional physicians to learn more about Kodiak and about KSI-301. And not just about the molecule, right, but about the exciting science that underpins its design. And that is driving a number of these very interesting and differentiated features, right? Despite its large size, the bioconjugate really acts as a piece of molecular water, right? That's what this phosphorylcholine component of the ABC Platform delivers, right? That's what gives us the big size that gives us the long dwell time in the eye. But surprisingly, we get very high penetration into the retina, right, because the phosphorylcholine and the water lets us noodle into the tissues, right? And we have a very low co-efficiency friction, which are driven by the conjugate, right, as an integrated molecule, we call it more than the sum of its parts, right? And then how the conjugate combined, right, to its target, right, with the very high or even what we see as a deeper potency than say an EYLEA or a LUCENTIS. So a number of really interesting properties. And I think our focus in this sort of time between now and pivotal study readouts to focus on education around some of the science that underpins our lead molecule 301 but also beginning to build awareness also of the broader pipeline. And I think the fact that what's special also about Kodiak is our unique and dedicated focus in the retina. And so not just pushing 301, but that we're also deeply investing in our pipeline. And actually, even our triplets that we haven't spent a lot of time talking about scientifically, is really actually quite exciting. And we want to be -- we think of ourselves a little bit -- or trying to be ambassadors, in a way, to retina doctors to patients into the retina community. And we just have to balance what that means versus our time that's available, given that we have so many execution-related activities in terms of our clinical and manufacturing and pre-BLA activities. So it's a long way to say that, well, TBD in terms of additional readouts because the focus from our investors really is top line data.

Two quick ones because I know we're running short on time here, which is, one is a theoretical question. In DAZZLE, if you showed a 2-letter gain, with KSI-301 in EYLEA, a 6-letter gain, would it still be a noninferiority margin?

Jason, do you want to highlight a little bit how that works?

Remember, the non-inferiority margins are based on where the boundaries of the confidence intervals are, right? So it's not just the point estimate of the mean. It's where the confidence intervals lie.

Okay. And then can you talk about how you think about KSI-301 in a sort of biosimilar EYLEA LUCENTIS world? And if you would expect any pushback from payers on price?

Right. Well, the more we learn about the retina marketplace and how it functions in terms of, say, EYLEA with Regeneron, LUCENTIS in the United States with Genentech Roche and also, of course, Avastin, and all of the rebating and how that market actually works. The more we learn about it and speak with people about it, right, it's not appropriate to apply lessons learned for, say, Herceptin or RITUXAN or other markets and just rotely apply those lessons into the retina marketplace, right, for a variety of different reasons. So I think there are many hurdles for LUCENTIS biosimilars, in particular, in trying to enter the retina marketplace in the United States, especially vis-à-vis Avastin, which is ultra-low-cost, right, in a buy-and-build marketplace. And Genentech already has demonstrated that they're willing to decrease pricing to retain volume vis-à-vis EYLEA. And there are very tight relationships between the retina practices which are also consolidating with the existing manufacturers. And so there's a very tight relationship. And so why exactly do those practices and physicians want to take risks on unknown biosimilars agents for LUCENTIS when they already have Avastin-branded LUCENTIS and, of course, branded EYLEA? And soon, there'll be faricimab, which I think will try to market aggressively in DME. All of this, of course -- all of those agents are all traveling in a pack. And our objective to have a lot of white space between our agent and having all of the different diseases and to have a very broad label as a branded agent with a science story, driving the broader concept of the superiority, right, a medicine for all physicians and all patients. We don't haven't -- provided any guidance on pricing. But physicians in buy-and-bill have an incentive to use the best product, especially when you have a broad data package and the best science. So we think we'll be in a strong position, and we think LUCENTIS biosimilars, in particular, are going to find it a bit complex. And we're interested, of course, to see where they come out in terms of pricing and discounting. It will be interesting to see where for us about where they choose to price that as well, and we'll have all of them...

Would you price on an annual basis or per dose, given the durability? That was an e-mail question that just came in.

Well, based on discussions with payers, they definitively understand the importance of durability and have offered that -- one could imagine pricing on the same annual amount, even having fewer doses. But we have -- TBD on that.

Quickly, you're stuck on an island, you need to have a bottle of wine, but you only get one. What would you -- what would it be and why?

Well, I guess despite all of the recent fires that they've had up in Northern California, one of the vineyards that I quite liked a lot was called Hourglass, and that they have a unique location, kind of in that area in Sonoma with kind of a unique tier war. And the Hourglass Cabernet, I found to have a nice chalky flavor and to be quite special. So that's I guess what I would bring a piece of California.

Jason?

Oh, man, I like the Wagner Family of Wines. I mean Caymus is always very nice, but it's quite expensive. So I mean, if I had my druthers, I would take a bottle of Caymus, that sounds nice.

You can actually get Caymus at Costco for 2:1 -- it's like 2 for 1. But it's actually 15% cheaper, just as an FYI, at wine.com. So anyway, thank you, guys, so much. Thank you for a productive session. Thanks to all the listeners, and hope everyone has a great rest of the day.

Thanks so much, Anupam. Bye.

Thanks, Anupam.