Aldeyra Therapeutics, Inc. (ALDX) Earnings Call Transcript & Summary

Okay. Thank you all for joining us today. It's great to see so many of you here. Those of you that know me know that I take great pleasure in R&D days. They allow us to talk about data in ways that we don't typically talk about in standard data releases and press releases and so forth. And there's a lot going on at Aldeyra, as many of you know. And so we're thrilled to be here today and thank you all for coming. And for those of you that are on the webcast, we appreciate your listening in as well. As always, we do have a forward-looking statement slide, which I encourage you to review, which I will get to when I figure out how to advance the slides here. Good. There we are. Great. It's hard to believe that some years ago, this company started based on a novel pharmacologic target called RASP. No drugs, no animal models, just an idea and RASP was broadly applicable. And now today, RASP, thanks to the success at Aldeyra, is the subject of numerous Phase III trials. And as of last year, we acquired another company, which added an additional Phase III trial. So now we are truly a platform company across different molecules and different mechanisms of action and, of course, many different diseases as well. And we're quite proud of that fact. We have successfully made the transition from the front of the eye, where we started, to the back of the eye with our latest asset in proliferative vitreoretinopathy, which we'll talk about at the end of today. And in addition, as we speak, we are completing a Phase I trial with a systemic RASP molecule, an orally available compound that we will talk about later this year, and we look forward to updating you on the progress with that program as well. So we aim to treat diseases that affect all of the body, not just the eye. Today, we'll focus on 3 of our late-stage ocular diseases. As you know, this morning, in our press release, we announced that now for the second time, we have successfully met the primary endpoint in symptom control in dry eye disease with our Phase II formulation trial results. The dry eye disease is going to be the first topic of today, we will show you a great deal of data. We have, as you can imagine, based on today's announcement regarding achieving the primary endpoint, initiated conversations with the FDA, and we look forward to updating you on RENEW 2 and other aspects of our development path going forward once we hear back from the agency, which we hope will be shortly. I do want to make a couple of points about dry eye disease before I introduce Dr. David Clark, our Chief Medical Officer, to take you through some of the data. The first is that symptoms matter. I don't think that patients with this disease are waking up in the morning, thinking what is my fluorescein staining score? What is my Schirmer test? No, they're thinking that their eye hurts that they're miserable that it feels like sandpaper running across their eyeball every time they blink, and doctors and physicians really treat symptoms. And you'll hear this in great detail from our keynote speaker today, Dr. Paul Karpecki, who is truly an international leader in the dry eye disease space and other forms of ocular -- anterior ocular inflammation. So symptoms are important and really what drives patient care today. The second point I want to make when I was an investor, way back when, I always, with small trials ask companies to show me the pool data. Because if I'm going to fund a trial, if I'm going to spend time on a larger trial, I want to know how that might look. And one way of getting around variability in small trials is to combine data. We're going to show you that in dry eye disease across trials that had common time points and common formulation and common dosing regimen that the pool data are outstanding. And as we said in the press release this morning, highly statistically significant results in both symptoms and in staining, and we'll detail those data later on. And then finally, we released new data this morning on a head-to-head tolerability trial with Xiidra, which is the only drug approved for dry eye disease per se in the label. And you'll see a very compelling tolerability profile versus Xiidra, which I think makes for a great commercial story going forward for reproxalap. Allergic conjunctivitis I think, in many ways, represents a market that is larger than dry eye disease. We'll hear Dr. Karpecki discuss that. We'll also have comments from Dave McMullin, our Chief Commercial Officer, about the growing pandemic, that is allergy, thanks to global warming and the spreading of pollen-producing plants and the lengthening of the allergy season. INVIGORATE is our next key milestone in allergy that is a Phase III trial, our second Phase III trial in allergy. As many of you remember, last year, we announced positive results from ALLEVIATE, which was our first Phase III trial in allergy last year. And then this morning, we disclosed further guidance that INVIGORATE, we think, will be announced in the second half of this year. And then finally, proliferative vitreoretinopathy or PVR, which is a rare retinal disease, for which ADX-2191 has received orphan designation and also in the second half of last year fast track designation from the FDA. We're going to, today, highlight the patient experience of PVR, which is remarkable given that the disease can be blinding and that there is no therapy for PVR, and we'll conclude. As far as the agenda goes, I mentioned that we'll have presentations from Dr. Clark on dry eye disease and allergic conjunctivitis. We're going to do something slightly different this year and that we're going to take questions after each section. So we'll have some dry eye disease questions, allergic conjunctivitis questions. We'll have a break and then introduce Dr. Karpecki, which will be the highlight of the day. I can tell you right now. I met Dr. Karpecki, I think it was at the American Academy of Ophthalmology last year, and what a fantastic key opinion leader. Also our latest addition to our clinical Advisory Board in the Anterior segment. So we're thrilled to have him here. As I mentioned, Dave will follow-up with, I think, fascinating, if not novel insights on the commercial landscape for allergy. And then we have a patient video with which we'll conclude on the firsthand experience with PVR and ADX-21 which features not only patient but also the founder of the ADX-21 technology, Dr. Dean Eliott as well. Well, without further ado, let me invite Dr. David Clark, our Chief Medical Officer, to the podium to talk about our latest in dry eye disease.

Thank you very much, Todd. So starting off with dry eye disease. Here is a summary of all the studies we have completed in dry eye disease -- in the dry eye disease program. So what you see here is a very comprehensive body of work we have evaluated in Phase II and early Phase III dose ranging, which is standard. We've also evaluated dose regimen. As you know, we studied the constant dosing, QID dosing versus an induction and a maintenance dosing regimen in RENEW Part 1 and also evaluation of different formulae. So in total, almost 1,000 patients in the dry eye disease program to date. As Todd told you in the lead-in, and as you saw from the press announcement this morning, Aldeyra has now completed demonstration that we meet the dryness symptom, primary endpoint, in 2 trials. And in both of these trials, it's a prospective endpoint, and we've agreed this endpoint with the FDA. So this is the endpoint where we have agreed the specific population, it's moderate-to-severe dry eye disease as outlined in the criteria you see here. And also, it's weeks 2 to 12 repeated measures that we agreed with them. So what you see on the right-hand side panel is the data from our formulation Phase II trial. In both of these, this and the RENEW Part 1, it was ocular dryness with a VAS was the primary endpoint. And what you -- what we studied in the formulation trial was a slight modification to the current formulation. So we increased the amount of one of the key excipients from the current formulation for this formulation we studied in Phase II. As you see here, the greatest separation from vehicle that's seen with the current formulation. So at present, we would plan to continue forward with the current formulation for the dry eye disease program. This slide shows you the data from all of our completed vehicle control to dry eye studies. So what you see here is you've got Phase IIb, and then you have both components from Phase -- from RENEW Part 1 and you have the Phase II trial, all versus vehicle. We have switched endpoint here because the Phase IIb trial did not include the ocular dryness VAS. So what we're showing you here is the OD4S dryness output from these trials for that reason. And what you see is a generally consistent pattern of activity across all of these trials versus vehicle. The only exception for that would be the constant QID dosing arm in RENEW Part 1 where the vehicle response was larger than the other vehicle responses you see across these 4 comparisons. Todd made a really important point in the lead-in to me taking you through this dry eye data. So these are all sample sizes of just under 100 per arm in these 4 comparisons versus vehicle. So what we have done and what we will show you is a pooled analysis, where you take all 3 of these constant dosing in Phase IIb, constant dosing in RENEW Part 1 and the induction maintenance dosing in RENEW Part 1, where we take all those data with the current formulation, and we do a pooled analysis at the time points where we have the same time points in these trials and when the dosing regimen is stable. So it's in the first month. And that is shown on Slide #10. So what you see is when you do this pooled analysis, you get up to numbers which are more in line with what people would study in larger later phase studies. So you're up just over 200 -- almost 250 per arm when you pull these data. And what you see with this combined data pooling is you've got the rapid and the potent symptom control. It is statistically significant when you run a repeated measures analysis over these time points. Here is the same data, but now we've switched to Fluorescein Staining on Slide 11. And it's from all 4 comparisons versus vehicle in the same way as I showed you ocular dryness. This is Fluorescein Staining. What you see here is a generally consistent effect with reproxalap on the Fluorescein Staining responses. What varies is really the vehicle response. And there's a very important footnote to this slide, okay? For RENEW Part 1 and for the Phase II formulation study, we were impacted, we believe, by a shortness of fluorescein liquid drops, which you use to measure the fluorescein staining. So in the U.S. last year, there was a shortage. So all studies running, basically, you have to run it with the fluorescein liquid drops and also some fluorescein strips. And we believe that has increased the variability of these 3 outputs. And I think you can see that is the likely explanation for their difference between Phase IIb and what you're seeing in the other comparisons here. If you take the same approach as we did for ocular dryness, and you do a pooled analysis, where you've got the same formulation. So Phase IIb, both parts of RENEW 1, despite the increased variance, we believed, was occurred because of the fluorescein shortage. You still see a statistically significant difference with this early onset profile on potent sign control here with fluorescein staining. So in summary, what I've taken you through here is that reproxalap has met the pre-specified symptom endpoint from both RENEW Part 1 and the Phase II formulation trial. The pooled data for both symptoms and signs suggest early and potent activity versus vehicle. And as Todd mentioned in the lead-in, the next step would be discussion with the FDA about forward plan. Before we move into the Q&A session on dry eye disease, just want to show you the other data set that Todd mentioned in the lead-in. So here, what we did was a drop experience study. The design is shown here on Slide 15. So we ran this study last -- at the end of last year. The objective was to characterize the eye drop experience, reproxalap 0.25% both the current formulation and the novel formulation, which we used in the formulation Phase II trial versus Xiidra. The design was a 3-arm crossover study. We had 19 dry eye disease patients, and they all had 3 visits over the course of 1 week. They took each of these medications. And the endpoints we were interested in, primary exploratory endpoints we were interested in, ocular discomfort, blur vision and dysgeusia ratings, profiled out to 1 hour. And what you see on Slide 16 is the outputs for these endpoints. In all cases, the response with the 0.25% concentrations of reproxalap is very similar between the 2 that you see here. And Xiidra -- both doses of reproxalap 0.25% produce less of an effect on all 3 of these endpoints than Xiidra. And when you ran a statistical analysis, it was statistically significantly less with our agent. So that was the data we wanted to take you through, including some new data in dry eye disease. So we'd be happy to take questions at this stage. And I think there'll be a microphone passed around that will help people on the call to hear what question was.

Dr. Clark, it's Adam Walsh from Stifel. What is the go-forward plan as you move into the meeting with the FDA? What's the timing on that? What are you hoping that the FDA will allow you to do in the Phase III? And I remember, there had been some talk earlier surrounding the timing of the fluorescein staining where you had been statistically significant at an early time point, but not at a later time point. So is the discussion with FDA going to center around the timing of the fluorescein staining partially and then the timing on the meeting?

So we have submitted the meeting request. So you can sort of evaluate that we'll -- we expect to have the meeting within a few months' time. I think at this stage, we weren't planning to be more specific than that. And the main items we'll be discussing with them, I mean, one is, as we described, now we have demonstrated this really early onset and broad symptom activity in 2 prospective trials. So that will be one of the major topics of conversation. And you are right, we will also discuss with them what the strategy and the output should be for the signs. Those would be the main elements we discuss with them at that meeting.

Yes, Adam, I do think that, as we alluded to in the new release that one advantage of reproxalap versus other medications is the rapidity of onset, how quickly the drug starts to work. So your supposition about running a shorter trial and look at an earlier onset activity, I think, is one that's reasonable, and that's reflected in the pool data that you just saw as well.

Just a quick follow-up to that. The other thing we've discussed in the past, I think in fourth quarter last year is, the agency is fine with different duration for symptom and a different duration of endpoint for sign.

And within the bracket that it covers...?

Yes.

Yale Jen from Laidlaw & Company. Regarding the new formulation that the alternate formulation, what's the strategic goal at this point moving forward for that formulation compared to your current formulation?

That's a great question. Thank you. So at this stage, with the responses you've seen, it probably won't surprise you that our plans would be to move forward with the current formulation for dry eye indication. So at this stage, we would not plan to do additional work with the modified formulation you saw in the Phase II trial.

Hi. Esther Hong, Janney. So on this head-to-head study with reproxalap versus Xiidra, the data are impressive, do you have any plans to evaluate against RESTASIS?

Not that I'm aware of at this point. As you know, no drug is perfect. RESTASIS has its own version of tolerability issues, not so much the taste disturbance that you -- and blurry vision, I think, that you see with Xiidra, but other ocular discomfort challenges. My guess is that most people see Xiidra as the leader in the novel anti-inflammatory space in dry eye disease, and that's why we chose Xiidra for this study. I think the data speak for themselves. What was interesting to us is the 2 formulations of reproxalap were very similar to each other. And back to Yale's question, I think it felt like for us, it didn't necessitate advancing a novel formulation, we can now stick with the old one and push forward, in part based on the Xiidra results and in part based on the pool data you've seen today.

Yes. My name is Sudan Loganathan from Cantor on Louise Chen's team. So a quick question kind of on the nasal staining component. So you're able to show whenever pooled a difference. But in terms of what the FDA is seeing and what they want to see compared to what Xiidra, RESTASIS or other trials have shown, how does it compare? Is there kind of like a threshold that FDA is like looking for like a certain number? And then second question, when looking at the Xiidra kind of the head-to-head trial on these sort of like blurry vision and taste dysgeusia, is it -- if you put it out further for a longer time point, could you see any differences, any more differences? Or how do patients in this -- these other treatment options...

Thank you very much, excellent questions. So in terms of the requirement with fluorescein staining, statistical significance is the regulatory requirement. There is not a threshold for a degree of change that you need to see. I mean, in general, if you compare our data with the Xiidra program, I think it varies by study, as we've shown you today, but it would be similar. Some of the studies are very similar, some of the studies are slightly more than you've seen with Xiidra. So it's probably in the same ballpark. Your second question was the -- if you go out longer in the drop experience study, probably wouldn't have learnt too much. You're seeing these profiles that you see in the data, they're basically flattening out, we would have profiled that Xiidra is still causing some effects. But in our mind, it was clear enough, stopping the profiling at 60 minutes to profile the separation of our transient effects.

Samantha Semenkow, Citi. And just how are you -- how do you plan to manage the variability that you've seen in the vehicle arm going forward in the Phase III? Are you going to be able to have more supply of the staining? And additionally, are there any differences in the Phase IIb population outside of the lack of supply that we should know in any terms of baseline characteristics or in other assessment differences?

Thank you. So the increase in sample size is likely to be one of the factors that most people would utilize for the variability that you see here. And it's the justification that we ran through for the -- in fact, for the pooled analysis. I think you see that from the pooled analysis that you can control some of this data set to data set variation with sample size. In terms of -- we would ensure that there was a full amount of the fluorescein liquid drops available before we started the study rather than they being caught out mid study. I think that would be reasonably easy to secure. I'm sorry, I know there was a third component to your question, what's that again?

Outside of the lack of supply that you saw in RENEW, were there any other differences in baseline characteristics or other assessments for the Phase IIb versus RENEW?

No, no, great question. Not that we have noted, no.

Yes, this sounds a great series of questions. And I think what you'll hear from Paul later on today is that the challenge with strips, fluorescein impregnated paper strips is variability, right, consistency. So obviously, a dry eye is a disease that's already fraught with variability, particularly with vehicle. Vehicle has 2 effects. There's a placebo effect: I'm taking something from my eye, I'm feeling better, I changed my behavior, I eat better, exercise more, I get more sleep, whatever. There's a placebo effect, which is a mental issue, the mental change that provides behavioral change. And then there's a vehicle effect. So you're putting something wet and soothing on the eye. So there's -- this is why the vehicle variability in this disease is quite high. And as Dr. Clark mentioned, most of these trials are 400 to 500 patients per arm. And everything you see today is 100 patients per arm, which is why we combine the data and the combined data, we're so pleased about those outcomes.

And then on the pool data topic, have you looked out further than 29 days? And do you still see -- and do you expect in the Phase III then to potentially cap it at 29 days? Or would you go up further to 12 weeks, say, for ocular dryness?

Yes, thank you for that. I think for the signs, you can get a flavor of what we would plan for shorter duration would be indicated from the data set we've generated across this number of Phase II and early Phase III studies for the sign. I think that would be indicated, yes, shorter duration.

You have to be careful with pool of data, right? Everything has to be the same. The formulation has to be the same, the dosing regimen has to be the same, the time points have to be the same. And so that's why we made it out to 4 weeks. Because after that, everything changes in some of these arms. And yet, we were still able to come up with 500 or so patients where we can combine the data and see these, I think, pretty powerful effects.

Matt Cross from JonesTrading. Was curious looking now as you're moving into RENEW Part 2 and discussions with the FDA. I know one of the variables in RENEW Part 1 that you're really looking to essentially tweak outside of the things that have already been discussed was the timing between -- which you switch between induction and maintenance. And now you have kind of this a different formulation dosing schedule trial that's used the same induction maintenance dose, was there anything you learned? Did you use the exact same schedule as RENEW Part 1? And any learnings from that as you kind of consider changes to that variable moving forward?

We would believe that the current induction maintenance scheme has worked. I think it's been successful. That's one of the reasons we have -- we are not aware of another sponsor who has such an early and broad symptom improvement. So we believe it's working. But as we discussed, I think, at the end of last year, there is the potential for the signs that we may consider some changes to the specifics of it, but we have not made those decisions yet.

Justin Kim from Oppenheimer. Just a question on the tolerability study. Is there -- when thinking about the intra population, are there a subset of patients who are driving sort of maybe this poor response to Xiidra? And can you maybe characterize sort of the intra-patient experience from reproxalap as well?

That is really important question. If I go back to the data slide. So it varies by endpoint. So the majority of subjects with both treatments complain of discomfort. So discomfort is the majority of patients, no matter what the treatment. And then the frequency drops off. But for example, Dysgeusia is probably 1/3, 40% of the population would complain of dysgeusia. So it varies by the endpoint, and it kind of moves in that direction, pretty much everyone with the ocular discomfort and a lower proportion with the Dysgeusia. Blurred vision, somewhere in the middle, although I think it's still the majority of patients are complaining of blurred vision.

I think that's a question worth asking Dr. Karpecki later on after his talk as well. These are common side effects. Well, certainly, discomfort and blurry vision with almost any drug that's instilled and some patients seem to want that. Because they have the artificial experience -- the artificial tear experience, where nothing is going on, and they don't feel anything different. And so the drug adds a different layer of complexity to all that, in some cases, beneficial to the patient experience. But in this case, we were thrilled to see that, again, both reproxalap formulations outperform Xiidra.

My question is forward -- sorry, I'm [indiscernible]. My questions is forward looking. You have very, very nice results, no question. But given the state of health care today, cyclosporine is still -- has a much larger market share than Xiidra. And how you're going to convince doctors to prescribe your drug when you don't even have head-to-head with cyclosporine? And given the state of payers, cyclosporine is already generic. So can you talk within that, please?

Yes. The -- you can sense our enthusiasm, and when we make the description, we're really not aware of any other sponsor who has managed to obtain the early symptomatic, what matters to the patients, as Todd importantly stated in the lead-in, it's symptoms. We're not aware -- so my answer to your question is we are really enthused by the early onset and the breadth and the clinical significance of what we're seeing with this broad symptomatic improvement. So that would be our answer to your question. If you -- maybe Dr. Karpecki can speak to it later on in the session. But certainly, our information when we've spoken to other experts in this field is the -- you get a lot of nonresponders to existing therapy. A lot of patients, they try it, and it really doesn't help them, other existing therapies.

I think the other thought, to echo what Dr. Clark is saying is it takes RESTASIS weeks to work, if not months. And so -- and probably even closer 2 weeks of Xiidra for sure. And so I think that the question from the payer standpoint, from the physician standpoint, from the patient standpoint is, do I want to stay on something for weeks or months, to see if it works when I can test a drug and see if it works quicker, more quickly? And in that way, the onset of the symptomatic improvement is critical. And I agree with Dr. Clark, that that's the key differentiator. I think you will find physicians out there they would argue that RESTASIS sort of doesn't work. I mean symptomatically, it really doesn't work. And this is the challenge with RESTASIS and generic RESTASIS and Cequa and so forth where you have perhaps increased tear volume that may or may not make a difference to the patient symptomatically. So this just gets to my first comments as symptoms matter. And that, I think, would be our major differentiator versus the cyclosporine and related products.

I understand that ultimately, you need to speak with the FDA to finalize the Part 2 or the Phase III study. But at this moment, is that the setup of induction followed by maintenance is the preferred, so the regimen you want to take? And secondly, is that if you have a shorter time for particular for signs, that will be a potential home run for you guys?

Yes. Yes. I would agree with both of the positions you stated there. Yes, so currently, we plan to stick with the induction maintenance dosing regimen because of the overall profile we've seen with it across these different studies. And there is an advantage with the sign. There's also an advantage with the sign of going with a shortest trial. What happens is dry eye disease is an element of flaring the disease. So at some stage, vehicle is going to work because the flare is settling. So there's an advantage in the -- in going for a shorter duration for the sign for that reason.

Thanks for taking the follow up. Just kind of ping off of that one as well. So you gave some background on meeting with the FDA coming soon. So in that case, we'll the Part 2 RENEW initiation, will that be pushed to -- is it still expected for first half '20? And then is it any way going to be kind of pushed into the second half of '20 for any reason?

Yes. So the plan is to hear back from the FDA, first. So RENEW 2 timing is contingent upon FDA feedback. As I think you can imagine, based on the fact now that we've hit symptoms twice in 2 different studies, I think that is important information for the agency to consider and very important relative to our future development plans. So yes.

Thank you very much for your questions. If it's okay, we would plan to move on to the allergic conjunctivitis section. We're going to follow a similar format. Let me start off by saying a description. How much have we done so far in allergic conjunctivitis? What this slide, importantly, outlines is that in the model, which has been used primarily for antihistamine registration, we've done a lot of work, Phase IIa, Phase IIb and a positive primary and key secondary and a Phase III with the CAC model that we have conducted to date. We will share with you some new data from a pilot allergen field study in just over 50 patients, which we conducted. And we've also, as you know, we've done a pilot allergen chamber data set, which we have shared with you previously, and the Phase III allergen chamber INVIGORATE study is ongoing. So it's another extensive body of work that we have undertaken in allergic conjunctivitis. Similar to our approach in dry eye disease, we really want to understand it. We would make the case that we think we're understanding it better than some other people who have run programs in these fields. It's certainly more extensive in its breadth than some people have undertaken. A little bit about what these different models are. So decades ago, allergen field studies were the way that people would try to register drugs with, as you know, relatively straightforward. You wait for the allergen season. We've been doing our work in ragweed. So you'd wait for the ragweed season or a different seasonal allergen and you basically give people a diary for a month, treat them for a month and how does it improve versus vehicle, which is a nice natural model. The problem with the allergen field studies and the reasons they fell from favor a few decades ago is, there is a very large element of uncontrolled allergen exposure that you experienced in that. And you cannot control the participant behavior in these outpatient studies either. Those are the 2 main factors that drove that from being the primary mechanism for getting an AC drug approved. And you'll see some examples of that when we show you the data from our pilot study. The content table allergen challenge model extensively used developed for antihistamines. We, as you know, we've described before, we have modified it to fit with our mechanism when we ran our Phase III study, which was successful. It's good because it's controlled. That's the main reason it was developed. You have a controlled allergen exposure. The downside -- the biggest downside of the CAC, it's actually quite a nice model, but it's not real world. It's a relatively artificial. When you've got allergic conjunctivitis, you don't go outside and take a lot of the allergen and put it on your conjunctiva. That's not what happens. So it's a good model for its purpose. It is controlled, but it's not real world. Allergen chamber overcomes that. So the allergen chamber has the advantage that it is a controlled model, but it's also real world. So what you've set, again, we've run ours with ragweed, but the FDA is -- doesn't mind which seasonal allergen you would chose. What you do in the chamber, in our case, we've studied for 3.5 hours, you set the chamber up and you have the equivalent of the allergen exposure that a subject would get on a high pollen day in season. That's what you set and you continuously maintain it for 3.5 hours. Very good for our pharmacology. Because what that allows us to do is to assess both prophylaxis and treatment phases in the same model. So it's a very beneficial model for our mechanism of action in terms of understanding how to construct a label to say, here's how the drug will be used. So let's go back to the field study. So this is the results -- some results from the pilot 52-patient field study we ran, okay? And basically, what happened was, you've got this pollen variation limitations that were the main reasons for their larger studies falling from favor and that's what happened in this study. So we ran the study at multi-centers in Texas in the ragweed season. It was a rainier period than usual when we were running the study. So what happened was the allergen levels, you really want to get around about 300. That's your high allergen pollen level with ragweed, okay? 300 is your target. What you see here is a plot of all the individual subject's allergen levels during the peak 14 days that you take from the 28 days that are in the study. You see that the levels were very low. Again, it was rainier than usual. That is one of the explanations. But that just speaks to variability you can get when you're running these field studies. However, what we had, you still had quite a number of patients. About 25% of the subjects still had met the target allergen levels. So we did a subgroup analysis in them, and that's what you see in the right-hand side panel. It's small numbers, but we wanted to look at the data that actually achieved our target allergen levels. So you've got 5 subjects on active, you have 4 in vehicle. And as you would expect, based on the other data we have shown you from the other models, you do have activity when you look at the population who actually achieved the target allergen levels. And it was statistically separated from vehicle in that small subgroup. The next slide, 22. This is data we shared with you previously. This is the Phase III CAC data outputs that you previously. So as you remember, from us disclosing this data, we basically had a primary of total ocular itch score AUC approach. We went from 10 minutes out to 60 minutes and we met the primary endpoint. We were statistically lower than vehicle for the AUC for itch from 10 to 60 minutes. And you see the key secondary endpoint from Phase III on the right-hand panel. Responder, a 2-point responder analysis where, again, we were statistically superior to vehicle in how quickly, and in this case, the degree of response you have on this responder analysis with the GEE model. So we met the primary and the key secondary endpoint in our Phase III CAC model. This is the data. Now switching to the allergen chamber. So this is the data from the pilot study we have shared with you previously. As a reminder, what we can do there is you can give 3.5 hours of exposure to ragweed, in this case, continuously set at the same level that you'd get on a peak pollen day with ragweed. And we gave 2 doses. We pre-dosed 5 minutes before the chamber, and we gave a second dose, approximately 90 minutes during the chamber visit. So we can look at both prophylaxis and treatment during the occurrence of the itch. And we showed statistical separation, both for itch, shown here on the left, and also for redness score in this model. And as we have disclosed to you previously, we spoke with the agency, and we reached agreement that the primary endpoint for Phase III could be after the second dose. The majority of the time points vehicle versus reproxalap need to be statistically significantly different after the 110-minute time point. So that was the data that we've disclosed previously as a reminder from the allergen chamber study. And here's the INVIGORATE Phase III AC design. The study is ongoing at present. Primary endpoint, as I described, after the second dose, we basically need to have statistical significance on the ocular itch score at the majority of the 11 time points between 110 and 210 minutes. That's what we've agreed with the FDA. And the design is very similar to what we ran in the pilot. The only difference is, this is a 2-way crossover. We have 2 active doses in the pilot study. Now we've just got the current formulation of 0.25 versus vehicle, and you basically have 60 subjects in each group. There's approximately 120 subjects will be randomized in this 2 way crossover design. So that study is ongoing. Results, as we spoke earlier, expected in the second half of this year. So in summary, we've really demonstrated -- we've done a lot of work in allergic conjunctivitis. And we've really seen this robust drug activity in multiple AC clinical models. What we've demonstrated today is a rapid and durable, importantly, durable activity with reproxalap. We've demonstrated they're clinically relevant. That's one of the purposes of having the responder analysis as part of this work. And we've really shown that our novel mechanism of action can be differentiated relative to existing therapies. And as described, INVIGORATE Phase III expected to give us trial results in the second half of this year. Before I finish and go to the Q&A, just wanted to show one more data slide. And it's a nice one because what it does is we've shown you the data as a reminder from the 3 different looks we've had, CAC model, allergen chamber and the pilot field study and we've got positive results in ocular itch in all 3 different models. What we're showing here is the ocular itch with the same endpoint, ocular itch from the dry eye study, okay, where we also had statistically significant improvement in ocular itch in the dry eye patients. So that's important because now we've got these 3, this adds a fourth demonstration that we have significant and clinically relevant [ reduction ] of ocular itch, and we wanted to make that point and happy to answer your questions about AC at this stage. Thank you.

My question here is that you mentioned you need to measure majority of the readings during that period of time. Could you be more specific in terms of 2 out of 3 or whatever number that might be?

So yes, the majority -- so there are 11 time points, you need to be at least 6, at least 6 out of 11.

One more follow-up question here is that the filing for this potentially will be ahead of the dry eye. So strategically, how do you think about this issue?

I think the current plan is a concurrent filing. But it really depends on a lot of factors, Yale, including the FDA dry eye response, the outcome of future trials and so forth. Obviously, there has not been a novel product that works in both dry eye disease and allergic conjunctivitis, but we would all prefer to tackle the dry eye disease market first, given pricing and recognition and so forth. But I think the current plan is a concurrent filing.

Adam Walsh with Stifel. So when you think about allergic conjunctivitis and the number of patients there are and you kind of add up the patients that you'll have in the safety database for that specific indication, I think you'll have, by my math, around 750 from this, is that big enough? Or do you think that the crossover from the dry eye data as you file as one will be sufficient for a safety database of FDA?

It's a great question. You are right, the dry eye data would be applicable and will help you. And should we choose to go, as Todd said, should it work out to be more expedient to go ahead with just dry eye or AC first, you can cover the additional subjects in the safety study in a relatively easy, low-risk manner.

Matt Cross, JonesTrading. Had one about the, I guess, the amount of pollen that you're exposing these patients to in the allergen chamber model. I guess, relative to the CAC data you already have, this is designed to mimic a high pollen day, like you said. How does that -- would we still expect that to be less, I guess, direct exposure to the patient's eye over that time period than a CAC model? And so I guess would you expect vehicle to perform better or worse or maybe reproxalap perform a little better in a full allergen chamber study model? What did you kind of learn from maybe the smaller allergen chamber model as we consider that kind of interplay?

It's a really interesting question. I can't answer for you right now, but we can easily do it after this meeting, exactly how it compares the total amount. So 3.5 hours of the 3,500 parts per meter squared, how that compares to the -- and part of that is, when you do the CAC, you titrate it. So you're giving different amounts, and it can vary by -- at least log, maybe more than log, maybe 30-fold the amount. So that comparison may not be too easy. But it's an interesting question. I think we can probably try and do that exercise to compare those.

We really made a point, Matt, to try and demonstrate activity across different models. So the CAC is a lot. It's acute. The chamber is less over time. The field is obviously even less over time. The dry eye data with regard to itching wasn't even -- the study wasn't even designed to test itching. But now, as Dr. Clark said, we have 4 models, very different, showing a reduction in itch. Itch is important. When I was in medical school, that -- no one cared about itching. And now itching is very, very important. Look at the atopic dermatitis drugs that are selling billions of dollars today. So itch has become something that is really critical to patients and physicians. And we didn't expect to see reproxalap to work across all allergic conjunctivitis models. That's why we tested so many, 3 different ones. We certainly didn't expect to see anything in dry eye disease, but lo and behold, they all work. So we're actually quite thrilled to be one of the few drugs that is definitive in terms of reducing itching across a variety of different situations.

Esther Hong, Janney. So for patients with both dry eye disease and allergic conjunctivitis, how would those patients be treated? What would the dosing regimen look like? With someone with dry eye, would they be able to tolerate the dosing regimen?

So that's not a discussion we've had with the FDA yet, but you can imagine a situation where the dry eye will have a dosing regimen, similar to what we've shown you today. So our expectation, it will be an induction than a maintenance. And certainly, we have safety data available, which suggests you can dose more frequently with that, if you have a dry eye patient who also has allergic conjunctivitis. So you could dose PRN on top of the dry eye, but that's not something -- it's important to state, this is not something -- a discussion we've had with the FDA yet.

So I think we're going to take a short -- we'll take a short break and we'll reconvene at 1:10. [ Break ]

So thank you very much for your attention so far in the day. It is my pleasure to introduce Dr. Paul Karpecki. It's an interesting story that Dr. Karpecki told us when we met with him and getting his expert advice. I mean, basically, he was in -- you were in the vanguard of clinics, focusing on ocular surface disease about 20 years ago, focusing very specifically AC, allergic conjunctivitis and dry eye disease. Currently, I mean, you're basically -- you and your team are running one of the largest ocular surface disease clinics in the U.S. So it's with great interest, we're looking forward to this talk -- talking a little bit about the clinical relevance and some of the factors of these diseases. So thank you very much.

Honored, David. Thank you. Great introduction. Yes, David is right about being involved really early in dry eye. I'd love to say that I knew this was going to be a big thing of the future. And that's why I got involved in it, but it was definitely not the case. I had practiced -- I did a cornea fellowship in Kansas City, after doing a residency in Kentucky and Lexington, where I'm at today. And it was one of the top centers for doing refractive surgery research. In fact, Dan Durrie at the time had done somewhere around 800 procedures in the first 3 years before me and then 2 years after. And unfortunately, we were doing a refractive surgery on patients who had dry eyes. So we're looking for people who were contact lens intolerant because we didn't want to interfere with all the optometrists we worked with already. So we ended up treating probably 600 dry eye patients with this huge dry eye clinic. And I was the last doctor to join. And they said, well, we've got a job for you. We would need someone to run the dry clinic. And I said, "Well, is there anything else I could do? And they said, no, that's it." So that's how I got started in dry eye. Amazingly, it has evolved to being something kind of exciting. But for about the first, I'd say, 7 years, it was a tough job. Half the patients came in, and you didn't make them much better. And they're all looking -- I remember having days where like 5 patients in a row would come in and say, is there another doctor I can see? Imagine doing that every day. Fortunately, it's come around. Today, we're having really good success with dry eye, but we still know there's need for newer drugs and more advances in this field. And that's why I'm excited about this potential here. This is going to be an overview. I'm going to go through a lot of slides, but rather quickly on each one as we go through. Ocular surface disease, as you know -- and honestly, I may have made the presentation too basic. Just listening to some of the questions, they were very advanced and having discussions even in the hall, you know more than -- your questions are better than questions I get from colleagues about drugs and about trials and stuff like that. So I apologize if it's a little under, but we'll try to cover it and then move up the scale. As you know, ocular surface disease is really the ocular surface, conjunctiva, the weight of the eye, the cornea and the eyelids are kind of the key to that. So there's a number of very common conditions that affect that, as we think of things like blepharitis, we think of conjunctivitis, the allergic, in particular and then we think of dry eye. So it's a -- it's definitely a systemic condition when you get allergies. What we mean by that is it's one of the -- normally, you don't over respond to something in the air or something in the environment, but some of the allergies over does it. An extreme example would be anaphylaxis, where you eat shellfish one day and you get hives. And if you were to do it a second time, you would probably have difficulty breathing. It kind of builds on that T cell immunity that's present. So it is fascinating in the sense of the varieties we have. But it's incredibly common. As many as 100 million people have allergies in some form in the United States. So one of the largest populations. We talk a lot about dry eye being enormous with 30 million people, and we need to be covering it, and it's such a big field right now. Well, there's 30 million people that have allergies as well. We don't get into that level. I mean, as far as allergic conjunctivitis, it's about 30% of the population. So we're kind of in that same camp that's there. There's a number of studies that have shown that its sixth leading cause of disease as far as chronic diseases in the United States. So really one that patients suffer with a lot, and it's only getting worse, as I think you've already seen an introduction, too. There's a lot of reasons why we believe it's getting worse. Some people believe it's the hygiene theory. We just live in much cleaner environments. And children don't get exposed to allergens. I saw a comic, I would have loved to put in here. I found it in one of the -- in a paper a few years ago. And I thought if I could put this in the presentation, it would have been perfect. It was going back to the 1970s, and the mother is calling out to her son, Billy, who's out in the dust playing baseball. And she's saying, Billy, you come on inside it is time for your vitamins. And Billy, saying not now mom, I'm playing baseball, and there's dust all around them, and he's in the outdoors, and he's been exposed to allergens and everything else. And then they fast forward it to the year, at this point, it was 2014, because I think we're in 2016, but we could imagine it'd be in 2022. And instead now, 30 years later, mom's calling up to stairs and saying, hey, Billy, it's time for your Lipitor as things have kind of changed. And Billy saying not now, I'm playing baseball. And of course, he's on his Game Boy. But it's a good example of why we're seeing perhaps so much allergy today. We're just not getting any exposure to antigens or allergens, in this case, early, not developing that. And then -- so we do have obviously, climate change, which plays a huge role. We're seeing longer periods of allergens now much more significant release allergens over a longer period of times and even genetics. They say if both parents have allergies, the child has 65% chance of developing allergies, pretty high chance of that passing on as well. So that would be all 3 of my children, unfortunately. And it does impact life. Patients who have this, will tell you they don't drive as well. They can't get outdoors. Obviously, that's the biggest one, reading, working, sleeping. I mean, anything that affects that's going to have an effect on cost on productivity. So it is significant. There's a number of allergies that we deal with in my clinic, in particular. My clinic is really only a referral clinic. It's one of the more advanced level clinics. I don't see a lot of general patients or primary care patients. I have, for example, dry eye Sjogren's Syndrome is one of the worst forms of dry eye. I have over 500 positive diagnosed Sjogren syndrome patients in my clinic. So I do see this type of allergic eye disease quite often, but they aren't common. The top one, seasonal allergies, as we talked about could be -- is about -- seasonal allergic conjunctivitis is 30 million -- 20 million to 30 million people. But there are other ones that are more sight threatening on that list. All have great needs to be controlled, but the majority of what we're dealing with are the top and the bottom, seasonal and perennial. The difference between those 2 is, as it says, perennial is going to last all year long. It's going to be something that's in the air, dust, dust mites in particular, animal dander, are something that's always going to be there. Seasonal's only going to be around certain times a year, ragweed, grass, pollen, things like that. And then there's also this whole area of dry eye. This is the TFOS DEWS Committee. I was part of this committee here as well. And really, not to go into in any great deal, but the key to dry eye as far as we know, is both a combination of signs and symptoms, at least that's what the FDA also looks at it from that standpoint. So anytime you see that, that's that main category of dry eye. It is a little bit of a difficult category, though, because it's one of the only diseases where as you get worse, your symptoms get better. You don't have any other eye disease or any disease you could think of. Think about macular degeneration, as you progress in the disease, you have a lot more symptoms, you can't see your central vision or glaucoma, where you lose your peripheral vision. Dry eye, you actually get less dryness and less irritation the more you've had the disease. You get more signs and a lot more staining of the eye, but you don't get the dryness and other things. So it's a difficult disease in that sense as far as being able to take care of it or to diagnose or to manage or even get drugs through FDA trials. Currently, we diagnosed dry eye is actually this. This is my committee that I was part of for TFOS DEWS II and a credit to TFOS. They did a really good job on this last big expert consensus because they included a lot of clinicians. I do research, I will tell you that; a fair amount of research, but I wouldn't consider myself the smartest dry eye researcher, like, people like Don Corb and Kelly Nichols and Abelson and all these other people that spend their lives researching all the stuff. They have far more knowledge than me. I see a lot of patients, 60 patients or more a day. But what they did is they include the clinicians like me who could kind of guide a little bit of what would you do in a typical clinic day? So this is how we come up with dry eye. We look for risk factors. We have symptomatic questionnaires. We do things like staining, which we talked about, break up time of the tears, maybe osmolarity. These are good global markers. They tell us we have dry eye, then we break down the type of dry eye. We have to decide if it's evaporative, which means your oil glands aren't working or aqueous deficient, meaning the lacrimal glands aren't working. And the reason we have to do that is the treatments are different. But what is fascinating is the only overlap between these treatments is inflammation. That's the one consistent component. And that's why new drugs that can control inflammation are going to be critical to how we manage dry eye disease. So if I'm trying to see if someone has a form of evaporative dry eye, that means the oil glands, or meibomian glands, those are in the lower eyelid like you see here, I can do something as simple as pressing on them and if the oils come out like olive oil, that's perfect. That's what they're supposed to be and then we look for other forms of dry eye. But if they come out like toothpaste or gelatinous like this, then I know that's evaporative dry eye. 86% of the population have some level of meibomian gland issues. So -- and that's the reason why we're seeing such huge numbers there is right here, digital devices unless these things are going to go away, which they're not, we're only going to continue to see more and more dry eye. And that's why it's such a big number, 86% are involved with this type of dry eye. The more classic dry eye is actually are aqueous deficient. It means our lacrimal glands and even to some degree, our goblet cells are not producing proper tears and this is the big volume of tears. The way you would then define that out is to actually look at this little tear meniscus height here and be able to tell that it's extremely thin. And so that's how you would know that, that type of disease is typically present. So we have a lot of ways to figure out the disease. We have to decide which type of dry eye disease. And we're still not good at differentiating it from allergic conjunctivitis or other comorbidities. So the most common things that we do today are typically, we're going to try and get rid of some exacerbating factors. We're going to talk to patients about getting off antihistamines like oral ones, for example. We might talk about smoking cessation. We might talk about using your digital devices less if possible. It just depends on what is blinking more often, taking breaks from things. We're going to put artificial tears in the eyes, and we'll typically introduce some sort of palliative things, warm compresses and nutritional supplements like omega fatty acids, maybe some lid hygiene. The problem with this is we don't get at the root of the disease. We really don't control a lot of why we're progressing. So these are important. I wouldn't go without these. They're critical steps, but they don't actually treat the disease. There's nothing there that I show you that I've been showing a slow progression of this disease. In my clinic, patients come in with their last 5 meibomian glands left. I don't see patients that have full complementary glands very often. So they all come in and say, could someone have done something sooner to stop me from getting to this point? And the fact is, we didn't know what to do 10, 15 years ago to the level we do today, but it also makes the point that we need things that can control the inflammation that caused the damage that allow this disease to progress. So this is my algorithm. I didn't know, it's actually going to be in the presentation. I was just going to share it with the group here. This is how I treat evaporative dry eye. It seems kind of complex, but it helps things to really get a good understanding. It only took me about 20 years to figure all this stuff out, I mean, worked in this field. Well, maybe sooner than this year, maybe it was maybe 15 years. But still, we realized that if we are treating a person with evaporative dry eye, we have to focus on also the obstructed glands, whether it's compresses or thermal pulsation, we've got to keep the bacteria down because they build up very quickly in dry eye patients. We had to focus on inflammation because that's what's causing progression. And yes, we might as well take care of the tear film at the same time. But we have to have all of these. And for years, what we did is we did this one. We put artificial tears in an eye and wondered why the person never got better? And then cyclosporine came along, and RESTASIS was the first drug, and we started tackling this one, but we didn't realize how important these are. It's only today where we're starting to control this disease a little bit better by understanding all the elements of it. For aqueous-deficient dry eye, my algorithm is slightly different. I focus on 2 elements: inflammation and tear volume. That's why things like Punctal plugs with little plug in to keep the moisture high or the tear film it shows up here, but not in the other algorithm. We are able to look at no anti-inflammatory, starting off in times with corticosteroids and then using it for flare-ups. In the meantime, having some sort of maintenance-type treatment that's in there. We use biologics like serum. So different approaches, but these are all forms of dry eye, and they're all critical. And the only thing that really stays consistent is inflammation, the progressor of the disease across every form. There's also a mucin form, but I'm not going to go through all of that as well. But the biggest challenge -- I was asked this question in putting this presentation together, what's the biggest challenge that optometry ophthalmology faces when they're managing this? I think one of the biggest challenges, we're not able to differentiate the types of ocular surface diseases well, and there's so much comorbidity. So it's a combination of either, we're missing 1 or 2 or more often, we have multiple levels, multiple things going on. And if you treat 1, but leave the other 2, you don't get the success that you need. So patients with dry eye, for example, will allow more bacteria to build up because they can't wash it away, so they tend to get blepharitis and vice versa and it may be a precursor. Patients who are on allergy medications, will take antihistamines. And what do antihistamines do? They dry your eyes. So now you got a dry eye situation where the further allergens have more opportunity to stick and to stay and works vice versa too. Dry eye patients to begin with, who get exposed to more allergens are osmolarity goes up further, and their dry eye gets worse. So these things are difficult in managing the disease because we don't really have anything that can chronically treat both conditions. We can treat acute phases, but not on a chronic version and maybe not both types of diseases, allergic conjunctivitis and dry eye. As we mentioned, patients who've been -- one of the most common treatments -- say, 80% of patients that see an eye doctor have already started to treat themselves, which makes sense. There's a lot of this stuff is over-the-counter. And that didn't surprise me at all. You can go and get ketotifen over-the-counter and put it in your eyes. And they said, no, Dr. Karpecki, that's wrong. They actually most commonly treat themselves with oral antihistamines for their allergic conjunctivitis and rhinitis. And that's the majority. And those are the ones that have very significant drying effects. So if over 80% are doing that and the large majority are using oral antihistamines because they have an antimuscarinic, anticholinergic component, you're going to get a lot of drying effects. In fact there is a study that was done by Ousler where they took patients and they put them on Claritin or Loratadine, one of the lesser drying antihistamines. And unlike Kentucky, where I practice, where patients take these every day for years, they only were allowed to put -- take the pill 4x, once a day for 4 days. And they noticed a 34% drop in tear volume. That's insane. For 4 days on a QD once-a-day drop, that's the problem that exists for so many of these patients who have concurrent or comorbid diseases. So the primary treatment tends to be that, and this is also showing that we're starting with about 14% of the population already having dry eye, let alone those that we're inducing. So we need to -- you need to have adequate tears. These drugs we talked about like the Loratadine study, which I just alluded to, there's a study by Mark Abelson showed 50% reduction in tear production itself in this patient population. And then as I mentioned earlier, these things play off each other, and that's why patients continue to get worse and continue to progress. It is difficult, I'll admit to separate the 2. I wish we had a little tear marker that we can measure IgE or something that would tell us, yes, this is more allergy than it is dry eye. We don't have that. You know, you go to a pediatrician -- I had to bring my daughter to a pediatrician earlier this year. They do a swab of the throat, they tell you if it's strep or flu or whatever, you're finished. We don't have those capabilities. We have to -- currently, although we have osmolarity and it's a very good test, we have to -- we don't have anything for allergies. We have to look at the eye, we have to empirically decide what's going on and try and rule out all the other conditions that are there and it is difficult. In fact, I'm going to show you some research that shows these symptoms of tearing, burning, grittiness, stinging tend to be consistent in both forms, dry eye and in allergy. And the signs of inflammation are very nondiscrete as it showed there as well. So allergic conjunctivitis and dry eye disease are the most -- 2 of the most common disorders as we talked about. I like this Hom study because it is one of the first studies to go into breaking down the different groups. And what they showed really to kind of sum this up is that 28.2% of the patients who tended to have dry eye had symptoms of itching. Those who also had itching tend -- 35% had dryness and redness was there as well. So about 1/3, regardless of what type of condition you had, had these same symptoms. So can imagine being in clinic, getting the same symptoms, having to decide which disease they have. Or if you have to kind of figure that out. Of the 194 patients is with itching, 57% of them also had dryness. Of the 247 patients with dry eyes, 44% had itch. And then the odds of a patient with itching eyes experienced dry eye was 2.1x greater. So I bring this up to talk about how important this whole area of ocular service disease is, and it's nice to have a drug that could be used on a chronic basis, should this go through FDA trials and succeed that works on both disease states from an inflammatory standpoint, there's so much overlap. This is actually a much better slide showing that exact same thing. You can essentially see that the combination here of dryness, itch and redness is very consistent amongst all these forms. And these people who present with dry eyes, how many of them have itching? 44%. Presenting with itching have dryness 34% and then redness as well. So it is an important aspect as we look at drugs and you guys analyze companies and look for the potential of what's out there, this combination is quite huge. So we wonder why are we seeing so much of this. And this is actually a great slide that talks about the 3 P's of ocular surface inflammation, which includes our dry eye and our allergic conjunctivitis. And then put it down to 3, pollens, pollutants, and I like the last one, parched environments, like dry environments, Arizona, middle of the winter in the Northeast. Any of these sort of things that will contribute. And we're getting, obviously, a lot more of these. And so these allergens do tend to cause the allergic conjunctivitis that comes here. These things cause the irritating air, they're both of these caused the dry eye. And perhaps this is the #1 reason why we see so much overlap amongst these diseases. We talked already about a number of allergic eye diseases. These are more severe forms. Everything ranging from a -- that's actually vernal to atopic keratoconjunctivitis to GPC. But real quickly I want to take you through what we spend most of our world in, most specially primary care practitioners like optometrists and general ophthalmologists to some degree, and that's the seasonal and perennial allergic patients. And we kind of covered this already. Typically we deal with conditions that are all-year long. In fact children who tend to have perennial allergies tend to have asthma too, tend to come in. So the point is there's no way to get around this. In fact, people are allergic to dust mites. Hopefully, none of you are because it's ubiquitous. It's actually not the dust mites you're allergic to, it's the dust mite droppings. 70% to 80% of allergens are dust mite droppings. The mites are only 10 to 24 microns. You can never get a filter that would actually absorb that in any way. I heard a terrible statistic that showed that 10 to 20 waste pellets per day, that after 5 years, if you don't have a protector on your pillow, as much as 50% of the weight of your pillow is probably dust mite droppings. I sure hope this hotel knows that statistic because I stayed here last night, but it's fascinating to see that, that is the ubiquity of what exists within these kind of disease states that are here not really appealing versus what we deal with, which is the seasonal more severe forms. Perennial tend to be milder, but they're all year. This is obviously our ragweed, our pollen, our mold that can come up at certain times where they're much higher. This is kind of what I suffer from in the spring in Kentucky to a great extent as opposed to other forms. And you could tell that this would stick around. This is what ragweed looks like. It's almost like those little burrs if you're hiking or something that would stick to your socks. So there's almost no way to get rid of it when it's in your eye to a great extent. You have to treat the condition, the itch and the inflammation, same with that little image of pollen there. So how do we try to manage that? Well, we do preservative free tears. We do cool compresses, we try to make the patients feel better. And we know the signs. We can look at a patient and kind of get an idea because they have that swollen eye look. Now there are other conditions that do this, but if they're itching with it, that's kind of how we make our diagnosis. Redness or hyperemia, chemosis or swelling of the white part of the eye, the conj, mucous discharge and sometimes lid edema. We can usually see the patient when they walk into our lanes and say, "oh I think that's allergic conjunctivitis." But you'll notice, as we talked about earlier, a lot of overlap of symptoms, and that's why treating both conditions is going to be, I think, a huge impact. So what I do today or what most clinicians do, is we break down what the symptoms are and the stage of the disease. So if I look at the pathophysiology of allergies, I will see that if you were to go, say, you had an allergy to grass and you go out and you're out and outside in an area that may have -- maybe over one of the key parts here, some of the nice areas there, you have a reaction. The immediate response is more of a histamine release. So you can get histamine, heparin, chymase, and tryptase. This is what we call are immediate and truly immediate response. Antihistamines are effective there. They tend to work very quickly. And that's why CAC trials for antihistamines as David, described early seem to work well in that category. But as the disease progresses, you get more of an inflammatory response. This is the synthesis phase. We get leukotriene, prostaglandins and cytokines. And that's where we have to deal with other kind of medications that can control that, maybe like a steroid effect. The way I decide to treat patients is if itching is their primary problem, currently, today, we use an antihistamine combination. And if signs like redness and swelling are their main problem, then we probably would use a steroid. But things are changing a lot there, too, just simply because of the self treatment with over-the-counter products. So we have to be more aggressive in how we manage these patients. One of the nice things that we're talking about today with reproxalap is that you're going to have one of few drugs that's going to have an effect here and here. We don't have that today, where we can actually get some coverage in both areas, meaning that intermediate stage as well as some in the early stages within that first hour. So I think -- but I like this slide, a lot of times when I put the slides up that show all that pathophysiology, my colleagues are like, "oh, I've seen that," but actually, it's a great way to know how to treat a patient if itching is really a significant problem. I often ask my residents too to come in. I say if you had a patient who had just incapacitating itch, what would you use? And they all say a steroid because that's really powerful. In actuality, if you look at the pathophysiology, antihistamines going to control it more in the initial phase. It just doesn't do what you need for the signs. There's no recent approval of a combination antihistamine, mast cell stabilizer that has any indication for signs, for redness for chemosis, they're only for itch and only for that early stage that is there, but it is better on symptoms. It's not what we would think, it's the better option if the symptoms are itching. Now however, if I get more signs, like swelling and redness then our late phase person who have this disease for more than a few days then the pathophysiology at least points to more of the inflammatory cascade. And that's where RASP inhibitor is going to help as well. So we haven't had that to date, something that can work on both stages of the disease, and that's what excites me about the potential of this product. And then that recycles into more chemokines, cytokines, which are inhibited by RASP inhibitors, chemokines, and then, of course, the inflammatory components. So what that basically shows us is, depending on how long you've had the disease or whether your signs are worse than your symptoms, you only have a couple of options. We never had anything that would work on both fronts. We do need a new therapy. If right now, when a patient goes and tries an over-the-counter drop instead of the pills, maybe they do decide they're going to try an over-the-counter drop. And now we have a new one that just recently went over the counter. The doctors are going to be limited going forward. In the past, we had ketotifen over the counter. So some doctors might argue, well, "when they showed up in my office, I'm going to put them on a better antihistamine combination." Well, that doesn't happen anymore. We now have one of the best combinations is over the counter, just got released. So now when a patient comes into our office, we're not going to put him on the same thing. All we can do now is go the other route, which is steroids. And although steroids are effective for signs, they're very slow to act on symptoms, and patients don't like the slower effect. They do well on hyperemia. They do well on chemosis. They've had approvals for both of those on the signs. So we need something that's a little faster acting, one that treats both signs and symptoms, one that works with a steroid, but like a steroid, but can be used long-term without any risk and won't add to the dry eye comorbidity. This is really the Holy Grail of what we need in this field, especially with the overlap of these 2. We technically don't have it unless you use multiple drops. We don't have number 2, no matter what. And we certainly don't have things like orals, we talked about that can cause significant drying and even topical agent. Steroids won't do last one, fortunately, but they also have the risk of long-term use. Now a little bit about the professions, things have really shifted. I saw a study that showed there are 76 million baby boomers, still needing to undergo cataract surgery. It's an incredible number. That means we have to have a full-time equivalent of surgeons, ophthalmology surgeons of around 25,000 in order to take care of those patients over the next 12 years. So anyone let me know how many ophthalmologists they're currently are? About 18,000. That includes retina specialists and others that don't even do cataracts. And so we are very short on that. And so ophthalmology is going to have to step up. They're responsible for 88% of comprehensive eye exams today. So that's at least one good sign. There's 431 graduating ophthalmologists, but that has not changed in the last 20 to 30 years. 76 million baby boomers we talked about. And so we're obviously short of surgeons. And we're going to be much shorter in the next few years. Optometrists are going to have to do much more at the front line, which is good because there's 40,000. So things like allergy are in their wheelhouse. They're very good at treating that. They're #1 prescriber of antihistamines for many years when it was only Rx level. So I think that would be an important area to manage. And as you talked about, there's only 18,000 current ophthalmologists, of which many don't do cataract surgeries, because they're retina specialists, glaucoma specialists, et cetera. One of the consistent components, though, as we look at the versatile therapies is inflammation. And I showed you that earlier. Inflammation played a role in every type of dry eye and in allergic conjunctivitis. And that was why I believe we see progression of these diseases. Doctors have difficulty as we talked about in differentiating any of these 3. The comorbidities really do make it difficult. So a drug that can address both would solve a lot of our problems. And we do need a new drug class. We haven't had anything in the allergy space in well over a decade, maybe we're approaching 2 decades now. So I think it would really help us to get to where we need to be. What excites me about RASP inhibitors is it plays a role at the degranulation phase, which is where we're talking about AC here. As you get the increasing allergy signs and symptoms, obviously, the symptoms come in as we progress, the chemosis, the redness, then you get your anti-inflammatories, they come in later on. Your post histamine phase, which now becomes more of that sign based are cytokines, chemokines, et cetera, and that's where fortunately RASP activation occurs. So it really allows us to have a very upstream effect, which is typically what we need to have as opposed to downstream or later in the disease. And the great thing about that is it applies to allergic conjunctivitis and all are forms of dry eye disease. So obviously, I'm excited about the potential. I know the need is there. That's why so many patients you talked about have not succeeded. Studies have shown as many as 70% of patients don't stay on current dry eye therapies beyond 3 months. And it's just because of the understanding, but it's also because of the need, as we've described here. So with that, I'll answer any questions you may have. And that was a lot of stuff. It doesn't have to be clinical. I'm glad to answer anything related to these diseases.

Sudan Loganathan from Cantor. So in terms of reproxalap currently, if you're to incorporate that into your practice, how do you see that as patients come to you and ask, these are the other options here? And how would you explain the mechanism to them? Are they willing to try a new option -- what are -- what patients are asking you?

Yes. So it's a great question because I think your question is so pertinent because of what has recently happened. We finally have a really good over-the-counter antihistamine combination agent. And so because of that, we are going to be very hamstrung in trying to put them in an equivalent drop. We could do that for a while with -- and ketotifen was good. It just had -- wasn't as comfortable -- maybe -- and our perception was, it wasn't as good as some of the newer antihistamine combinations. Now with that no longer being the case, we've -- we're probably going to have something new. Currently, that's steroids. But there's a lot of doctors that are apprehensive to steroid prescriptions. The -- even though things like loteprednol are much safer and very effective, their ideal treatment is short term, 2 to 4 weeks. In fact, it's one of the best treatments we have for dry eye. But dry eye is chronic and steroids are acute treatment. So if they were a chronic form, we would have it made. Now they're essential in managing dry eye. Especially currently, we have to have them and even in allergic conjunctivitis, especially we have signs. So what I would say that with this, where it would fit in, it'd probably be a little of the both. So any patient who tried anything in the allergic conjunctivitis over-the-counter and came in and said, I've already tried you name it, because they're all there available, this would have to be our next drug class. I mean, it really gives us the opportunity to have something that should have an effect early and late and should allow us to maintain that effect. And the data showed that in the 1-hour and 3-hour data that David presented so well, Dr. Clark. So we see that in the clinical studies, and we also see the long-term anti-inflammatory. So it allows us to feel good about having different agent, different mechanism, not worrying about the patient using it too long without coming back to check their pressures, which can go up in glaucoma to lead to cataracts, although loteprednol is most likely to do that. But there are side effects that worry some doctors and should, and patients need to be monitored more closely. In today's society, people are busy. Having a drug with this safety profile, and none of those risks would obviously fit that middle spot. And so it would become first-line for doctors, though, because you can't put them on what they're already on. And you have a question? Okay right here, yes.