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

Good morning, and welcome to the Aldeyra Therapeutics conference call. [Operator Instructions] I would now like to hand the conference over to Joshua Reed, Chief Financial Officer. Thank you, sir. Please go ahead.

Thank you, and good morning, everyone. On the call with me are Dr. Todd Brady, Aldeyra's President and Chief Executive Officer; and David McMullin, our Chief Business Officer. Please turn to Slide 2. This presentation and various remarks which may be made during this presentation, contain forward-looking statements regarding Aldeyra and investigational drug candidate, reproxalap. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Aldeyra's actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. These statements reflect Aldeyra's current views with respect to future events and are based on assumptions and subject to risks and uncertainties, including the development, clinical and regulatory plans or expectations for Aldeyra's product candidates and systems-based approaches, the risk that results from smaller clinical trials or portions of clinical trials may not accurately predict results of large-scale trials or the remainder of a clinical trial and Aldeyra's continuing review and quality control analysis of clinical data. As a result of the COVID-19 pandemic, clinical site availability, staffing and patient recruitment have been negatively affected, and the timelines to complete our clinical trials may be delayed. Aldeyra assumes no obligation to update these statements as circumstances change. Future events and actual results could differ materially from those projected in the company's forward-looking statements, including the current and potential future impact of the COVID-19 pandemic on our business, results of operations and financial position. Additional information concerning factors that could cause results to differ materially from our forward-looking statements are described in greater detail in the company's press release issued this morning and our filings with the SEC. I would now like to turn the call over to Dr. Brady.

Thank you, Joshua. It is my pleasure to review the initial clinical results from the run-in cohort of our Phase III TRANQUILITY trial in dry eye disease that were announced this morning. As is summarized on Slide 3, in a relatively small number of dry eye disease patients, the run-in cohort of TRANQUILITY achieved statistical significance for a dry eye disease sign, ocular redness as well as all symptoms assessed in a dry eye chamber as part of an FDA-sanctioned trial design. The changes in redness and a number of different symptoms were demonstrated acutely within minutes of drug administration, further supporting what we believe is first-line positioning among dry eye disease therapies, the current standard of care of which often requires weeks or months of therapy to generate even modest symptomatic improvement. We expect to initiate the main cohort of TRANQUILITY in February of this year, once tear RASP levels have been assessed and the trial design has been finalized. As Slide 4 illustrates, in December of 2019, we announced data supporting the rapid onset of action of reproxalap in dry eye disease occurring as early as 1 week after initiation of therapy as well as the breadth of therapeutic activity, which includes a large number of symptomatic endpoints associated with dry eye disease. While the activity at week 1 represents the earliest of activities that have been announced for chronic drugs administered topically to the eye, and that activity was sustained for 12 weeks, TRANQUILITY was designed in part to assess the activity of drug within minutes after dosing in a challenge model of dry eye disease, the dry eye chamber, across symptoms and signs. Slide 5 summarizes the TRANQUILITY run-in protocol, which was a single-center, randomized, placebo-controlled parallel group trial designed to confirm the endpoints and number of subjects for the main cohort. 12 patients were randomized to receive 0.25% reproxalap and 11 patients were randomized to receive vehicle. Doses were administered 4 times on day 1, and 2 times on day 2, as part of a controlled chamber challenge. In the chamber, test article was administered just before and halfway through a 90-minute dry eye chamber that features rigorously controlled low humidity, high airflow and forced visual tasking. A broad array of symptoms were assessed over 24 hours before chamber entry, and again in the chamber. In addition, ocular redness, an FDA-approvable sign of dry eye disease, was assessed in the chamber. Chamber assessments occurred roughly every 5 to 10 minutes at prespecified time points. Throughout the run-in, tears were extracted to measure RASP, the assessment of which is in process and is expected to be available by early February. Slide 6 presents the activity of all the symptoms measured on day 1 over 24 hours, during which 4 doses of test article were administered. Change from baseline as assessed by MMRM for all symptoms was directionally in favor of reproxalap over vehicle. And reproxalap was statistically superior to vehicle for the visual analog or VAS dryness scale, the same endpoint used for RENEW 1 and the Phase II formulation trials that we intend to submit to a new drug application as pivotal trials for symptomatic improvement in dry eye disease. Statistical superiority over vehicle was also achieved for the ocular discomfort and 4-symptom questionnaire scales for discomfort, dryness and grittiness, remarkably similar to the findings observed over 12 weeks in the RENEW 1 trial. Schirmer test and measurement of tear volume was also assessed after a single dose of test article, and tear production was directionally in favor of reproxalap over vehicle. Slide 7 describes in more detail the chamber, which represents a severe challenge model for dry eye disease patients. Recently, the FDA has issued draft dry eye disease guidance, which includes the use of the dry eye chamber as a challenge model for the assessment of signs and symptoms. Importantly, the chamber allows for rigorous quantification of the acute effects of drug administration, and thus is particularly well suited for assessment of drugs with potential rapid activity that occurs within minutes of dosing. Slide 8 illustrates the chamber results for the VAS dryness symptom score. Not only did the VAS dryness results on this slide confirm the 12-week results of RENEW 1 in the Phase II formulation trial, but the results also offer insight into the timing of symptomatic relief, which as the data suggests, occurs within minutes of drug administration. The data also suggests a prophylactic effect of reproxalap, given that the drug was administered prior to the chamber as well as a therapeutic effect of reproxalap near the peak of symptoms at about 45 minutes, reflected by the activity of the second dose. It is important to note that the activity of reproxalap over vehicle was maintained throughout the entire duration of the chamber, and that the superiority of reproxalap over vehicle was highly statistically significant over all time points in aggregate, as assessed by MMRM of the change from baseline, where baseline is defined as time 0 in the chamber. Slide 9 indicates similar findings for a different symptom scale, the ocular discomfort scale, which is not focused on dryness and is reported by patients for each eye and uses anchor descriptors of discomfort on a scale of 0 to 4. Like with VAS dryness, the activity of reproxalap over vehicle was maintained throughout the entire duration of the chamber and the superiority of reproxalap over vehicle was highly statistically significant over all time points in aggregate as assessed by MMRM of the change from baseline, where baseline is defined as time 0 in the chamber. Slide 10 presents investigator-assessed ocular redness quantified by central review of digital photography using a 4-point scale. Reproxalap-treated patients had lower redness scores at chamber entry, likely reflective of the drug activity as a result of the 4 doses on day 1 and the dose just prior to chamber entry. While acute effects of drug and vehicle are demonstrated, the superiority of reproxalap over vehicle was statistically significant over all time points in aggregate as assessed by MMRM of the change from baseline, where baseline is defined as time 0. The time course of redness following the second dose of test article is of particular interest in that overall redness increased in the vehicle group and decreased in the drug group. Finally, as many of you already know, redness is an FDA approvable objective sign of dry eye disease and may represent the only dry eye disease sign that is of interest to patients. In fact, during visits with health care providers, redness is a primary complaint of dry eye disease patients. Slide 11 compares the dry eye chamber results from the run-in cohort to the allergen chamber results from our Phase II allergic conjunctivitis trial and indicates a remarkable similarity in rapid onset of prophylactic and treatment activity of reproxalap. Approximately 1/2 of patients with ocular dryness also complain of ocular itching, the primary symptom of allergic conjunctivitis. And thus, we believe the overlap between dry eye disease and allergic conjunctivitis is considerable. Accordingly, the 2 patient populations responded to reproxalap in a similar manner during chamber challenges, highlighted by rapid improvements in ocular itching, dryness and discomfort as well as ocular redness. Following completion of the ongoing tear RASP assessments, the design of the main cohort of TRANQUILITY will be finalized, and we expect initiation of enrollment next month. Slide 12 diagrams 2 potential design options for the main cohort, which include either a 2-day challenge trial similar to the run-in protocol or a 2-day challenge followed by 26 additional days of dosing as was originally proposed. We've discussed both designs with the FDA. And to our knowledge and based on the recent guidance, we believe that either design would be acceptable. Slide 13 summarizes our upcoming milestones, which include initiation of TRANQUILITY 2 this quarter. TRANQUILITY and TRANQUILITY 2 are expected to represent the 2 pivotal sign trials required for NDA filing. In addition, we expect INVIGORATE, our second Phase III clinical trial with reproxalap in allergic conjunctivitis, to complete in the first half of this year. And on those happy notes, we'd now like to open the call for questions. Operator?

[Operator Instructions] Louise Chen with Cantor.

Congratulations on the data. So I had a few. First question, we got some questions from the audience, just asking if you can confirm that these other signs and symptoms from the chamber study are acceptable as Phase III endpoints for the FDA. And based on this data, how do you think about RASP reduction readout that's coming up? Second question I had for you is what is your payer and commercial strategy for reproxalap, assuming that you do get approval? And when will you start building out your commercial infrastructure?

Thanks, Louise, and I will answer the first question, and I'll turn the call over to Dave McMullin, our Chief Business Officer, to answer the second question. The data announced this morning are quite spectacular in so many ways. The direct answer is absolutely yes. Disease signs and symptoms are all approvable in the eyes of the FDA. I want to point out that we have, we believe, already achieved the symptom endpoints or the symptom trials required for NDA submission. We're quite focused on signs. What's remarkable from today's results is that we were able to confirm the symptomatic effects, the symptomatic activity of reproxalap that we've already previously demonstrated over 12 weeks of therapy, and we were able to confirm symptomatic drug activity within minutes of dosing, which is completely unique. As I mentioned in my prepared comments, we believe this is the first drug for chronic administration in dry eye disease to demonstrate activity within minutes of dosing, which is quite important to patients and physicians, especially in a standard of care landscape today where drugs require weeks, at least, of therapy to demonstrate effects. The ocular sign we described today, ocular redness, is an approvable sign endpoint. I think one of the key take-home messages from our call today is that the run-in demonstrated that we have options regarding our signs. We're not dependent on one sign or another now that we've demonstrated ocular redness changes acutely in dry eye patients, which is consistent with what we previously demonstrated in allergic conjunctivitis patients. We believe now we have important options as it relates to FDA approvable signs. Dave, I'll ask you to comment on the commercial implications of these data.

Happy to, Todd. Thanks for the question, Louise. As you know, it's been our strategy at Aldeyra to produce the best product profile possible with reproxalap as the first novel entrant in eye -- in dry eye disease in years, and we're very excited by the data that we've achieved to date. We've seen chronic efficacy and now we've seen, with reproxalap, acute efficacy. This is important in combination because the profile simplifies the journey that patients have to go through in order to manage their disease. That's important because it affects the way that we'll be able to position the product in the marketplace. We believe that we have a first-line potential with our profile, and we believe that payers will recognize the advantages of having one chronic treatment that can also address the signs and the symptoms of the disease acutely. Today, it's not uncommon for patients and physicians to use multiple treatments as they initiate and try to maintain control through flare-ups of the disease or bad days. We believe with reproxalap that in the future that can all be simplified. So you can have one product that addresses the disease chronically and that allows you to address those bad days as well in an effective manner. The pricing will be decided at a later date, but we have done payer research, and payers are very interested in the profile that they see with reproxalap. We've gotten good feedback, and we're confident in the guidance we provided previously that we will price reproxalap in line with leading dry eye disease branded products. Your question on the build-out. As we've guided previously, we expect to be in a position to file our NDA at the end of this year. So this is the year, Louise, that we also will be looking at building out the organization in preparation for commercialization. In addition, we're committed to finding the best path forward for making this product a success and that includes partnering discussions, and we continue to have ongoing partnering discussions and keeping them up-to-date on the latest developments.

Kelly Shi with Jefferies.

My first question is for ocular redness score, do you have data beyond 90 minutes? And do you have more time points over a longer-term period for the full Phase III protocol? That's my first question. And the second question is, I'm just curious like what actually drives the decision to include this new sign endpoint for Phase III beyond the tear RASP level assessment?

Thanks, Kelly. And I think the second part of your question is the key question that the Aldeyra management team will be addressing over the next several weeks, and that is what endpoint will we designate as the primary endpoint for the main cohort of TRANQUILITY? The answer as to how we decide that is quite simple, and that is, we will pick the endpoint that is most cost and time efficiently powered. That is the endpoint that generates the largest effect size and thus supports the smallest and fastest trial that yields a 90% chance of demonstrating a difference between drug and vehicle. The first part of your question, which is also very interesting is, have we studied redness beyond 90 minutes? We have not. In this particular trial, we only studied redness during the chamber. The FDA only requires statistical significance between drug and vehicle. The FDA does not appear to be concerned with chronicity of dosing or number of doses or the duration over which signs are assessed. The purpose of the sign, which is primarily a regulatory check box, is to demonstrate that the drug has a physiological effect other than relief of symptoms. And that can be achieved, per the recent FDA guidance that came out last month, in a chamber that could be achieved over a longer trial. And from our conversations with the agency, they appear to be quite neutral as to how statistical difference between drug and vehicle is demonstrated, per the FDA sign.

Yigal Nochomovitz with Citigroup.

Congrats on the data. I had a few questions. So as I understand it, one of the goals of the run-in was to inform the powering for the main cohort of TRANQUILITY. So with that being said, the 200 patients that you're referencing on the slide, does that already reflect the learnings from the run-in? Or is there a possibility that that 200 will change, go up, go down, given what you've seen in the run-in cohort? And then secondly, with respect to the RASP endpoint, could you just explain the reason as to why the RASP analysis is taking a bit longer? And also I'm assuming that you will wait for the RASP data from the run-in before initiating the main cohort of TRANQUILITY, if you could just confirm that?

Yes. Thanks, Yigal. I can confirm your last statement that we will finalize trial design, which includes the powering, once we have the RASP data, which I -- as I mentioned in my prior comments, we expect by early February. The RASP data are obviously more complex to derive. Measurement of RASP and tears isn't as simple as looking in someone's eye and seeing how red it is or asking a subject's opinion of their ocular dryness. Tears have to be collected. They're then stored at a low temperature, they're shipped to a laboratory for analysis and that analysis has to be per FDA guidelines for test validations. I think the -- I think it's safe to say that the powering is mostly reflective of what we originally thought when we began the run-in cohort of TRANQUILITY. We are, obviously, going to finalize powering once we see RASP data. Were we to power on redness, I think the numbers that you cited, roughly 100, perhaps a few more patients per arm are consistent with 90% power to detect a change in redness during the chamber. So either way, I don't think we're too far off. I think they could go up a little bit if redness is the primary endpoint, they may be able to go down a little bit if RASP is the primary endpoint. But I hesitate to speculate further until we see the RASP data.

Okay. And if I could just ask a hypothetical, assuming the RASP results are also statistically significant and on par with what you see for the redness. Is there a current preference for which sign you'd want to select? Or are you just going to wait and see? I mean what's the current view on where you're leaning there?

I think the -- for the trial, for the main cohort of TRANQUILITY, the preference will be entirely determined on statistical powering. Our goal is to complete our Phase III program and to complete the Phase III in the most time- and cost-efficient manner possible. So the answer to your question is statistical powering. We will select the endpoint that is most easily powered. However, I will say that there are advantages, a priori to RASP; and there are advantages, a priori for redness. For RASP, we will be the first drug to demonstrate the mechanism of action in a human eye. We're not aware of any dry eye disease drug that has done that, certainly not lifitegrast and certainly not cyclosporine. So whether or not we select RASP as the primary endpoint ultimately for the main cohort of TRANQUILITY, but we're committed as a company to continuing to explore RASP. And at some point, I think it behooves Aldeyra, and I think it behooves the ocular inflammation field for us to further explore the relationship of RASP levels to reproxalap dosing. We're, obviously, quite interested in that. And the fact that the FDA allowed RASP to be a sign of dry eye disease and then, thus, ocular inflammation, it's hugely validating for our company. On the other hand, redness has considerable advantages, especially as far as physicians and patients are concerned. As I mentioned in my prepared comments, redness may be the only sign that patients are truly interested in. We were speaking with a key opinion leader yesterday, who noted that one of his dry eye disease patients has coworkers who thinks that he's on drugs because his eye is so red all the time, and the cosmetic appeal of reducing redness is obviously considerable. The fact that reproxalap works so quickly, not only in the dry eye chamber but also in the allergen chamber, for reducing ocular redness has tremendous advantages, and Dave touched on this a little bit in his comments, redness as a sign is maybe particularly useful commercially.

And then just one operational question. Should we expect that you convey the results of the RASP analysis in early February on your -- or are you just going to announce the start of TRANQUILITY's main cohort?

Well, either way, I think The Street will know the outcome of RASP because we will disclose, ultimately, the trial design for the main cohort of TRANQUILITY. Precisely how the RASP results are announced is not clear at this point. But as I mentioned, we're obviously very interested in RASP. And so you will hear from Aldeyra much more about RASP and ocular inflammation, especially as it relates to reproxalap dosing at some point in the future.

Justin Kim with Oppenheimer & Co.

Congratulations on this morning's results. Just a couple of questions from me. As you think about our -- rather, are you thinking about engaging regulators on the recent findings and finalization of the trial design? Or are there any specific areas that you anticipate might be sort of key points to discuss, if you do? Just want to clarify.

Justin, an interesting thought. We anticipated redness as a potential dry eye disease sign when we spoke with the FDA in the middle of last year. The reason we anticipated redness as a potential dry eye disease sign is illustrated in our slides from this morning from the allergen chamber. Where in the allergen chamber, we were able to demonstrate acute prophylactic and treatment-related effects of reproxalap on ocular redness, which is tremendous because for allergic conjunctivitis, that we are aware of, ocular redness is the only objective sign of that disease. And so when we spoke with the FDA about dry eye disease, we knew that ocular redness could be an objective sign of dry eye disease. And in our meeting with the FDA in the middle of last year, we specifically discussed ocular redness, not only in terms of an approvable objective sign endpoint, but also in terms of how redness might be assessed in terms of duration of therapy, the use of a dry eye disease chamber and other aspects of assessment. So I think the direct answer to your question is that we don't feel that we need to discuss further with the FDA any of the findings released today, which are obviously very encouraging. As I said in the earlier part of the Q&A session, the key takeaway from these data are that we have now options as it relates to our Phase III development.

Okay. Understood. And then as you sort of weigh the differences and potential benefits from, I guess, the 2-trial design option. I know you talked a little bit about sort of the rationale behind redness versus RASP. But just for the sort of 2-day acute versus adding in sort of 4 weeks of sort of treatment, can you just maybe walk us through what considerations those may play? And also, if you might see your one study do one, and another do the other?

The 2-day versus 28-day trial question is one that we have also spent a lot of time discussing internally. As I mentioned, our view is that the FDA is neutral as to the length of clinical trials designed to assess signs. In fact, in the recent guidance from December on dry eye disease, the FDA specifically says that a chamber can be used essentially to demonstrate signs and symptoms. So we are not aware that a 28-day trial is, in any way, required going forward. The upshot of today's data is that a 2-day trial is imminently possible. In fact, the strength of the data in so few patients is really quite remarkable. So whereas some weeks ago, we were not considering a 2-day trial, I think that is now a possibility for the company going forward and may have ramifications for the size and the timing and the cost of Phase III development going forward. We're particularly fortunate in this regard because many dry eye disease drugs are relegated to 12-week or longer trials. Obviously, from the drug developers standpoint, a 2-day trial is considerably more preferable than a 28-day trial.

Okay. That's really helpful. Maybe then talking about sort of the results today. When you think about the measures of the ocular redness and symptoms of dry eye, is there evidence in the literature on the impact of the chamber on participants sort of broadly? And to what extent has there been any influence based on patient baseline characteristics entering, if there's any evidence there?

We have no evidence that in the run-in cohort, the baselines differed between drug and vehicle, between reproxalap and vehicle. There probably is some evidence somewhere that more severe patients may behave differently in a chamber than less severe. But obviously, at baseline, we're trying to control for a uniform baseline characteristic of patients that enter the trial and then enter the chamber. I think what's interesting is that we gave drug 4 times, the day prior to the chamber. And we believe that the day 1 dosing explains the differences in groups that you see at time 0 in ocular redness in the chamber -- which is a very powerful finding that even in the very beginning of the chamber, drug was substantially lower than vehicle and ocular redness -- and that that difference between drug and vehicle was maintained throughout the duration of the chamber. But in terms of other characteristics about patients and how they behave in the chamber, there probably are some data out there. But as far as we're concerned, we're looking to make sure that all patients are coming into the trial, at least, with uniform baseline levels of disease.

Okay. That makes sense. The last question is just on the vehicle. Can you just remind us what the sort of formulation used here was? And whether there are any differences between that and sort of the prior studies for dry eye or AC?

Good question, Justin. The formulation we use for this trial was the same formulation that we used for RENEW Part 1, our Phase III dry eye trial, and the same formulation we used for the Phase IIb dry eye trial announced at the end of 2018. We have tested a novel formulation we announced in January of last year, positive data from that trial, that's the Phase II formulation trial. But the current data that were announced today are from the standard formulation from RENEW Part 1.

Julian Harrison with BTIG.

Congrats on the data. First, together with clean safety and tolerability, I was wondering if you could speak a little more to how important onset of action is from a compliance standpoint in dry eye disease? And how these data today further move the needle for you with that in mind?

Julian, thanks for the question. The activity, the onset of activity is critical. As I mentioned in my prepared comments, we had what we believed was industry-leading onset activity -- of activity at 1 week after initiation of therapy. And that's the data we presented today from RENEW Part 1 that had disclosed previously. TRANQUILITY was about how quickly can we measure differences in activity or onset of activity following acute dosing, that is give a dose of drug, measure within minutes, signs and symptoms. What's so remarkable is that reproxalap works within minutes. The dots on these graphs that you see from the chamber are about 5 minutes apart, in general. So within 5 minutes, one can see activity in signs and symptoms, which is tremendous. We are not aware, as I previously said, of any drug for topical ocular use, for chronic use in dry disease that can make such claims of rapid, within-minutes onset of activity. And for those reasons, we're obviously very thrilled. Part of the challenge from the health care provider standpoint is that patients must take standard of care, the current standard of care, for weeks before feeling any relief, and, in some cases, for months. And so the challenge of the health care provider is to keep those patients on therapy. Imagine now, though, a patient coming in to a health care provider's office, a drug being administered, reproxalap being administered in the office, and before the patient leaves the office, in fact, within minutes of the dose, the patient feels better. And the patient can observe his or her ocular redness levels diminishing. That's a game changer, that's a potentially new paradigm, which is highlighted in the KOL quote, Dr. Perez's quote in our press release today, this is really of interest to physicians. I don't think the current challenge in dry eye therapy today is efficacy. I think it's keeping patients on drug to reach levels of efficacy over weeks or months of therapy. And the great news from today's data is that reproxalap seems to work acutely. The other way of thinking about the data, Julian, versus RENEW Part 1, which was a 12-week, a highly durable effect, is that the data from RENEW Part 1 is really a culmination of acute-acting or rapid-acting activity, both the symptom and the sign level of reproxalap. And so in a sense, we have what we believe potentially the best of all worlds: an acute-acting drug that is able to sustain activity over a long period of time. And in the case of RENEW 1 and the Phase II formulation trial, that was 12 weeks.

Okay. Great. That's helpful. And then on the 2-day versus 28-day topic, I'm curious, is this contingent at all on how clean the mass spec data are, if you like, RASP as a registrational sign? Or could ELISA possibly show meaningful changes within 2 days as well?

We believe that either RASP or mass spec have the potential to demonstrate changes in RASP over 2 days. The idea that throughout a chamber or over 2 days of dosing, during which patients are stressed -- and they're stressed because at tear levels -- tears are extracted from their eyes in multiple occasions -- that RASP levels could change both 3 RASP levels and protein-bound RASP levels. So either one in theory could work over 2 days. I think over 28 days, ELISA is probably best suited because that's measurement of protein-bound levels, those change a little bit more slowly over time. They represent the accumulation of RASP in tears. I always tell people that it's a little bit like hemoglobin A1c versus glucose levels for those of us that are familiar with diabetes -- that really it represents, over time, a RASP level. But for the 2 day, I think either RASP assessment can work. I say that not having seen the data, of course. But in theory, we have possibilities there.

Matthew Cross with Alliance Global Partners.

Congrats on another round of expectedly positive data. Just had a couple of questions kind of related to the theme of chronic usage or a chronic treatment of dry eye with reproxalap as opposed to the acute, which I know we're kind of focused on acute here, specifically with regards to redness and dryness. But I wanted to touch on kind of 1 point of the data that was maybe less favorable, but maybe less appropriate for this trial, which was the Schirmer's testing. Then I wanted to get a sense for -- it looked like there was a footnote in here that the Schirmer's had only been done in patients after a single dose exposure. So I wanted to get a little bit of context around that. And maybe just some detail around your view on the use of Schirmer's in general for these kinds of short duration studies? It sounds like that's usually a measure. I know you've previously shown over a number of weeks that you see an improvement in Schirmer's with reproxalap in prior testing. So is this kind of 2 day -- we could talk about it maybe in a situation where you go forward with a 4-week trial -- but in 2-day settings, it make sense to test Schirmer's and then you continue to do so? Or is that not really such an appropriate endpoint to keep in the trial, if it does remain a very short time frame?

Thanks, Matt, and thanks for bringing up Schirmer's. I'm thrilled with the Schirmer's result. This kind of difference for an anti-inflammatory drug, I think, is quite remarkable. In fact, it's consistent with the differences we announced in the Phase IIb trial back in 2018, where we achieved statistical significance between drug and vehicle. I think the patient numbers are very small here. So that's why the p-value isn't significant. But the effect size, not only is it in the right direction, but in terms of magnitude, I think, is particularly exciting for us. That said, I don't know that it makes sense for us to power a trial on Schirmer's test. Our mechanism of action is not stimulation of the lacrimal gland, and instead is an anti-inflammatory effect, which indirectly probably increases tear volume. The really selected Schirmer's test for a single dose is that in the allergic conjunctivitis Phase II data in the chamber, which we announced and released earlier, I should say, late last year at the American Academy of Ophthalmology. There is an acute increase in tearing, at least tearing scores reported by the patients after reproxalap administration that exceeds that of vehicle. And that's why we tested Schirmer's here after a single dose to quantify that effect, not from the patient standpoint, but by using the Schirmer's test, which most of you know, it consists of inserting a strip of paper into the eye and measuring in millimeters, the wicking of tears into that piece of paper from the eye. I'm quite pleased with the Schirmer's results. I'm glad that we were able to demonstrate that kind of effect size. To your question about endpoints, my suspicion, not having all the data from the trial, but my suspicion is we will continue to include Schirmer's test as a secondary endpoint and that that endpoint has a reasonable chance of reaching statistical significance with a larger -- in a larger number of patients in the trial. Having said all that, I don't think that Schirmer's is critical to Aldeyra, as I mentioned. This reproxalap is an anti-inflammatory drug. It is not a direct stimulant of the lacrimal gland. I do not think that patients care about Schirmer's tests. I haven't heard a patient say, I wake up every morning and think, what is my Schirmer's score. Tear volume is something that is of some interest to primarily academic and [ tear segment ] physicians. But general health care providers that treat patients with dry disease and allergic conjunctivitis do not routinely follow patients using Schirmer's tests. Obviously, dry eye disease is a culmination of many different pathologies, reduced tear volume is probably one of those. But I don't think it is in any way as important, say, as ocular redness, which patients do care about, and physicians do care about and hear about. And that's why we're excited about the results that we generated and announced today.

Absolutely agreed. And I don't in any [ way ] mean to overly preoccupy us with focusing on the p-value for that test, more just to get a little bit of additional background around the appropriateness of Schirmer's in these kind of more rapid studies. And then I think the only other question I wanted to touch on was, again, related to the kind of long-term data as we're also focused on the short-term sign confirmation. I wanted to get a bit of a status update on the long-term safety study that's meant to support chronic use for dry eye and allergic conjunctivitis. Just to make sure that the timing is on track for -- as INVIGORATE wraps up and these 2, TRANQUILITY wanted to do as well.

We are on track with the safety study. The safety study is often something that investors forget about, and thank you for bringing it up. We've undergone thorough NDA gap analyses and reviews and are internally very focused on putting our best foot forward for NDA filing, and the safety study is part of that. The FDA guidelines, again, which were highlighted in the December guidance, are very clear regarding safety studies. The data needs to include approximately 100 patients at 12 months. And then there can be a submission prior to that with earlier time points and so forth. But we're certainly on track. And at this point, I don't see the safety study is necessarily gating for NDA submission.

Esther Hong with Berenberg.

Congratulations from me on the data. So first, assuming positive data, I'm really looking into crystal ball and assuming positive data from both TRANQUILITY and TRANQUILITY, the second study of the Phase III studies. What steps remain for NDA submission other than the safety study?

Right. So the -- thanks for the question. TRANQUILITY 1 and 2, as I mentioned in my prepared comments, will be the 2 pivotal sign trials. The safety study that Matt just asked about will be part -- a key part of the of the NDA submission. Although, I will note that we have never, in over 1,100 patients, now almost 1,200 patients, seen any safety signals with subjects that were dosed up to 12 weeks and in some trials up to 8 times a day. So we feel very confident about the outcome of the safety trial in terms of data. And then finally, a large part of the NDA submission has to do with chemistry manufacturing controls, which means that your commercial process has to be clarified and qualified. It means that the commercial batch, the commercial product needs to pass stability requirements and so forth. So that's another major ongoing effort internally. I would say, between the completion of the TRANQUILITY trial and the safety study and the CMC requirements that I just mentioned, those would be the major components remaining for NDA submission.

I-Eh Jen with Laidlaw.

Congrats, guys, on this very positive outcome. My first question is that you mentioned about the prophylactic potential of the drug or at least aspects of that. And how do you see this particular potential attributes could impact on the future real-world prophylaxis in patients?

Thanks for asking about prophylaxis. I was hoping someone would ask about prophylaxis. One of the advantages of the chamber is that the drug can be administered prior to challenge, prior to entry to the chamber, which is really an assessment of prophylaxis. Can you present the escalation of symptoms or signs. That's exactly what we showed, both in the allergen chamber data and in the dry eye chamber data. That pre-administration of drug prior to challenge, prior to the escalation of symptoms or the escalation of redness seems to have a marked effect. And if you look at some of the graphs from the slides we presented today, you can actually measure the slopes of the lines from time 0 to the second dose. So the effect of the first dose that was administered prophylactically. And you can see that the slope is lower with drug-treated patients than with vehicle-treated patients. And that's true not only in the allergen chamber, but also in the dry eye disease chamber. So what does that mean commercially? Well, I think what it means is that subjects or patients can, in the real world, administer drug prior to exacerbation of symptoms and prior to exacerbation of redness, prior to exacerbation of inflammation. And that's quite meaningful to people, as you can imagine. It's one thing to experience worsening symptoms and in this case, say, ocular redness and then treat it and ameliorate those symptoms. It's a whole another thing to prevent those symptoms. So our view in Aldeyra is that the prophylactic activity of reproxalap is really quite meaningful. The bonus from the chamber data is that there's also a treatment effect -- so both in the allergen chamber and the dry eye chamber -- around the peak of symptoms that subjects reach in those chambers. If you administer a second dose, you see this more or less immediate effect of reduction, especially relative to vehicle in both signs and symptoms. So I think internally, we're quite thrilled about the prophylactic effect and the treatment effect. We are not aware of another topical ocular drug that has been able to demonstrate this with acute dosing, both of those effects -- prophylaxis and treatment.

Okay. Great. That's very helpful. And maybe to follow up actually on this issue, which is that is there a thought, or maybe in the future, to be able to put this effect in a clinical approved, so you'd be able to put that on the late -- the future -- potential future label for the drug? Or is there any other activity you need to do?

The answer is potentially label discussions were always part of negotiations between the FDA and the sponsor. I do think, however, disease data that we announced today will be public in some manner. If they're not on the label, they will be in a manuscript for all the reasons that, Yale, you and I just discussed, which is this has never been shown. Acute activity within minutes for symptoms and redness has never been shown for a chronic therapy for topical ocular use. So this will come out in some form or other, and it should come out. I really do believe what Dr. Perez said in our press release this morning, which is, this is a potential paradigm shift in the acute activity occurring within minutes is a potential paradigm shift for the treatment of dry eye disease and thus, these data deserve to be announced and promulgated, either in the form of a label or a manuscript.

Okay. Great. And maybe the last question here is that in terms you use RASP as a endpoint, or one of the endpoints, whether this thought potentially could have impact, not only in the dry eye and the AC on dry eye, but also in other indications you guys are exploring because this will be the first time sort of officially the RASP level been assigned important sort of gating factor or measurement for a drug progression or lack of it?

The implications for RASP are broad for Aldeyra. As you know, our company was founded on RASP as a target. We are the leader in RASP inhibition. And RASP inhibition as a therapeutic modality applies broadly, not only to eyes, but also to the remainder of the body. That is the subject of ADX-629, which is the orally available RASP inhibitor that's currently in 3 Phase II programs for systemic inflammation; at the moment that is COVID, psoriasis, and asthma. In a way, the FDA's decision to allow RASP as an objective sign of dry eye disease, which is clearly an inflammatory disorder, is hugely validating for Aldeyra, regardless of the RASP results in tears. What it really says -- what that decision from the FDA really says is that RASP is an important target and an important mediator and an important sign of inflammation. And to your question, Yale, not only ocular inflammation, but also inflammation broadly or just systemically.

There are no further questions at this time. It is now my pleasure to turn the call back over to Dr. Brady.

Well, thank you all again for joining us this morning. And as always, we look forward to keeping you updated on our progress as we continue to bring forward potential best-in-class, immune-modulating therapies that improve the lives of patients and serious unmet medical needs.

This concludes today's call. We thank you for your participation. You may now disconnect.