Ocular Therapeutix, Inc. (OCUL) Earnings Call Transcript & Summary

Good day, and welcome to the Ocular Therapeutix conference call announcing 12-month data from the U.S.-based Phase I clinical trial evaluating OTX-TKI for the treatment of wet AMD. [Operator Instructions] As a reminder, this call may be recorded. I would now like to turn the call over to Antony Mattessich, Chief Executive Officer. You may begin.

Well, hello, and thanks for attending the Ocular Therapeutix press conference for our 12-week top line data or OTX-TKI. Let me start first by emphasizing how encouraged and excited we are with this data as it continues to support our product's profile and the potential to set the standard of care of durability in wet AMD, which is the highest unmet need in the space. I'll be very brief and get directly to Dr. Arshad Khanani. Transitioning to Arshad is important not only because the he will be presenting the data, but also because Arshad is our largest enroller, has by far the most clinical experience treating patients with OTX-TKI than anyone else in the world. After Dr. Khanani completes his presentation, Dr. Peter Kaiser will follow up with a bit of a discussion on the new paradigm that we believe that continuous dosing can bring into the market. We'll then open the floor up for questions. Joining Dr. Khanani and myself, to help answer those questions, will be Dr. Peter Kaiser, our Chief Adviser for Retina; Dr. Rabia Ozden, our Chief Medical Officer; Donald Notman, our Chief Financial Officer; and Chris White, our Chief Business Officer. Just before handing it off to Arshad, I want to get everybody's attention to Slide 2. As you'll notice that we will be making forward-looking statements. And with that, I will hand it off to Arshad and get to the exciting data as soon as possible. Arshad?

Thank you, Antony. Good morning, everyone. I'm really excited today to present the first-time data for the 12 months from this study. As practicing physicians, we know that there is a big unmet need for our patients with neovascular AMD to receive treatments that have better durability. And as a field, we are -- we have been looking at durability for almost a decade now, and we have made some headways where we have agents that can last 3 to 4 months instead of 1 to 2 months. But -- even with those agents, we have a large number of patients who still need treatment very frequently. So I am super excited to be an investigator in many trials looking at sustained delivery. And today, I'm really excited to cover OTX-TKI. As you are aware, OTX-TKI uses a proprietary [indiscernible] polymer matrix, and this is bioabsorbable and this enables sustained targeted drug delivery, and it has a TKI, and I've been involved with all the trials, and this one has axitinib, which is a multi-target tyrosine kinase inhibitor. When you look at TKI, you need to make sure you look at the drug that's present in TKI because the concentrations and the innovation of the receptors is different in terms of affinity. So when you look at axitinib, this is on Slide 3, it's a highly selective inhibitor of all VEGF and PDGF receptors, with very high affinity and low solubility compared to other ocular TKIs. Also, as an investigator, when I started participating in this trial, I was very thrilled to see that this is a very easy injection. It's a single implant that's administered by a 25-guage needle. And the hope is that the target release is 9 to 12 months. And as I said earlier, it's completely bioresorbable. So hopefully, after looking at the data today, you'll be able to see that this implant can really help patients with neovascular AMD decrease their treatment burden. Looking at Slide 4, which shows the OTX-TKI U.S.-based study trial design, this is a multicenter, randomized double-mass study. We know patients who had subfoveal neovascularization due to neovascular AMD. These patients had controlled fluids. So they could have some fluid at entry or no fluid at entry, but they had to show a response in the path that -- to anti-VEGF and we needed to control patients for this trial. In terms of randomization, patients were randomized 3:1 to either receive OTX-TKI versus aflibercept. Patients at baseline received OTX-TKI or a sham injection, and then a month after, both treatment groups received aflibercept injection. After that, patients in the OTX-TKI were evaluated for disease activity using the criteria listed at the bottom or at investigator discretion to receive a supplemental injection of aflibercept. In the aflibercept arm, patients receive on-label aflibercept, which is q. 8 weeks. As I said today, I'll be sharing the results of the 12-month analysis. Looking at the baseline characteristics. These appear to be well balanced. Slight differences in terms of mean BCVA and CSFT. If you look at OTX-TKI, these patients had slightly lower BCVA at 70.9 letters compared to 73.8 letters with aflibercept. And looking at CSFT, 273.8 versus 240.6. So patients with aflibercept had better CSFT at baseline. As you can see, 16 patients in the OTX-TKI and 5 in aflibercept. I think this slide really highlights the results today. When you look at patients with neovascular AMD, you need to look at prior treatment history. Criticism in the past with many trials that they are enrolling patients who don't have any disease. I enroll most of these patients, and they all had disease. So here, you can see patients who are receiving injections anywhere from every month in most cases, to every 2 or 3 months with a variety of anti-VEGF in the past. After receiving a single in-clinic injection of OTX-TKI, you can see on the right that there is an 89% reduction in treatment burden when you look at the data at 12 months, really highlighting that this technology is really helping patients control their disease. Obviously, this is a treatment burden slide, but we need to look at visual acuity as well as anatomy to prove that, but I just want to again highlight that these were patients who are receiving frequent injections in the past. And after receiving OTX-TKI, we see 89% reduction. And also, when you look at the rescue injection, in this study, investigator discretion was allowed. So you can see those purple boxes, those are injections that are given at investigators discretion. And I like that because as an investigator, my hope and goal is to control disease for my patients so they can do well, And sometimes, if I feel like that the disease is active and patients still don't meet the rescue criteria, we were allowed to give supplemental treatment. And that's why I respect the company for doing that so that we can better take care of our patients. Looking at Slide 7. you can see the rescue fee rate over time, OTX-TKI demonstrated extended duration of action. 60% of patients were rescue-free up to 12 months with 4 additional subjects rescued at 12 months. So you can see that there's great durability here where majority of the patients can go without treatment for 8 to 9 months or even longer. So here, we are taking patients who are receiving treatment very frequently, and we are able to extend majority of them past 6 -- to 8 to 9 months. which again highlights that this technology is really providing sustained delivery to control disease. Looking at Slide 8, here, what we are seeing is vision and CSFT. So if you see on top, we are showing mean change in BCVA. And what these graphs show that -- looking at BCVA, this was comparable to aflibercept when you look at patients treated with OTX-TKI. We are also showing the light blue dotted line, which is sensing rescued subjects. So patients with OTX-TKI had mean BCVA of minus 1 letters at week 52 compared to gold standard aflibercept, which was plus 2, and this was comparable to OTX-TKI. So again, BCVA is stable. As a reminder, these are patients who were previously treated. So we don't expect these patients to have improvement in visual acuity. As I said earlier, these were prior treated with essentially control disease when they were enrolled in the trial. So a stable BCVA actually is the goal of this trial. When you look at CSFT, we have to look at a few things. With aflibercept every 8 weeks, we have seen sawtooth or fluctuations in CSFT in essentially all trials. So a sustained delivery platform should be able to stabilize anatomy and we should not see fluctuations. Here, we can see, again, comparable results, but OTX-TKI arm shows stable OCT as fluctuations are at minimum with OCT improving over time during the weeks 32, 36 and 40 time points, again showing that this sustained delivery is helping patients stabilize anatomy, stable vision, highlighting the biological activity of OTX-TKI. When you look at the subjects that are sensoring -- the dotted line showing sensoring rescue subjects, this also shows similar results. Looking at Slide 9. This is safety. Obviously, it's an ocular implant. It bioabsorbs completely, but we still need to pay attention to safety. I am happy to report that there are no reports of drug-related ocular or systemic SAEs in either arm. We did have one event of acute endophthalmitis in OTX-TKI arm. This is actually one of my patients. But this endophthalmitis happened at the mandated aflibercept injection at month 1. So this is not related to OTX-TKI, but rather the standard of care, aflibercept injection that patients -- all patients receive in this trial at 1 month. This patient did well, we treated them with an intravitreal antibiotics and over time, patient resolved and we have vision returning to baseline. Other than that, all events were mild and manageable. There really were no safety signals here that were concerning in terms of OTX-TKI. We did not see any retinal vasculitis, retinal artery occlusion or anything else. Looking at Slide 10. There are some cases from the study. This is an 81-year-old female with anti-VEGF injections given every 8 weeks prior to study and this patient has remained rescue-free up to 1 year. As you can see, the CSFT is very stable over time. There is increase at the end of the first year and patient received supplemental treatment at that time, looking at BCVA again, stable. I want to point your attention to the OCTs on the right. You can see minus 16 weeks that before patient was enrolled in the trial, you can actually see fluid. You see the red area on the grid which shows thickening. You can see black circles inside the retina. This is intraretinal fluid. So this patient actually had very active disease. The BCVA was not available because this is from standard of care clinic visit. And sometimes patients don't get BCVA or they get BCVA that doesn't get reported. So it's not available. But when you look at baseline in blue, you can see patient had control disease with 83 letters of BCVA, which makes sense, looking at the OCT. Patient got enrolled into the trial, received OTX-TKI, week 4, they got their aflibercept injection that was mandated. And then you can see the OCTs remained very stable until week 52, where you can see activity, you can see some intraretinal fluid and subretinal fluid. And that time, patients received a supplemental injection. Again, showing that this technology is really helping patients control disease with extended durability. Looking at another patient, which is on Slide 11. You can see this is a 65-year-old female with anti-VEGF given every 4 to 8 weeks prior to study and this patient has been rescue-free through 1 year, looking at central subfield thickness, again, very stable central subfield thickness. You can see that patient had increase initially and with injections, it was stabilized, and then after OTX-TKI, the CSFT stayed stable. In terms of visual acuity, some fluctuations, which we can see in real world from patients' effort and other parameters, but again, within range. And you can see we have stable visual acuity up to week 52. Again, looking at the OCTs on the right, you can see active disease with the red area on the grid, all around the fovea. When you look at OCT scans, you can see there is thickening. There is subretinal fluid, the black line under the retina showing active disease. At baseline, patient was controlled with no fluid. They received OTX-TKI. 4 weeks after, they received a mandatory aflibercept injection. And you can see this patient has done really well over time, up to week 52, really showing the benefit of OTX-TKI in patients with neovascular AMD to achieve stable vision, stable anatomy and having good safety. Going to Slide 12. In conclusion, what we have seen at the 12-month data that OTX-TKI maintained vision and CSFT compared to aflibercept every 8 weeks with a 89% reduction in treatment burden over a 12-month period. Safety showed OTX-TKI was generally well tolerated. The implant observed to bioabsorb over time completely at about 8 to 9 months, informing that potential redosing time line. What we have seen here that the data from this trial supports the characteristics of a potential treatment for neovascular AMD with durability between 9 to 12 months after a simple single injection of OTX-TKI implant which bioabsorbs completely in patients. So with that, I'm going to pass it to Dr. Peter Kaiser to give you an overview of the program.

Thank you very much, Dr. Khanani -- the great presentation, and thanks for all your work on the study. I want everybody to switch to Slide 13, which really shows how we feel the U.S. trial supports the use of OTX-TKI. As a practicing retina specialist along with Dr. Khanani, we would look at using the OTX-TKI after we've maintained and gotten controlled fluid with any anti-VEGF agent of choice than it had shown, especially in the case cases where once the fluid is controlled, we then placed OTX-TKI on board, and that allows us to maintain the fluid status and vision. In this study, we know that by doing this and using OTX-TKI, we could have outcomes with central subfield thickness and visual acuity comparable to be using the gold standard of just EYLEA every 8 weeks. As we mentioned at the 10-month data release, about 73% of patients were rescue free. We also knew that the drug would eventually wear off. And as we hoped, we would see that these are not patients who are simply dry and needed no treatment, these are actually active patients. And as the drug wore off, we would expect to see more rescues. And in fact, that's what we saw, especially at month 12, where there were 4 additional rescues. This led to a rescue-free interval of about 60% up to 12 months. And at the 12-month period, accounting for the patients who are actually treated at that 12-month visit, we still had an 89% treatment burden reduction compared to the previous 12-month period. So occasionally, we would need to supplement with anti-VEGF, but we would anticipate maintaining the fluid status with OTX-TKI and then reinjecting as the patients needed treatment as the drug started to wear off. If you looked at Slide 14, we would hope, based on the results of this 12-month study, to continue our development in wet macular degeneration. We are prepared to initiate a Phase III clinical study as early as the third quarter 2023. I would also note that we have completed enrollment in the HELIOS study. And if you switch to Slide 15, you can see that this study was a U.S.-based double-mask multi-sector randomized study in patients with moderate to severe nonproliferative diabetic retinopathy without diabetic macular edema. This study was enrolled very quickly. And the patients were randomized to receive either a single OTX-TKI implant or a sham injection and then were followed over time. And the key outcome that we were looking at in this study is the improvement in diabetic retinopathy severity score. As you know, this is an approvable endpoint used in other studies for diabetic retinopathy, we expect the 6-month interim data to be presented in the early first quarter of 2024. So we're very excited about the use of OTX-TKI in both the age-related macular degeneration as well as diabetic retinopathy. And I'll turn it back over now to the operator, so we can take some questions.

[Operator Instructions] And our first question comes from Dane Leone with Raymond James.

Great. Congratulations on the data. One question for me. When you look at the 12-month data and just the time course of fluid control with the OTX-TKI administration, is it plausible or something that the team should consider in future clinical work to perhaps try a second administration of OTX-TKI without a standard of care injection, meaning that once you do the run-in shot, give OTX-TKI, the first time, there's somewhere around a 9- to 12-month mark where you could administer the drug product again and actually omit the need for another standard of care injection?

Thanks, Dane. I mean, that actually is the product vision. And the idea is that you would get dry, you would induce with antibiotic therapy. Once they're dry, put them on maintenance therapy and they stay on maintenance therapy for the rest of their lives with need for supplements only on an as-needed basis. So we're looking at time horizons and dosing intervals of when we would, in future clinical trials, do redosing to obvious the need for continuous delivery of antibiotic therapy. So yes, we're actually considering that. We're thinking about -- this gives us great information in the trial that we have now to look at what a redosing interval look like. So we will definitely plan that moving forward.

Our next question comes from Jon Wolleben with JMP.

A couple for management and then one for Dr. Khanani, if I may. The first, can you talk a little bit about the timing of the hydrogel resorption in the patients that needed these late rescues versus those who didn't? Just wonder if there's consistency in quicker hydrogel resorption in patients that had retinal fluid versus those who didn't. And then can you give any more color on the IOP elevations that are new here, the 2 new cases?

Jon, this is Rabia. The hydrogel bioresorption is not related to when the patients are rescued. We -- what we have seen is that consistent resorption of the hydrogel, it's around 8 to 9 months, majority of the patients, be it a month earlier or a month later, in some patients, very few patients. But -- and also [indiscernible] which provides that continuous -- the effect -- the continuous effect a little bit more to provide a potential resolving window. That's why the rescues and the hydrogel bioresorption is not related. For your second question, the IOPs, I'll just start, and I'll just ask Dr. Khanani to continue. Those 2 patients were about a year after the implant was injected. And in one patient, it was in both eyes and there was low levels of increase. And if you -- please, Dr. Khanani, just on your patients, if you would like to just put more color on that?

Yes, Rabia, absolutely. The little change in IOP in both of my patients was not concerning at all. This was unrelated to OTX-TKI. As Rabia said, one patient had bilateral slight increase in IOP. But since this is my first experience with OTX-TKI, we actually looked for several things. We looked -- we did gonioscopy to look at the front of the eye. We did thickness of the cornea on both eyes. So we did things to make sure that we are not missing any safety signals. And we didn't see anything. So patients can have some fluctuations in IOP depending on the time of the day. And really both of these patients had no issues, and they are being followed in after the 12 months, and they have not had any issues with IOP. So unrelated, happens sometimes with the patients, and I'm not concerned. Back to you, Rabia.

Thank you so much, Arshad. Jon?

Yes, that's helpful. And Dr. Khanani, you mentioned that you've been involved in trials for all the TKI candidates. Can you talk a little bit about what you've seen from this class of drugs and how you think OTX-TKI compares?

Absolutely. So I think there are a few things that I have seen. I was involved with the GrayBug study in the past with many patients in that trial also. I think the main thing is that we need to have a platform that's safe. We need to have an implant that bioabsorbs completely. And we need to have a drug that actually works. So as a class, I have seen that it does take some time for tyrosine kinase inhibitors to kick in because they have effect intracellularly, they are pan-VEGF inhibitors. And so I think that's why we had that mandatory injection a month after, so that we give coverage for the first 4 to 8 weeks before the TKI starts working. So I've seen that as a class, and that's why Peter was alluding earlier that we will give injections in the acute phase. And then once the patient is stable before or around that time, introduce OTX-TKI and you're able to control disease. And that's actually the paradigm that's being used for all sustained delivery. We did that for port delivery system. We are doing that for gene therapy trials where we want to make sure that patients get stable before they start getting the benefit of sustained delivery with the technology. So that's -- so a few things, implant bioabsorbs, as you remember, we saw particle dissipation all over the vitreous and in the front of the eye with the Graybug program and that's not the case here. The implant bioabsorbs and the drug sometimes is still present after the implant is bioabsorbed but it's stationary in the area of injection, which is great. That's why we have not seen any safety signals. In terms of efficacy, I can compare this to what I saw with the Graybug study, where we did see some efficacy, but it didn't last as long as what we have seen here. So I think also having axitinib as the drug that has the highest affinity when you look at the OTX-TKI class is helping the patients. So those are my experiences from being an investigator in the OTX TKI versus GrayBug.

Our next question comes from Albert Lowe with Piper Sandler.

This is Albert on for Joe, and congrats on this nice-looking data. Maybe just for my first question, I was wondering for this additional follow-up for these patients past -- week 52, what your plans were to share any additional observations from this extended follow-up?

Thank you. This is Rabia. Thank you for your question. The follow-up with TKI patients after week 52, and the reason is to -- we have still some patients in the trial and still not rescued, just see the effect -- the efficacy, how long it's going to persist. And the reason is that longer [indiscernible] for the TKI. That's why we're going to be seeing and reporting on the safety and also the further efficacy of the TKI.

Okay. Great. So I guess we can expect to hear from that at some point in the future?

Yes. We are heading to do presentations. Depending on them, we complete the follow-up on those patients.

Okay. Great. And -- I was wondering, how do you think the rescue-free rate that was observed here in this -- end of these clinical trial conditions would maybe compare and translate under real-world conditions?

Well, first of all, I think we need to think of rescue rates differently with continuous therapy than we do with antibody therapy. And I think rescue rates are a obsession with antibody therapy, in part because when you rescue a patient, you truly are rescuing them because there is no drug, continued delivery within the target tissue -- to the target tissues, with an antibody therapy. So you really are rescuing the patient. From our standpoint, we're giving a continuous drug delivery for 9 to 12 months, and you do need a top up or a supplement of a rescue medication in that period. It isn't a clean rescue in the same way as you have in an antibody study -- sorry, in an antibody approach. So we had a patient, for example, that was supplemented around month 3 or 4, and then continued through week 52 without the need for additional supplement. So with the background of continuous therapies, the way you react to fluids -- some increases in fluid may be different because you know you have drug on board. So we use rescue rates because that's what the industry is used to. We think of -- if you look at the revised model and the high dose EYLEA treatment, they're really obsessed on this idea of how many patients you can get to a certain time period. And that's really about gaining the time to disease reactivation after the drug has already left the vitreous. So we'll continue to look at those rescue rates. But really, the more important thing is injection burden. And that's where we really think that we'll try and move the goalpost to look at injection burden and also look at retinal variability. So as you look at the central subfield thickness line in the OTX-TKI arm, as Dr. Khanani mentioned, you don't get that subfield pattern. Now that subfield pattern is a need. So you look at the individual responses that drive that subfield pattern, you actually get quite a lot of variability in the retina when you use immediate-release pulse dosing in antibody therapy. You don't get that with that individual variability with a continuous dose product. So we'd like to move this [indiscernible] in the future to injection burden. And to work on some form of metrics, it really looks at the variability of the -- variable thickness of the retina over time because we do think that, that variable is good data to show us that the greater the variability, the worst the vision outcomes.

Our next question comes from Colleen Kusy with Baird.

Great. So on BCVA, it looks like a 3-letter difference at 12 months. If you do go the noninferior route for the pivotal, what do you understand to be the margin for BCVA? How many letters worse than EYLEA would you -- can you be and still be noninferior?

This is Rabia. I can -- those are -- yes, I mean, the noninferior routes, the -- it is very clear in the very -- like, recently established guidelines, is if you use the Lucentis, then it's 4.5 letters. And if you use EYLEA and your competitor, that's 4 letters. The -- that's why currently, what we are seeing in our trials, BCVA wise, we cannot comment on noninferior -- being noninferior because we don't have the numbers to make that claim. But we can say that those numbers are very comparable.

Okay. That's helpful. And then just...

I want to add that, Colleen. I mean, I think it's pretty clear that getting out to a 52-week time point that we would need to consider redosing. I mean, what we do get is the central subfield retinal thickness, you really start to see a separation by week 52. And clearly, it's a precursor to vision loss. So if we kept running this trial out for another 4 weeks, you would start to see, I believe, a difference in BCVA start to open up. But when we look at this from the pharmacodynamic data of this trial, which matches the pharmacokinetics that we expect in the target tissues is that we would need to consider redosing for a 12-month time line.

Okay. Got it. And then those 3 patients that were rescued for the first time at 12 months that they didn't meet the criteria, but they were rescued based on physicians' discretion, do you have a sense of what was going on with those patients? And do you think that, that was like true disease kind of recurrence in those patients, even though they didn't meet the criteria?

That's a perfect question for Dr. Khanani.

Yes. So what happens is we are watching these patients in extension, but it's standard of care extension, essentially. So when a patient finishes the study, the option is -- we know these patients have neovascular AMD, should we just give a treatment now so they don't have to come back as often as they were in the clinical trial? Some of these patients -- I have one patient actually using this trial that moved 6 hours away and flies in and again -- and gets seen. So it depends on multiple things, why we treat the patients once they finish the study. It's more like the paradigm we have in the real world where we treat and extend to kind of decrease treatment burden. So that's why these patients were treated even if they did not meet the criteria for treatment because in the extension phase is standard of care and the study finished at month 12 in a controlled setting.

And if I could add, we showed you one of the patients who -- on Slide 10, I believe, it was that basically was rescued at the 12-month interval. And this is a really great patient. The reason it's great is the patient had a lot of treatment burden prior to the enrollment in the study, did very well. And then at that month 12 visit, you can see obvious fluid coming back. Now most companies when they have polymers or other types of things who are trying to sort of limit rescue will require both a loss of vision and an increase in OCT. In our case, we allowed the investigator discretion to treat. And in this case, they had still a gain in vision. So they didn't really meet any criteria, but there's obvious fluid and to investigate correctly injected at that point where you could see that the drug is really wearing off, in this case, probably somewhere at that 11- to 12-month time point. You can see at 11 months, they were doing fine and then the fluid started to come back, indicating the sustained nature of the anti-VEGF TKI. And as that wears off, the patient needs treatment. And as Antony mentioned earlier, probably in clinical practice, we would be reconsidering reinjecting with it some sort of TKI at that point, maybe it's 11, 12-month time point. And in the future, we'll have home OCT to help us guide this. We'll actually be able to see these sort of changes in fluid fluctuations without really having a patient come in for that. They'll do it at home, so it will be nice in the future.

Our next question comes from Tara Bancroft with TD Cowen.

Congrats on the data. So my first question is -- what is the biggest factor after these data now that a partner would need more information on? Is it the MC or something else? Just curious to get your thoughts there.

Well, I mean, obviously, this data from a drug developer standpoint is much more exciting than the month 10 data because what you want to see when you're developing a drug is that the pharmacokinetics and the pharmacodynamics line up. And as we've been telling the market and showing our people investigating this compound that our insert bioresorbs at around 8, 9 months. We have a release of [indiscernible] into the vitreous, which lasts for another couple of months and then begins to clear by month 12. So we -- the difference is -- the increase in rescue rates is one thing, but really the separation in central subfield thickness is what demonstrates that these people really are having disease reactivation when the axitinib clears from the vitreous. So that is very exciting for growth developer because you want to have those things match and want to feel excited about what the future looks like. We just got this data about a week ago and just dropped it into the data room. So the response from our -- the people that are in that data room at the moment are yet to be seen. Clearly, they're looking at the data now and they're absorbing it. But we feel obviously that's a key piece of information that they would need in order to really feel confident in being able to enter pivotal programs in diabetic retinopathy and wet AMD.

Our next question comes from Chaitanya Gollakota with H.C. Wainwright.

This is Chaitanya on behalf of Yi Chen. Congratulations on the data. The first question is regarding the ideal target patient population. I know you mentioned extensively about OTX-TKI as a potential maintenance therapy. Is that where you would ideally like the product to be used upon commercialization, essentially patients with controlled fluid and perhaps without active disease? And then I also have a couple of quick follow-ups.

I'm not sure I got all that question. The sound, at least where we're sitting, it was a little bit difficult. But I think this goes back to the vision of what we see this product and what continuous delivery of anti-VEGF therapy and how it would work in practice. I think it would be good for maybe Dr. Kaiser or Dr. Khanani -- maybe Dr. Kaiser, you can start and sort of suggest how this would work and what type of patients you would use it on?

Yes. I mean, there's -- as a retina specialist, to me, it's sort of intuitively obvious where I would use this product, which is control my patients with anti-VEGF, but as any patient or a caregiver of a patient will tell you, is there any way to reduce these injections but keep the same efficacy, and that's the most important part, keep the same efficacy. Of all our real-world studies of anti-VEGF, the patients do really well at the beginning, but then there's patient burnout, there's caregiver burnout, there's the people that are giving them taking a day off and giving them rides to the appointment burnout and the number of injections go down. And any time that happens with anti-VEGF, the visual acuity results get worse. The hope is to use something like OTX-TKI after the patient has done really well on anti-VEGF, they're controlled. Give them the TKI, watch them theoretically with home OCT and then as we start to see the fluid returning, bring them in for another injection of the OTX-TKI. And by doing that, maintain the vision gains that we had achieved early for an extended period of time, but dramatically reduce the number of injections. If you told the patient, look, I need to do this every 9 to 12 months, they're like, yes, sign me up. This is fine. But when you tell a patient, I need to do this every 2 to 3 months, that's when burnout occurs. So the hope is to have just better outcomes long term using a product such as this.

Yes. And if I can add to what Peter just said, I agree with Peter completely. When people are looking at the uptake, I think this is an injection that's going to be available essentially for all patients with neovascular AMD. We have the port delivery system. Now obviously, it's recalled, but that was a surgical treatment. So it was difficult to justify in patients who are going 3 or 4 months already with anti-VEGF. And so that has a small subset of patient population that could be treated. But here, we have a simple in-clinic injection, the hydrogel bioabsorbs completely. So this should be given, in my opinion, as Peter said, the burden is high even with every 2- or 3- or 4-month injections. So this can be a therapy that can be given to essentially all patients to extend their durability and decrease their treatment burden and then give supplemental injections as needed, and that's the variability, right? So patients are variable in terms of their disease. And if we can have a baseline level of control in all patients and then we supplement them as needed based on their individual disease activity, that's how I would think about this platform to decrease treatment burden to have better control in anatomy and hopefully have better outcomes in terms of visual acuity for our patients with neovascular AMD.

That was very clear. And lastly, one quick one for the management. Could you comment on the expected cost for those pivotal studies, please?

Yes. We've laid that out. There are 3 approaches moving forward that are viable approaches that we believe that have a high probability of success and we believe that they would be acceptable to the FDA given the new draft guidance. There are 2 approaches in wet AMD. One is the noninferiority trial that would look very much -- the 2 treatment arms would look very much like the trial that we're discussing today, with an additional arm for masking purposes because sham is no longer recommended by the FDA. We would expect 2 trials, so it would be about 900 patients in -- per trial. That looks upwards of probably $300 million to -- for NDA applications. There is another possibility of a superiority trial that we believe would be far less expensive because we think that we could see bigger differences between a single dose of an on-market -- currently marketed product versus a single dose of OTX-TKI. Clearly, we know that we've delivered drug continuously for 9 to 12 months. We know that any comparator antibody drug would be out of the eye by about 2 months, that we could see a separation superiority in a relatively short period of time, and that difference would be fairly profound. That trial has issues that make it difficult to execute. But we do believe that, that is an executable trial, whether we choose to take that path is another question, but that would be significantly less expensive because it would have far fewer patients necessary to execute that trial. So that would be more along the lines of $50 million per pivotal or $100 million [indiscernible] NDA. The final pathway that we're considering is the diabetic retinopathy approval, which would be fairly similar in size and actually in structure to the superiority trial in wet AMD. And that would be a trial that we could, I believe, easily execute that we would get a lot of support from local key opinion leaders around and an area that we believe we could open up a market environment that does not exist today. Because when you look at diabetic retinopathy, well, the end point is about the improvement of the severity score. In fact, the reason why you would treat diabetic retinopathy would really need to prevent disease progression to prevent proliferative disease. And when we have current therapies, which are pulse dose antibodies. The one thing you really would not want to use pulse dose where you have very high concentrations and then the drug leaves the eye and then you dose it again, would be in a prevention paradigm. Continuous dosing of an intracellular drug like TKI on a 9- to 12-monthly basis, we believe could open up that market in a very substantial way. I remind you that there are a very, very high number of patients suffering from NPDR, about 8.5 million in the U.S. and about 3 million of those have -- are on the more sort of severe end of that spectrum. So that's -- all of these pathways we see are viable, and we're working extremely hard now to kind of decide which one we think is preferable in a go-it-alone scenario. Because clearly, we are -- we have partnership discussions ongoing, but you cannot plan our future with a partner because it takes -- you can't say yes to a deal you don't have. And right now, we don't have a deal. So we are plotting our future to do this without partnership. If we're lucky enough to receive a term sheet that makes us reconsider that pathway, then we will do that and make a decision that's in the shareholder interest. But we're blazing ahead with those 3 options moving forward and thinking about how we would do it if we were to go alone, and then speaking with partners about how they would do it if they were to join us in the development [indiscernible].

[Operator Instructions]. Our next question comes from Caroline Palomeque with Berenberg.

Congrats on the data. So my question is just when you're thinking about pretreatment, the patients that come in having been pretreated with Lucentis or EYLEA, I'm just wondering, are there any trends that you're seeing that as to how that pretreatment affected being treated with OTX-TKI? I mean, just looking at the data, it seems like many of the patients with EYLEA and Lucentis did not get rescue, but then some of them had several different products that they were pretreated with. Just wondering if you could just talk about how it has affected results.

I think Dr. Kaiser might be a good one to answer that.

Yes. So we didn't really -- obviously, the study doesn't have a lot of patients to be able to make any determinations if there's a variability in the response rate, depending on what patients were treated previously. However -- the way EYLEA, Lucentis, Avastin or even faricimab work is mainly by blocking VEGF A. And for the most part, the response rates are similar. So if you look at any of the clinical studies with anti-VEGF, not one is any better than any of the others. So to us, we don't anticipate that there'll be any variability in response. I mean, this blocks all of the VEGF receptors, in particular receptor 2. And so because of that, we would expect to have a similar result irrespective of what anti-VEGF the patient was on previously. I'd also point out that the Australia study shows -- to me, the Australia study really shows the benefit of this. The U.S. study showed that we can use this as maintenance, but the ability of this drug to treat treatment-naive patients, which was in the Australia study with no anti-VEGF at all is actually very exciting. Now I'm not saying that, that's how we would use it. I maintain that we will use it the way I mentioned earlier. But the fact that even with fluid, we can eliminate that with just the TKI and OTX-TKI is actually very exciting from a physician standpoint.

Okay. Great. And then just a quick follow-up. I'm just wondering if there were any updates on the FDA conversations that you're having?

There are really no updates. We've been pretty clear for a while now about what the FDA would accept. And those 3 pathways that I mentioned, we are highly, highly confident that we have protocols that the FDA has seen and that they would accept if we decided to move in those -- in any one of those 3 directions. So there's no update. I don't think any update is necessary. I mean, we're hoping that maybe some of the endpoints can be adjusted moving forward, particularly -- and we'd love to be able to work toward a fluid end point rather than a BCVA endpoint because that's more in keeping with the way current practice works in the -- particularly in the U.S., where doctors really treat to minimize or eradicate fluid rather than wait for vision loss. But I don't expect there will be any changes within the FDA or the feedback that we've gotten from the FDA and that we really have enough at this point to understand how to move forward.

There are no further questions at this time. I'd like to turn the call over to Antony Mattessich for closing remarks.

Yes. Thanks, everyone, for attending the conference, and certainly, thanks, everyone who spoke and was able to answer questions. We are extremely excited about OTX-TKI. I assume that comes through in our voices and our excitement with this trial. I've been involved with drug development for 35 years now. And when you see that the pharmacokinetics and the pharmacodynamics match on a product, it is both tremendously exciting and feels also a tremendous sense of burden, because you know that there is a drug in here somewhere. And it's a question of how you unearth the potential of that drug within the framework of how physicians' factors what patients and payers expect. And obviously, all important is what the agency allows you in terms of a pathway to approval. So as we work through those issues, we try and please all of those groups, not to mention our investors along the way. We are very excited to have such a level of interest and enthusiasm among the investment community and scientific community. And we're helping them -- we're asking them to help us think through this as well. But we are very excited about this moving forward, and I want to thank everyone who spoke today and everyone who is online for joining us in this very important moment for Ocular Therapeutix and patients suffering from wet AMD.

Ladies and gentlemen, this does conclude the program. You may now disconnect. Everyone, have a great day.