Great. Welcome, everyone. I'm Yigal Nochomovitz. I'm one of the biotech analysts here at Citi. This is our panel on next-generation retinal therapeutics. It's my great pleasure to have with me today, from Aerie Pharma, Vicente Anido, who is the Chairman and CEO. From Aldeyra Therapeutics, Todd Brady, the CEO. From Opthea Limited in Australia, Megan Baldwin, the CEO. Welcome, everyone. Thank you so much for taking the time to participate in our panel. I think as a starting point, since some of the listeners may be less familiar with your companies, why don't we just do a two to three-minute intro for each of you as to what you're focused on, what the pipeline is at your company, and maybe one or two of the key upcoming data points. Maybe, Todd, you want to kick it off? Let's do it, Yigal, and thanks for having us on the conference today. Aldeyra is an immunology company at heart. We've started out in the eye, I guess hence our presence on the panel here today. Our lead product is an anterior segment disease, front of the eye inflammatory disease. We've expanded to include now numerous retinal programs, which feature heavily in our late-stage pipeline. Finally, we have a variety of earlier-stage programs, not only in systemic disease, but also in novel retinal therapeutics that I hope we'll get a chance to talk about later. Perfect. Megan? Good afternoon, good morning, Yigal, thanks for the opportunity to participate today. Opthea Limited, we're a dual-listed company. We're based here in Melbourne, Australia right now, listed on the ASX, listed on the Nasdaq, building out our team in the U.S. We have a portfolio of intellectual property around members of the vascular endothelial growth factor family, and we are specifically focused on VEGF-C and VEGF-D. We're developing our lead asset, which we call OPT-302. It's a trap molecule, actually not dissimilar in structure to Eylea. Very much binds VEGF-C and D with high affinity. We are looking at the development in wet AMD as our main focus. We currently have two pivotal phase III clinical trials that are ongoing right now. They're global clinical trials called ShORe and COAST. We're looking at the efficacy of OPT-302 administered in combination with both Lucentis and Eylea in order to determine the additive benefit, the ability to actually improve visual outcomes for patients with wet AMD. We expect the readout of those clinical trials in the second half of 2023. They're progressing very well right now. In the background, also very interested in developing a co-formulated form of OPT-302, which would, of course, provide the convenience of a single injection to deliver the VEGF-CD inhibitor with a VEGF-A molecule. Look forward to discussing that further with you today, Yigal. Great. Vicente, you want to give us a quick snapshot for Aerie? Sure. Again, thank you for the invitation. Aerie's an ophthalmic pharmaceutical company. We came out of Duke University back a number of years ago. We actually have two products on the market for the treatment of glaucoma, two eye drops. They've been on the market now for two or three years, respectively. Run rate's just over $100 million-$115 million. We're in pretty good stead there. We have our own sales force here in the United States. Ex-U.S., we've been moving forward with partnerships in both Japan. We expect to finish in a partnership in Europe for our glaucoma franchise. We hope to do that before the end of the calendar year. On the pipeline side, the most near-term project that we have is over the next couple of weeks, we will be reading out on our dry eye asset. It's a company we acquired a number of years ago from Spain. As the program is designated as AR-15512, it's a TRPM8 agonist, which is a cold-sensing receptor in the eye. We'll read out a big phase II-B trial, again, like I said, over the next couple of weeks. On the retina side, we actually have three shots on goal. Our nearest term program is, we reported about a year or so ago, phase II-B results on what we call AR-1105, which is a dexamethasone insert. Using our 3D printing, which allows us to use various polymers and deliver drugs any way we want to for as long as we want to, we were able to show that we had six-month efficacy. We're very pleased with that, and we'll be moving that into phase III before the end of the calendar year. Then we have two other programs. One is AR-13503, which is a Rho kinase, protein kinase C inhibitor that we're studying for both wet AMD as well as neuroenhancement, which is a big deal in glaucoma patients who have lost their eyesight. That's in very early stages. Then, this year, we added a small molecule VEGF inhibitor, axitinib, to our program, using, again, the 3D printing and various polymers to deliver that drug for about a 12-month period. We're excited about the prospects not only of our in-line products, but also our pipeline. Great. Thank you, Vince. Obviously, you're all engaged in clinical trials across the spectrum from early stage, phase I, through to the late stage, phase III. I'd be interested from each of you to give us your thoughts as to how you can design the phase I and phase II trials effectively, to support a positive phase III readout. Are there specific or classic pitfalls that you should avoid when it comes to designing ophthalmic trials? Todd, you want to give us your thoughts on that? Well, I think the secret to phase I and phase II trials is gathering data, as much data as you possibly can. I think some companies make mistakes where they're looking at one endpoint or two endpoints. In the early stage of our business, I think the goal is to gather as much data as possible. This particular division of the FDA is interested in symptoms and signs. I always advise other companies, as well as our own development team, if you're going to look at endpoints, include symptoms and signs in those early stages of clinical development. In terms of pitfalls, I think sometimes we learn too much from too little data. These trials are small, they're often exploratory, and then we rush into exceptionally large trials thinking we know the answers to all the questions, and that's generally a mistake. That's probably true not only in ophthalmology, but in development as a whole. I think by and large, though, the industry does a good job with early-stage trials. The beauty of ophthalmology is that you can generally enroll a lot of subjects. The demand for new therapies in ophthalmology is high, and overall, I've been pretty pleased with the industry in aggregate in terms of generating early-stage data. We need more innovation, Yigal, as you know. Understood. Megan, what are your thoughts? You did an important phase II trial, which you then used to develop your phase III strategy. Yeah, no, absolutely. I agree with what Todd said. I think in your early-stage clinical trials, it's gathering as much as you possibly can, going pretty broad on the endpoints. I think as much as you can, you want to keep your eye focused on the endpoints that you'll ultimately need to be interrogating in your later-stage clinical studies. As much as a read that you can get on those, I would encourage companies to sort of focus on those. I think it's the entirety of the data that you need to be looking at in that early-stage setting, That's where you want to have your anatomical endpoints as well as your visual acuity endpoints, because you're going to be, by the very nature of the early stage of the study, underpowered probably across multiple different endpoints, It's the totality of the data that you're going to be looking at. In terms of informing as you move forward, I agree with Todd as well. I think that even when you go into large phase II, you want to still try to gather as much information as you possibly can. We certainly had that experience in our phase II-B clinical study. We recruited very broadly, and it was incredibly informative, and we've been able to take a lot of learnings forward into how we'll analyze our phase III clinical outcomes because we went very broad and understood a lot now about what are the best responders to our therapy that we can incorporate with really not compromising too much in our phase III at all. I think it's really learning as much as you possibly can, but doing it in a smart way and then applying it in the right way in your later-stage clinical studies that'll stand you in good stead. Pitfalls, I think limiting the heterogeneity of your patient population and making sure that you try to understand the limitations around heterogeneity and the criteria that you'll need to apply for your late-stage clinical studies, so there's a consistency, at least in the patient populations, moving through from early to late stage to the extent that you can. Okay, got you. Vince, did you want to add anything? Sure. In our space, where we have glaucoma as well as dry eye, as well as back of the eye, it really all depends on where you're studying. Glaucoma is relatively straightforward. One of the interesting facts is that every drug that has made it through phase II has been approved, and so it's very predictive. The other opposite end is dry eye, where you do 1 study, that's all you've done. You've got to replicate it. We've got plenty of companies that have had successful trials, and then they have to do two, three, and I think an old company, Inspire, has a record of running eight trials in dry eye and ended up failing and closing shop. Again, you have to make sure, like Todd said, you have to learn as much as possible in the early clinical trials because that'll dictate not only the endpoints you can pick but also the time points because the FDA is incredibly flexible about what you can do in the phase II-B trials or the phase II trials. On the retina side, it all depends on whether you have a known molecule, like we have two of them, dexamethasone as well as axitinib. We know how much of that we have to deliver. We know what their activity is and what to look for. Our challenge is to design the insert so that we can deliver them over the period of time that we want the efficacy. All of our studies are designed to do that, and typically we can show that in the phase II-B trials. It's relatively straightforward on the retina side on how to do that. On the opposite side, on the retina side, is when you take a drug like we have on the Rho kinase protein kinase C inhibitor, where we just don't know yet how much of that active we need to deliver to the back of the eye to get the activity that we're looking for. We're designing all of the early clinicals of phase I and phase II as a proof of concept to really figure out how far down the path we can go. The good news about retina is we've got plenty of markers, and the retina guys don't mind telling you what it is that they need to see and in what kind of time frame to determine whether they're on the right path or not. We design our clinical trials that way. We do include Europe a lot in our clinical trial design, and so what we're finding is that harmonization is nonexistent, so they don't agree on anything between the FDA and Europe. Certainly, PMDA doesn't agree on much either. You really have to kind of thread the needle from a protocol point of view to try to encompass that. We notice that in spades as we try to get the dexamethasone protocol finalized, because the primary market for dexamethasone inserts or steroid inserts is in Europe. Yet we want to introduce it in the U.S. as well. It's been an interesting challenge for our regulatory and clinical folks to come up with the right protocol that'll handle both markets. Great. Well, you touched on some important themes related to the regulatory landscape, which I'll get to in a minute. You mentioned endpoints, I think all of you mentioned endpoints. In terms of the relative weighting between an anatomical and functional endpoints, does that balance change as you move from, say, phase I to phase II to phase III? Do you always attempt to keep a focus on both anatomical and functional endpoints sort of equally weighted? Todd? Yeah, I think there's anatomical, there's functional, and there's symptom. All three can be relevant. I know that in the retina these days, the FDA has placed more importance on anatomical endpoints, which I think is fine. I encourage our own staff and would encourage my colleagues in the industry to focus on symptoms as well. If patients aren't feeling better, if they're not able to detect a change in vision or something that improves the quality of life, I'm generally not in favor of measuring it, or at least basing approvals on endpoints that have no relationships to how patients feel or function. I do think that, as we were just saying previously, learning as much as you can in the early-stage trials is important. Whatever the endpoint is. If you had told me two years ago that we'd be in phase III looking at ocular redness in a chamber for dry eye disease, I would've said, "You're crazy. That's not something we're going to do." I sure wish we'd figured out a lot sooner that reproxalap, which is our lead asset now in phase III for dry eye disease and allergic conjunctivitis, worked acutely and in a chamber setting. That gets back to learning as much as you can in the earlier stage trials. I do think redness is important, that it is technically a sign. It's something that patients care about. None of us want to have red eyes. There's an example of a sign, technically, not a symptom, but a sign that really does matter to patients. As I mentioned, I encourage my colleagues in the industry to focus on signs that matter, not only to the FDA or physicians, but also to patients. Megan, do you have any thoughts in terms of functional versus anatomic endpoints and how that balance changes as you move through clinical development? Yeah. The way we've approached our early-stage and now our late-stage clinical trials is that vision is trumped, and we've always recognized that the regulators want to see the functional endpoint of vision changed. We've kept ourselves sort of firmly planted in really designing our primaries, at least around a visual acuity endpoint. That said, I think it is acceptable to have a greater focus on anatomical endpoints sort of upfront and center in your early-stage clinical trials, particularly if you can power a study around them where it's not necessarily able to be powered around vision because you need a much larger clinical trial. I think that's perfectly acceptable. The approach that we've taken is that I think the market and the regulators and the physicians want to see changes around visual acuity, particularly for wet AMD and the approach that we've got with a combination treatment. We've kept ourselves really focused on that. It's really important to have those secondary endpoints because I think everyone wants to see that the visual acuity is supported by anatomical changes that, of course, then validate the vision endpoints that you're actually seeing and the changes that you're seeing. They go hand in hand. Obviously as you move further along, you have to focus on visual acuity, at least in AMD, because that's how you're going to get your drug approved. Okay. Vicente, do you want to add anything there? We can move on. I think the FDA has been very open about making changes and taking a look at different things. They're far more open today than they were, say, five or 10 years ago in terms of allowing you to look at various functionalities of your drug. Certainly the doctors, as Megan said, really are looking for some functional change that dictates whether the drug is beginning to work or not, because especially on the retina side, they want to act quickly, even though it's a progressive disease, they want to act as quickly as possible. If they don't see an anatomical change relatively quickly that they're expecting to see, they know that they're on the wrong path with that drug, so they want to start something else. From an FDA point of view, it's still visual acuity on the retina side. Again, harmonization with Europe has always been tough because they allow you to look at other things, but still visual acuity is one of the big things that they're looking at. The thing that we have to think about is, again, from a balancing point of view is how much do we want to gather? Using our dry eye data, our phase II-B trial, we backed up the truck. We looked at everything you possibly can look at from endpoint point of view. We did pre-select a sign and a symptom at a particular time point, but we looked at multiple time points, multiple endpoints. Did it in both the chamber as well as in a normal environment, just to explore the art of the possible with the drug. You can't always do that on every side. Certainly retina, those patients are costing you a bundle. To try to do something that complex on a retina side with a small number of patients, is close to impossible. We do try to focus based on the disease that we're pursuing. Great. Well, a number of you mentioned the FDA, both the FDA here as well as the EMA in Europe. Obviously, the FDA is critical to the development of a ophthalmic drug. If you could talk about how do you leverage your FDA interactions to maximize the probability of success. I'd love to hear your thoughts on just how you and the FDA work together to achieve the best clinical trial designs that lead hopefully to approved products. I met Wiley when he started back in the 1990s when I was president of Americas at Allergan. Like him or not, the one thing that we learned over the years, and I've got a regulatory guy that's had something like 40 drugs approved by the FDA in ophthalmology, and if you listen to him closely, whether you want to do what he tells you to do or not, if you do what he says, you usually get an approval if your drug actually delivers. You may not want to do it that way. That's always been sort of the mantra. That's shifted over the years because the FDA ophthalmology group got moved around quite a bit. When he first started, it was part of Derm, and then it went part of the transplant group, then infectives, et cetera. Now, he's got his own standing group, which is terrific because now we've got a lot of experts that allowing us to do certain things. His guidance, though, ranges from very specific, like in glaucoma, he won't budge off of the intraocular pressure, comparing it to timolol. You can compare it against other things, but it's going to cost you to do that. Yet in other places like neuroenhancement for glaucoma patients that have lost their eyesight, he's very flexible. He's very open to looking at various things, whether they're functional or anatomic endpoints. It all depends on what the competitive landscape is and whether they've seen the activity before. We're finding him far more open in today's environment to listen to various arguments about how to move these drugs forward than it's ever been. Yeah. Todd, I'm sure you have thoughts. Oh, Megan, you want to go ahead. I was just going to say, I think I agree with everything that's been said. I think that the FDA can be very informative and provide a lot of guidance. I think, for the most part, if you take that on board, it stands you in good stead because you can get that guidance early on, and it's all documented and we haven't moved too far away from the standard expectations around a phase III clinical program, which is kind of nice in itself, right? We kind of know what's expected. There's a level of comfort in that. I do think that it's been good to receive the guidance. I just think you go early, engage early, get as much information as you can, even in your early clinical studies, and that's going to position you very well. You may not always hear what you want to hear, but the information you get will actually, I guess, de-risk any difficult conversations down the line with the FDA. We've tended to take it on board and then go back and, if we move from that, go back and confirm that the regulators are happy to the extent that they can be in the absence of you actually having the data. Yeah, early engagement is what I would say is the key to the regulators' engagement. Todd. I really enjoyed Vince's comments on Wiley Chambers. He's a true icon. Worldwide, I think the FDA ophthalmology group over the years has set the pace worldwide for innovation. I think, at least in our experiences, many other agencies across the globe follow this particular division's lead. Dr. Chambers has been there for 30 years, a true icon in every sense of the word. I agree with Megan's comments, too. This is a division that encourages early and frequent contact. I don't think it's a division, compared to other divisions that we've interacted with across the agency, I don't think it's afraid to think outside the box. As long as you have data, as long as you can support your argument with some sort of data, we found Dr. Chambers and his colleagues to be very amenable to thinking outside the box, especially in dry eye disease, which as we mentioned at the beginning of this chat, is a field that it really demands new innovation. Great. How do things look differently in Europe with the European regulators? I mean, is it very different or not so much in terms of how you have to interact with the EMA to get drugs approved in ophthalmology? Our recent experience, specifically on the retina side with the dexamethasone insert, has been pretty interesting. The surprising part, and really the only surprising part, there was no disagreement about endpoints or timelines or anything like that. It was the number of naive patients that they were insisting we find on the retina side. That's very unusual. It's a far larger number in terms of percent of the total patient population that we're going to be chasing than anything that the FDA has required. It really has put an awful lot of pressure on the clinical side and the CRO we selected because now we're having to go into countries where, in fact, we can find the naive patients. Because certainly in the U.S., you're kind of hard-pressed to go do that on as large of a number as the EMA has suggested. I think that there is a lot of agreement with the FDA, not only in Europe, but also in Japan, in terms of how to do the studies. What we're seeing is, at least on the retina side, for this first one that we're doing in Europe or in combination with the U.S., we're seeing the big discrepancy is the number of naive patients that they're expecting us to be able to get into the trial. It's no easy task and certainly makes enrollment a real challenge. Interesting. Anyone else wanted to add anything about Europe? We've certainly found the European, the feedback incredibly comprehensive and very, very helpful, actually. The written feedback is, at least in our experience, high quality and very, very detailed, very informative. I think we've been fortunate that we've actually been harmonized in the advice that we've been given from the Europeans versus the FDA. That's been nice. I think the Europeans do like to see you try to explore additional angles, but haven't been definitive that that's something that you absolutely must do. They've kind of tried to guide us around, encouraging us to, for example, look at extending out the dosing interval, reducing down the treatment burden, as well as demonstrating improved efficacy over and above standard of care. That kind of comes down to the whole pricing argument, the whole burden of care argument, and I think they're acutely aware of ensuring that you get the most out of your clinical trials, but not actually imposing that you can do everything necessarily in the one pivotal study. From our perspective, it's been harmonized, and it's been incredibly informative feedback that we've been able to walk away with it documented very, very nicely in written and then potentially follow-up conversations that we've taken down the line as well. I think, Yigal, the other thing is there's an increased emphasis on comparators in Europe, that you don't see as much here. Head-to-head studies, we started running some against Xiidra in dry eye disease carry a lot, I think, more weight than they do here, where the emphasis seems to be on placebo-controlled trials. It's also going to help you from a pricing point of view, because we ended up doing a phase IV trial of our combination drug in Europe. Because we found that the largest glaucoma products are all combinations, Europe has more combinations, prostaglandin plus timolol and prostaglandin plus something else than any other country in the world. What we found was doing a head-to-head comparison was a requirement not for approval, but for pricing. That's another added plus if you can do it. Interesting. Megan, you mentioned treatment burden, that sort of gets to one of my other questions as far as the thought process in terms of minimizing the treatment burden across for each of your drugs. I know you have drops in the case of Todd at Aldeyra. Megan's obviously an intravitreal injection. Vicente, you have potentially drops as well as intravitreal injections. Help us understand how you think about compliance risk and what you do to try to minimize the burden of treatment in ophthalmology. Well, on the eye drop side, we've got plenty of data that indicates that the drop-off in compliance, once you go beyond once a day, is pretty significant, especially in a disease that has no real symptoms, like dry eye. I mean, in dry eye, these patients are suffering, so if you can improve their symptoms, they will be compliant. A BID dosing there or even a TID dosing may not be a bad thing because they're used to putting artificial tears on 10, 15 times a day just to lubricate the eye, because that's all that was there. Again, we try to push everything to once a day, and our original founder, David Epstein, who was the Past Chair of Ophthalmology at Duke, was insistent that we not move forward with anything in glaucoma that wasn't once a day. That's what we did. What we're finding is, like in retina, it's a function of the reimbursement and the burden. We designed the original dexamethasone insert the last six months because the doctors are saying that's how often they want to see those patients back. Could we deliver it longer? Sure. Certainly, we can do it shorter. We could deliver it over a longer period of time, we picked six months because that's what they were going. Now, fast-forward a couple of years, with our excipient program, we're going to see a lot of competition from the biosimilars, et cetera. Pricing is going to become a bigger issue over time. We pushed that out for a full year because we think that if we can deliver that drug with one injection over a 12-month period, that lasts a 12-month period, that was the best thing to do, not only from a patient load point of view, but also from the reimbursement side. Yeah. I think I agree with Vicente. Compliance is a function of how important the disease is to the patient, especially acutely. A disease like dry eye, as Vicente said, where there are symptoms, patients often take those drops PRN. They take them when they feel like they need to, just like an artificial tear. On the retinal side, if a patient's going to go blind, we work on rare retinal diseases and have a plethora of them, but they all result in blindness to some degree, or certainly severe vision loss. If a patient knows that that's the outcome, that that's the end of their journey, compliance suddenly becomes a little bit less of an issue because no one wants to go blind. I think a challenging compliance case is the classic hypertension case, right? Patients don't feel bad. They don't feel like they're going to have a stroke in five years or what have you. Getting a patient to take a drug in that scenario is difficult. I think the other hard part about compliance is side effects. If drugs have side effects and the patients aren't feeling better acutely with that drug, as is the case in dry eye disease today with Xiidra and RESTASIS, there's a real challenge there because you're telling a patient, you're pleading with patients, "Stay on the drug, stay on the drug. I know it's not the most comfortable thing in the world, but trust me, in a month you'll feel better." That's a hard case to make. Yeah. I mean, we're looking at compliance from multiple different angles. I think from our perspective as well, I agree with Todd in the sense that if patients will come back if they want to optimize their outcomes, they don't want to go blind. From our perspective, we believe patients are going to come in, they're going to want to have the optimal response, and they're going to want to maintain that. I think there's been numerous surveys done that if you can maximize that early increase in improvement in visual acuity, that sets you up very well for better longer-term outcomes. Maintaining that over time is what's going to drive the compliance. In terms of delivery of our therapy, we're exploring multiple different dosing regimens, really to look at whether or not we've got equivalent efficacy on every four or on every eight-week basis. We fully anticipate, though, in the clinic post-approval that it will be treated as needed on an individual basis, just as the standard of care treatments are on a treatment extent, et cetera. It will be tailored to the patient to maintain optimal outcomes, and that is what's going to drive the compliance and getting the patients back in. I think the fact that many patients don't actually respond as well as they would like early on speaks to the fact that can also affect compliance and their motivation to come back in as well. If you can give them a better response early on, perhaps they maintain their adherence to their treatment on a much more frequent basis so that they can maintain and sustain the improvements that they're seeing. Ironically, the best way to generate an early response is more drug in many cases. Vince's comments about loading doses in these diseases make a lot of sense because, as Megan just said, if patients feel better quickly, they're going to stay on the drug. That makes a lot of sense. Obviously, you're all entering potentially very large markets, dry eye disease, wet AMD for Megan's company. Talk a bit about how you think about partnering. When would you partner? When does it make sense to partner? When would you potentially consider going at it alone? I know obviously for glaucoma, for Vicente, you're doing a good job independently. Curious for dry eye disease, Todd, what are you thinking as far as partnering, and then Megan for wet AMD, what are you thinking? I was hoping Vince would answer that question first since he's actually the one that's been through all this unlike the rest of us that can just talk about it. I divide the launch versus partner world into two sections. There are mass-market drugs. There are drugs that are going to be written by a large number of healthcare providers, in the case of ophthalmology, including optometrists. On the other side of the fence are rare diseases or specialty diseases. Many of them are retinal diseases where the commercial rubric is very different. There's not a direct-to-consumer, at least as much, for orphan diseases in the retina. It's more of an access issue. I think in that camp, small companies can launch and really even should launch in some ways because we all know the prescribers of those medications. They're the ones running our clinical trials. They're the sites in our clinical trials. In the former camp, I think companies should consider both launching and partnering. The good news in ophthalmology is it's feasible to launch in the anterior segment. Look at EyePoint, look at Kala, look at Ocular Therapeutix, look at Aerie. It's definitely possible, unlike large cardiovascular drugs or sleep drugs or CNS drugs or something like that. We're all fortunate that we have the opportunity to go both directions there, and Aldeyra is following both of those lines of advice. We're almost certainly likely to launch in retina. We hope to be filing NDAs as soon as next year in the retina with ADX-2191, which is our lead product there. For the anterior segment diseases, we're considering all options at this point. Yeah. I think it's about maintaining the optionality, as you said, Todd. I think in retina you can. You can set up a commercial organization prepared for launch with a relatively limited or at least comparably, you can do that with a reasonably sized team. It's feasible that you can undertake that even as a smaller company. I think it all comes down to your capacity to fund those activities, your capabilities in-house in order to do it, obviously, and then thinking about the timing. When is the right time to actually bring on a partner to maximize value for your patients, but also for your shareholders? All of those things play into the decision-making process. I think maintaining the capabilities that you can do it yourself, but remaining open to then accessing the resources and the capabilities of a partner makes perfect sense. Keeping all options on the table as a company is incredibly important because you just can't rely on one or the other necessarily. Yeah, ophthalmology is a little tougher to find partners because there aren't that many much larger companies that have the sales forces and have the capabilities that aren't already pretty full with their own products. That was one of the challenges when we launched this company. We'd done it before in another company where we set up our own sales force to do it. For generally in ophthalmology, all you need is 100 sales reps to capture about 12,000 doctors, including not only as eye care professionals, so you can do the high prescribers in both ophthalmology and optometry. You don't have to go all the way down to the lower deciles to pick up the huge number of docs there. On the dry eye side, it's kind of interesting. Again, not too many partnership opportunities, there are some. You can go down that path, or you can just simply focus on eye care, maybe expand the sales force a little bit, go down a little further and expand it from that perspective, and maybe find a partner that is just simply a co-promote in those therapeutic areas that may not be of interest to you. Like ophthalmology because of Sjögren's syndrome or the fact that there's a huge number of patients that get their dry eye prescriptions from OB-GYNs because of the post-menopausal women component that's driving some of that, et cetera. Again, there's plenty of options. We chose partnerships in Japan and Europe, even though we'd had success in clinical trials in Japan and got approvals in Europe, because Japan was an isolated case. You really have to introduce yourself as a company in Japan first. You can't just go straight through and introduce your first product where nobody knows you. Finding a partner like we did with Santen, who is the largest company in Japan in ophthalmology, was a great find for us. That was terrific. In Europe, even though we got approval for Rhopressa and ROCKLATAN, we decided to partner it. It was because any partner that we picked, and there's both Pan-European partners as well as a couple of global players that we talked to and are talking to, they can launch in all the markets right out of the gate. We couldn't. We would have to select Germany, we'd have to select some of the other higher value markets first, set up our sales force. It's almost like investing in a brand-new drug. I was going to be trading off commercial investments versus moving something else into the pipeline. We also moved towards partnering in Europe mainly because we think that the dexamethasone insert, AR-1105, will be a much bigger drug than our glaucoma franchise will. Certainly, with the number of retina docs in Europe, the cost to serve there is not as great on a commercial point of view. That's something that we can consider doing ourselves. I think for all of us, because funding is always an issue till we start making money, that partnership is always an important component of everything that we do. Whether it's get rid of some development expenses, you may end up having to make some choices. For us, if we ended up being a front of the eye company only and focus on dry eye and glaucoma and then partnered everything else in retina, we could live with that. If we decide glaucoma and retina is the right thing to do and partner off dry eye, we could do that. Again, I think the optionality that both Todd and Megan mentioned are critical to companies our size to consider. I think broadly, Yigal, small companies are better at innovation and not as good at sales. That's not always a good option, is just to innovate. I know Dicerna made the decision the other day not to market their orphan drug. It's in a different space, but you can make that decision, but you also have to have a good alternative, as Megan mentioned. The other thing that Vince said that I really agree with is OUS, and Megan, I apologize for OUS. I know that everyone outside the U.S. hates that term, but I think OUS is critical. As a small company, you're not going to run around the world launching sales force efforts. No matter what, partnering has to be in the mix. That's the perfect segue to my next question. You mentioned innovation. I'm getting a question coming in from one of our clients asking, could you talk a bit about what's going on at the discovery level in each of your respective companies? To the extent that you can comment, obviously. What are you working on in ophthalmology at the discovery level? Todd, you want to start? Yeah. We're, as I mentioned, sort of in the process going from the front of the eye to the back of the eye to the rest of the body. We do maintain a robust discovery effort in retina. Our lead target for reproxalap, which is our dry eye and allergy drug, is something called RASP, which is not only a new target, but really a new pharmacology. It's not a protein, it's not a receptor, it's not an enzyme. It's a whole class of inflammatory molecules that reacts chemically with our drug. Well, there's no reason that RASP should be relegated to the front of the eye. Now we're working on RASP in the back of the eye in the retinal diseases. RASP are interesting not only because they're pro-inflammatory, but because they're pro-aggregate. The components of lipofuscin or drusen in some cases really derive from RASP-mediated reactions. A RASP inhibitor would have two mechanisms, an anti-inflammatory and an anti-aggregate, and that's exactly what we're focusing on. The irony there is this company started, Aldeyra, out of Harvard, I don't know, back in 2004, and so from a retina group. For us, it's back to the future. We're committed to innovating in retina, and I think you'll hear more from us in that regard starting next year. Okay. Megan, I know you're very busy with the phase III's, but are you doing anything at the discovery level at Aldeyra at the moment? I think, as we've discussed in the past, we're very interested in looking at the various delivery options that we have around the key asset, OPT-302. That encompasses the co-formulation that we would like to be advancing through, which is the, I guess, the prime follow-on program that we would see coming through, after the sequential injection main focus that we've currently got going on. There's other options as well, looking at various delivery technologies or conducting clinical trials with potentially higher doses of OPT-302, not to get greater inhibition of our targets, but to potentially explore longer dosing intervals, not dissimilar to what Regeneron's undertaken with their high-dose Eylea. I think that kind of approach and having a program of work where we can explore the various dosing regimens to optimize outcomes for patients and really just get more information around optimal dosing for the drug is of interest to us, and we would certainly like to be advancing that over the short term as well. Great. From our side, we ended up building a pretty strong discovery group right up from the very beginning. We've continued that, and they've added a number of different things, even though we balance it out with outside innovation that we bring in and then make our own. Internally, we've really built a huge library of molecules, and we continue to have medicinal chemistry efforts around Rho kinase structures, if you will, and then keep adding other things and subtracting other things and go all the way to extremes. We are moving forward with a number of different things. The dry AMD space is obviously a critical one. No one's found the silver bullet there yet, and so we continue to look at that. We think a Rho kinase base delivered to the back of the eye could end up being particularly useful, as it is somewhat of an anti-inflammatory process back there. Now we have an opportunity to deliver it. We're looking at various what's the best molecules and the concentration of those molecules to get it to the back. We're also doing some blocking and tackling stuff, too. We ended up in the steroid space, on a topical steroid space in ophthalmology. Cataract surgery, one of the reasons why they can't give steroids over a longer period of time is because of intraocular spikes. That's why some of the labels that you see are only for 10-day dosing. What we've been able to do is actually take a steroid, link it up, and actually create a new molecule with Rho kinase inhibition component to it so that we can actually control intraocular pressure spikes. That program we've designated as 6121. It's actually moving into the phase I programs this year. We're excited about the prospects for that because cataract surgery is a space we know well, not only from originally at Allergan, but also when we were at ISTA. The cost to develop those products is negligible relative to the retina programs that we're spending money on. Yet it gets us into the cornea side of things, which is an important component because that's where a lot of the surgeons in ophthalmology make their money. If we can bring them something that's new and different that they haven't had before, we think we can make that a success. Okay, good. We're just about out of time, but let's just do a quick lightning round, just some company-specific questions. I can start with you, Vicente. Curious, when would you feel comfortable reintroducing revenue guidance for your products? Yeah. For whoever asked, it was probably one of the guys that I talked to yesterday. As soon as we know that COVID's totally out of the picture, and right now, one of the reasons we didn't reinstitute it was because the Delta variant started hitting, and we started seeing parts of the country that began to look like they were going to start restricting a lot of different things, and we didn't want to provide guidance and then a month later have to pull it. Hopefully by the end of the year, when everybody's pointing to, yeah, by then we should be okay, then we'll be happy to do it. Great. Todd, I know this will be hard to answer in 30 seconds, but to the extent that you can comment or summarize, what are the factors you believe position the phase III TRANQUILITY trials to be successful? I can do it in 15 seconds. It's all about redness. We have great data in redness. We just released the phase III INVIGORATE trial in allergy. Redness worked beautifully. I think the drug has a clear anti-redness effect, and there's a lot of reason to believe that based on those data and the run-in cohort from TRANQUILITY, that we'll see a good change in redness in the upcoming trials this quarter. Perfect. Megan, same question for you on your phase III trials, with the VEGF-C and VEGF-D blocker. What are the reasons why we should expect a successful outcome? I really think it comes because from all of the learnings that we've had from our phase II-B, we've identified the population of patients, the lesion types that actually respond best. We're recruiting all comers into our phase III, similar eligibility criteria than what we used in our phase II. What we're doing is going to analyze the minimally classic and occult patients first. They're the majority of patients that are in the real world, the majority of patients that we recruit, over 80%. In our phase II-B, we saw a 5.7 letter gain over and above standard of care treatment in that group. We think that that sets us up, gives us the best opportunity to show a very compelling visual acuity benefit over standard of care treatment. We don't lose out on looking across the total patient population as well, because assuming we hit in our high-responding group, we then step down without any compromise on our stats and get to look across the entire patient population. I think the way that we've designed that trial and the analysis plan really does set us up very well in terms of hitting the endpoint for the study and positioning us well with a compelling visual acuity gain over and above standard of care. We're really excited about how we've approached it, and I think it is a smart way to go in terms of optimizing the outcomes. Thank you all very, very much for a very lively discussion. Greatly appreciated. Best of luck for the rest of the year, and I'm sure we'll be chatting again soon. Thank you. Thank you.