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

Ladies and gentlemen, thank you for standing by, and welcome to the Aldeyra Therapeutics Conference Call. [Operator Instructions] I would now like to turn the conference over to your Chief Financial Officer, Joshua Reed. Please go ahead, sir.

Good morning, everyone. With me is Dr. Todd Brady, President and Chief Executive Officer of Aldeyra. This morning, we issued a news release reporting top line results from the Phase III INVIGORATE clinical trial of reproxalap in allergic conjunctivitis. A copy of the news release is available on the Investors & Media section of our website, www.aldeyra.com. The news release should be read and considered in conjunction with the slides presented and prepared comments made on today's call. 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 risks that result from clinical trials or portions of clinical trials may not accurately predict the results of future trials for the same or different indications 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 may 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. Now beginning with Slide 3, I will turn the call over to our President and Chief Executive Officer, Dr. Todd Brady.

Thank you, Joshua. I am excited to share with you all this morning, the remarkable top line results from our Phase III INVIGORATE trial in allergic conjunctivitis, in which statistically significant improvement over vehicle was observed for the primary endpoint of patient-reported ocular itching, the key secondary endpoint of investigator-assessed ocular redness and the secondary endpoints of patient-reported ocular tearing and of total ocular severity score. INVIGORATE is the second positive, large, well-controlled Phase III trial for reproxalap in allergic conjunctivitis and the third positive trial of reproxalap demonstrating improvement versus vehicle of size and symptoms in a chamber model of anterior ocular inflammation, including allergic conjunctivitis and dry eye disease. We wish to thank the INVIGORATE investigators and the Aldeyra clinical staff that worked so hard on the INVIGORATE trial over the past 2 years as well as the subjects that participated in an INVIGORATE. Most importantly, we are thrilled to provide new hope for the millions of patients and thousands of physicians that today are forced to rely on therapies that are often inadequate or cannot be used chronically due to serious side effects. Reproxalap represents true innovation in allergic conjunctivitis, a novel drug with a novel mechanism for the first time in decades. The results of INVIGORATE suggests substantial utility of reproxalap in a disease that affects approximately 1/3 of the U.S. population and more than 1 billion people worldwide as is described on Slide 4. With the rise in global temperatures and seasonal pollen counts, the prevalence of allergic conjunctivitis continues to increase. Current therapies are not effective in significant proportions of patients or cannot be used for chronic treatment due to serious side effects. And yet, new therapeutic mechanisms in allergic conjunctivitis are few and far between. As is illustrated on Slide 5, reproxalap represents a potential new approach for the treatment of allergic conjunctivitis that is independent of histamine, which after exposure to allergen persists for only a limited time. The rapid elimination of histamine may explain why an estimated 30 million people in the United States alone are not adequately treated with topical antihistamines, and while topical corticosteroids may be used for the treatment of the persistent effects of ocular allergy, corticosteroids cannot be used for chronic therapy due to serious side effects, which may include the potential for elevations in intraocular pressure, cataract formation, ocular infection, corneal ulcers and other potentially sight-threatening complications. In contrast to histamine, which is an acute and transient inflammatory mediator RASP, the target of reproxalap, lead to a chronic self-perpetuating inflammation that results in persistent symptoms occurring over hours to days. Reproxalap covalently binds to and has been observed to irreversibly inhibit RASP, providing a potentially unique and durable approach for the treatment of ocular allergy. Given reproxalap's safety profile and clinical results, observed now across 14 clinical trials, we believe that reproxalap, if approved, could represent an ideal complement to antihistamines and a replacement for corticosteroids. Slide 6 summarizes the INVIGORATE trial, which was conducted in an allergen chamber as part of an FDA-approved trial design. The allergen chamber model is an innovative and demanding method, we believe is optimal for testing allergic conjunctivitis drug activity because it combines the real-world exposure of a field trial with a controlled pollen exposure of directly administering allergen to the eye. In addition, the allergen chamber allows for the assessment of prophylactic and treatment effect of drug. To our knowledge, reproxalap is the first late-stage investigational therapeutic that has been rigorously tested in an allergen chamber. Slide 7 outlines the 2-way crossover design of the randomized vehicle-controlled, double masked INVIGORATE trial. Allergic conjunctivitis patients were exposed continuously to controlled amounts of ragweed pollen over approximately 3.5 hours. Subjects reported ocular itching and tearing scores, as well as investigator-assessed ocular redness score were recorded approximately every 10 minutes. Drug or vehicle was administered just prior to allergen exposure and at 90 minutes when peak symptoms typically occur. The administration schedule allowed for the assessment of the activity of reproxalap in preventing the allergy symptoms and signs as well as drug activity in treating the disease at near peak symptomatology. As shown on the right of the slide, the primary endpoint for INVIGORATE was statistical significance in ocular itching at a majority of 11 time points between 110 and 210 minutes in the allergen chamber. The key secondary endpoint was change from baseline in ocular redness. The trial also evaluated patient-reported ocular tearing score and the ocular severity score, an 11-point composite of itching, tearing and redness scores in the allergen chamber. The key secondary and secondary endpoints were assessed using a mixed effect model of repeated measures or MMRM analysis over the duration of the chamber. Remarkably, INVIGORATE achieved the primary endpoint of improvement over vehicle and patient-reported ocular itching score at all 11 prespecified time points each with a p-value of less than 0.0001 as is summarized on Slide 8. Over the duration of the allergen chamber, improvement over vehicle for the key secondary endpoint of ocular redness was achieved, as were the secondary endpoints of patient-reported ocular tearing score and the total ocular severity score. Consistent with the primary endpoint, p-values for all secondary endpoints were less than 0.0001, indicating definitive superiority of reproxalap across symptoms and signs of allergic conjunctivitis in a setting of continuously moderate to high pollen exposure. Importantly we are not aware that any other investigational drug has demonstrated similar activity in a late-stage allergen chamber trial. INVIGORATE enrolled 95 subjects, 89 of whom completed both treatments. Consistent with prior clinical experience, there were no observed safety or tolerability concerns in the trial and no discontinuations due to adverse events Slide 9 illustrates the results of the primary endpoint of patient-reported ocular itching. Per FDA recommendations, the primary endpoint required that a majority of time points between 110 and 210 minutes after chamber entry were statistically significant in favor of drug. As is indicated on the chart, all prespecified time points were statistically significant, and the p-value for each time point was less than 0.0001. Both prophylactic and treatment effects of drug were demonstrated, in particular, the slope of the itching score curve between the first and the second doses of drug was lower than that of the vehicle curve and the increase in ocular itching from baseline for each time point over the entire chamber was less in reproxalap-treated patients. After the second dose, progression of ocular itching was halted and trended slightly lower in drug-treated patients versus slightly higher in vehicle-treated patients. Similarly, the key secondary endpoint of ocular redness, on Slide 10, what was observed to be statistically significant over the entire chamber. Unlike with ocular itching scores, baseline redness was slightly higher in drug-treated patients. However, the increase in redness from baseline for every time point over the entire chamber in was less in reproxalap-treated patients than in vehicle-treated patients. The redness scores were remarkably consistent across patients. Standard errors were approximately 0.03 units for each arm and 0.01 units for the [ contrast-to-cross ] arm. Importantly, any noticeable change in redness, which is, by definition, what a redness scale measures, is clinically relevant. As we discussed with the release of the top line results from the run-in cohort of the TRANQUILITY trial in dry eye disease, ocular redness represents possibly the only objective sign of ocular inflammation that is of importance to patients. In allergic conjunctivitis, in particular, ocular redness represents the key of the disease, hence, the designation read as the key secondary endpoint. As with ocular itching scores, both prophylactic and treatment effects of drug were demonstrated, this slope for the redness curve was lower in drug treated patients between the first and second doses. And after the second dose, progression of redness was halted and trended slightly lower on drug-treated patients versus slightly higher in vehicle-treated patients. Similarly significant results were a secondary endpoint reported ocular tearing score illustrated on Slide 11, and the composite ocular severity score, which includes itching, redness and tearing illustrated on Slide 12. Ocular tearing is another thing and persistent symptom that diminishes quality of life for a conjunctivitis patient and represents the second most bothersome symptom besides itching. The activity of reproxalap versus vehicle, as assessed by the total ocular severity score, an omnibus measure of the signs and symptoms of allergic conjunctivitis indicates the near-definitive overall utilities of reproxalap for the treatment of the disease. Slide 13 summarizes the safety profile for INVIGORATE. There were no discontinuations due to adverse events, and there were no observed safety or tolerability concerns. Reproxalap has now been administered to more than 1,200 patients across 14 clinical trials with no observed clinically significant findings on safety assessments, including visual acuity, intraocular pressure, slit lamp biomicroscopy and dilated fundoscopy. Turning to Slide 14. In aggregate, reproxalap has demonstrated success across a robust development program for allergics conjunctivitis trials across 2 different allergen challenged models. In combination with ALLEVIATE, the INVIGORATE represents the second large well-controlled trial to achieve statistical significance for the primary endpoint, including the Board of the TRANQUILITY trial in the dry eye syndrome. INVIGORATE also represents the third chamber trial in which reproxalap was statistically superior to vehicle for symptoms and ocular redness. To our knowledge, no investigational allergic conjunctivitis compound has demonstrated comparable activity across symptoms and signs in a large, well-controlled allergen chamber trial. And in addition, to our knowledge, no recent investigational allergic conjunctivitis treatment filing has encompassed a comparable breadth of data across multiple models. The profound interrelationship between allergic conjunctivitis and dry eye disease, summarized on Slide 15 is well described in the scientific literature. About half the patients that complain of ocular dryness also complain of ocular itching and vice versa. The 3 common culprits of ocular surface disease, pollen, pollutants and parched environments make the etiologies of dry eye disease and allergic conjunctivitis, difficult to entangle for healthcare providers, necessitating novel therapies for chronic use that can treat both conditions. The potential importance of the relationship of reproxalap to the overlap of allergic conjunctivitis and dry eye disease is illustrated on Slide 16, which demonstrates the consistency of improvement in itching and dryness to hallmark symptoms of ocular surface disease across different challenge models featuring pollen and dry eye irritants and across patients with allergic conjunctivitis and patients with dry eye disease. The striking consistency for improvement and reduction of ocular redness is illustrated on Slide 17. As mentioned previously, ocular redness may represent the only sign of anterior ocular inflammation that is of importance to patients, and by extension to the healthcare providers. Looking at our upcoming milestones on Slide 18. Now having completed INVIGORATE, we remain on track to report top line results from TRANQUILITY and TRANQUILITY 2 in the second half of this year, and we look forward to discussing our NDA filing in allergic conjunctivitis with the U.S. Food and Drug Administration shortly. Slide 19 summarizes the potential commercial advantages of reproxalap in allergic conjunctivitis and dry eye disease. Reproxalap appears to improve symptoms and signs within minutes, and the symptomatic activity of reproxalap appears to be broad. In summary, reproxalap represents a new paradigm for the treatment of anterior ocular inflammation, a single drug with broad applicability in inflammatory diseases that affect the front of the eye. In conclusion, I reiterate my gratitude to the staff and patients involved in INVIGORATE and join the patient and healthcare community in welcoming a potential new approach for the treatment of allergic conjunctivitis. With that, operator, we'd be happy to take questions.

[Operator Instructions] First question comes from the line of Marc Goodman with SVB Leerink.

One is for the filing, can you tell us what is left to do with respect to the safety, the long-term safety, how many more patients do if you were to file for this indication? And then second of all, just -- you mentioned some thoughts, but maybe you could just give us your level of confidence now in the dry eye studies, just given what we know here?

Yes. Thanks, Marc. And we're thrilled you're involved. We know that you have been covering ocular surface inflammation for many years, and we're pleased that you're part of the team. Thanks also for the question regarding the path to NDA filings. As you correctly point out, NDA filings aren't only about efficacy, which I think we have clearly demonstrated with the INVIGORATE trial results, but also about safety and in addition, chemistry, manufacturing and controls. The safety database, as I mentioned in my prepared comments is large, over 1,200 patients now, 14 clinical trials, many different dosing paradigms of several different diseases. So I think from a clinical trial standpoint, the safety database is likely to be sufficient. What's left is the standard NDA requirement of a safety trial and allergic conjunctivitis that is a 6-week trial. So not a chronic trial like would be performed or is being performed in our case with dry eye disease over 12 months. The CMC question, I think, will be easily answered. We've identified our commercial process and commercial batches are on stability. I do think that the remaining requirements for NDA in allergic conjunctivitis, probably at this point, depend in terms of timing on the safety trial. Your second question about a potential read-through from INVIGORATE in allergic conjunctivitis to TRANQUILITY in dry eye disease is an excellent question. And one that we have been asked quite a bit about recently. I will say that there are many differences between the 2 chamber trials. The INVIGORATE allergen chamber obviously features allergen as an irritant, whereas the dry eye chamber features dry air as an irritant. The allergen chamber is longer, 3.5 hours of exposure versus the dry eye chamber, which is 90 minutes of exposure. And then finally, and I think most importantly, the dosing paradigm of reproxalap is slightly different. In the INVIGORATE trial for the allergen chamber, drug was administered just before entry to the chamber and halfway through the chamber, or I should say, 90 minutes into the chamber when symptoms are near their peak. In the dry eye TRANQUILITY chamber trials, however, drug is administered on day one, 4 times. And then day 2 is the dry eye chamber, like with the allergen chamber, drug is administered just prior to the dry eye chamber and then 5 minutes into the chamber. So in summary, the patients in TRANQUILITY will receive more drugs than in INVIGORATE. I do think there is potential read-through, as we mentioned in our prepared comments, and as you can see in the slides, the reduction in ocular redness is quite consistent, not only across the Phase II and the INVIGORATE allergen chamber trials, but also relative to the run-in cohort of the TRANQUILITY trial. So in some, I would argue that the data today in ocular redness and INVIGORATE bode well for the potential of TRANQUILITY where ocular redness is the primary endpoint.

And just a follow-up, the 6-week trial that's necessary for safety, has that started? When will that be done?

It has not started and that will require some discussions with the FDA prior to initiation. But I do not think, given the length of the trial, the safety study would impair our guidance of potentially filing NDAs by the end of this year, Marc.

Your next question comes from the line of Louise Chen with Cantor.

So I wanted to ask you a few. People are asking me if you will wait until the TRANQUILITY 1 and 2 results, to file an NDA? Or would you possibly file with just the allergic conjunctivitis indication? And if so, would you just launch with allergic conjunctivitis, if that got approved first? And then secondly, just a follow-up on this 6-week safety study for allergic conjunctivitis, can you use that dry eye 12-month data or does it have to be a separate study? And then last question is, any comments on your commercial efforts for the upcoming potential launch of allergic conjunctivitis and then potentially dry eye as well?

Great, Louise, and thanks for the questions. I do not think that we will wait for TRANQUILITY before speaking with the FDA. In other words, we plan to initiate conversations with the FDA based on the INVIGORATE results regarding allergic conjunctivitis very, very soon. Now the timing of the filing for NDA in allergy versus the timing of the filing for the NDA in dry eye disease really depends on the conversations with the FDA. In fact, our preference is to ask them how they would prefer to receive the NDA. And it could be together such that 2 labels are negotiated at the same time, it could be in series. And I would say, more or less, we at Aldeyra are agnostic as to how that happens, we believe we'll have the sufficient safety and efficacy data to file those NDAs, and the particular process, we'll leave up to the agency. In terms of sequencing, my guess is that dry eye disease would be launched first, mostly because the pricing in dry eye disease and the market in dry eye disease, I think is more optimal than that of allergy. And we'd like to get on formularies with a dry eye disease label first for allergy. But again, the timing of the NDA may not relate to launching formularies and so forth. In terms of commercial build-out, maybe I will turn that question over to Josh Reed to comment there.

Thanks for the question, Louise. So given our previous guidance regarding filing an NDA potentially at the end of this year, yes, we'll be getting our planning on building out the organization for commercialization. With that said, however, we are committed to making reproxalap a potential success commercially. And as a result of that, we continue to explore partnering and business development conversations.

And any comments on the safety study and potentially use a dry eye safety study or will they just be separate?

Thanks for the reminder. No, they have to be separate studies. The dry eye safety study is in normal subjects, whereas the allergy safety study needs to be performed in subjects for the history of ocular allergy. So it is -- it would be difficult to combine those 2 studies. As I mentioned, however, a 6-week safety study in ocular allergy is not going to be difficult or gating in terms of timelines.

Our next question comes from the line of Yigal Nochomovitz.

This is Yigal Nochomovitz. Todd and Josh, I just have one question on the label. Is this label going to be broad in the sense that it will just stay for the treatment of allergic conjunctivitis or will you have potentially some more specific language in the label referencing itching, redness tearing reduction and so forth? And then just the second part to that question is, do you believe that the label will indicate the reproxalap is for prophylaxis or for the onset of symptoms once symptoms appear?

This is a question that is particularly relevant to us these days. It has a lot to do with label negotiations, to some extent, the answers to your questions will depend on the in-label negotiation process. However, I can tell you that historically, allergic conjunctivitis drugs have received a label for the treatment of ocular itching associated with allergic conjunctivitis. Our understanding is that if redness can be achieved in clinical trials, then the label might be extended to the treatment of the signs and symptoms associated with allergic conjunctivitis. From a commercial standpoint, though, I don't think the difference between those 2 labels is significant. Obviously, we have fantastic efficacy in itching and activity in redness. So I think there is the potential for us to receive their indication as it relates to the ocular allergy. And of course, we would love to have the ocular redness data from allergy in the label because as I mentioned, it's very meaningful to patients and healthcare providers who are constantly hearing from patients that red eyes are not desirable and new innovative therapies for the treatment of redness, in addition to the symptoms of these diseases, are certainly in demand. In total, I think we'll go into the agency with that we are qualified to receive an indication for treatment of signs and symptoms. However, as I mentioned, I don't think commercially that a precise wording of that indication matters in allergic conjunctivitis.

Okay. And then is that also the case with whether the label might reference prophylaxis or that's too detailed?

That's an interesting question, Yigal, because typically, antihistamine has been approved. And what I would argue is a prophylaxis model, this treatment with drugs or vehicle prior on title exposure to allergens. I think by definition, that is a prevention model. However, labels do not reflect that terminology. So I am -- because reproxalap is the first drug that we're aware of to demonstrate both prophylactic and treatment activity in an allergen chamber model, I'm not sure how we'll wind up in terms of the wording of the label, but of course, we would love to have both prophylaxis and treatment somewhere in the label. I also think that prophylaxis and treatment activity is evident from the graphs that we've presented today. And I hope that some of those data will be in the label itself.

And just one other housekeeping question. Was there any particular reason that we did not analyze RASP in this study? Was it just sufficient to analyze RASP in the run into TRANQUILITY, so you didn't need to do that here?

Correct. RASP are difficult to measure in allergic conjunctivitis because of hyper lacrimation, which means excessive tearing. The tears of allergic conjunctivitis are so prolific and dilute, I think it has been very difficult to measure any biomarker consistently because of dilution. So RASP would not be appropriate to measure an allergic conjunctivitis, at least in tears.

Your next question comes from the line of Kelly with Jefferies.

My first question was regarding the RENEW 2 in dry eye trial. So actually it is my understanding from conjunctivitis to dry trial on the ocular redness endpoint? And my second question is how to position reproxalap in the market. So we know antihistamine class is pressured as the frontline treatment and topical steroids and that topical steroids maybe considered in patients with refractory symptoms. So how do you position the reproxalap in future marketplace. And also, what are the key driver attributes for reproxalap to enable breaking into conjunctivitis market?

Thanks for the question, Kelly, and I'm glad you asked the question about statistics, which is dear to our heart. All of us ultimately in the biotechnology are in the p-value business. And we take statistics very seriously. I've never understood why companies pick time points. Rather, that is more powerful to assess all time points in aggregate. And that's precisely what we've done with ocular redness and tearing and the composite severity score in this study, and it's precisely what we intend to do in the TRANQUILITY studies, that is affect -- assess redness over the entire chamber using all time points. I think that kind of assessment is more clinically relevant. As a physician, we're not -- as physicians, we're not concerned with how patients are doing at particular time points. We're concerned about how patients are doing overall. And ANCOVA and MMRM assessments are designed to assess just that. That is an overall picture of how patients are doing over time. We did have to select a predefined time frame for the primary endpoint of INVIGORATE, but based on items. And we selected the time frame after the second dose through the end of the chamber. Obviously, that was an excellent choice given the p-values we've seen in all of those endpoints. But overall, it's clear that the curves for the symptoms and signs of allergic conjunctivitis in the drug-treated patients are lower than the curves in the vehicle-treated patients. And we're just thrilled about the consistency of the data and the highly statistically significant differences in results. As we mentioned, we intend to continue to use overall assessment of the results, which includes MMRM analyses, for example, to distinguish drug versus vehicle-treated patients. Your questions about allergic conjunctivitis as it relates to the marketplace are also fascinating, Kelly, because the question is really, where would you use this drug? In which patients would you use this drug? I think that the key thing to remember is that now antihistamines are over the counter. And that means that when patients visit healthcare providers, generally, those patients have already tried antihistamines are our de facto antihistamine recalcitrant, meaning that they are not responding well or sufficiently or adequately to antihistamines, thus, a new therapy is needed. Now today, the only option is corticosteroid therapy, which, as I mentioned in my prepared comments, can be toxic, in fact, in some cases, severely toxic and cannot be used chronically. So in between antihistamines and corticosteroids is an unfilled, unmet medical need that I think could be filled with reproxalap. Imagine a patient that visits a healthcare provider, that patient's not responding to antihistamines, but the healthcare provider is, rightfully so, reluctant to put that patient on corticosteroids due to toxicity concerns. Well, now reproxalap in theory could offer a potential solution to that gap between antihistamines and corticosteroids. Does that answer your question, Kelly?

Yes. And congrats again.

Next question comes from the line of Justin Kim with Oppenheimer & Company.

Congrats on the results. Just maybe one first to begin. When you -- you visit the Phase II chamber results and compare them with INVIGORATE, were there any additional elements beyond size and powering that you believe contributed to the more robust activity at all time points compared with, I believe it was 9 of 11 previously?

Right. Justin, thanks for the question. That's correct. In the Phase II trial, I think over this time frame, we had 9 time points. And in the Phase III, we added a couple of time points. So we had 11 time points, but I think the results are substantially similar. The reason why the p-values went down, as you correctly surmised, Justin, is that the numbers of patients were higher in the INVIGORATE trial. I believe we had about 66 to 70 patients in the Phase II allergen chamber trial, whereas an INVIGORATE, as I mentioned, we had 95 subjects enrolled. So the power increased considerably. Also, as I mentioned in the prepared comments, at least about redness, the consistency of the data are remarkable across a time point to time point and assessment to assessment, standard errors are extremely low. So if you combine the more patients with a small standard error, low p-values will result. And I think that's what we're seeing here. There were really no other differences between Phase II and Phase III. Phase III was run over 2 winters. As you'll recall, allergy chamber trials cannot be run during pollen season, which is essentially spring through fall. So the trial must be run and at least in allergen chambers over winters. This was essentially a 2-year trial. As a result, the second year modestly hampered by COVID, like most clinical trials. But other than that, the 2 trials were identical.

Okay. Understood. And then thinking about sort of the upcoming safety trial, is there any potential to accrue experience in combination with antihistamine ahead of a potential initial commercial launch? Just thinking about how that sort of patient experience may be fleshed out even if it isn't necessarily going to be different than what's observed here.

I really like your comment about antihistamines, Justin, and as is illustrated on Slide 5, the histamine release is acute, histamine sits and it's pre-made once allergen binds to IgE surface of mast cells, histamine is released, the challenge with histamine is it's degraded rapidly and mast cells can't make it fast enough to replace extracellular histamine levels. However, antihistamines do work acutely because of that acute release of histamines. For the combination of an antihistamine with a more durable chronically acting drug like reproxalap may be attractive. And it's something we thought about and are continuing to think about. I think regarding the marketplace, it's fairly obvious that healthcare providers, if reproxalap is available and on the market, would combine the 2 therapies to sort of get that immediate effect of antihistamine in combination with the sub-acute effect and chronic effective of reproxalap.

Okay. Got it. Just a last question. Do you have a sense of what subset, if any, of the population enrolled participating in INVIGORATE suffered from overlapping dry eye and what those results may look like and whether we'll see those results, I guess, at future meetings or other presentations?

We don't know the overlap between allergic conjunctivitis and dry eye in INVIGORATE. Typically, Justin, we attempt to distinguish those 2 populations prior to enrollment. As you can imagine, for any clinical trial, it is very desirable to have a consistent standard, uniform patient population. And historically, sponsors running trials in allergic conjunctivitis and sponsors running trials in dry eye disease attempt to distinguish those 2 patient populations to eliminate any confounding variables that overlap the 2 diseases. The thought about running a trial in combinations of patients is really interesting. In fact, we've announced previously in our dry eye trials, effect of reproxalap on itching, which is interesting because itching is not typically thought of as a symptom of dry eye disease but as we all know, I think many dry eye patients itch, dry tissue generally itches, and thus, the anti-itch at reproxalap may have significant utility even in patients with dry eye disease. But we look forward to continuing to think about combinations of patient populations, which reflect, I would say, a real-world population in the near future.

Your next question comes from the line of Julian Harrison with BTIG.

Congrats on the data. On the redness read-through from INVIGORATE to TRANQUILITY, I'm wondering if you think minutes 90 to 180 are maybe a little more representative of what you might expect to see in the TRANQUILITY trials in terms of potential curve separation considering you have a full day of dosing prior to the chamber for these trials that really seem to correspond to a nice separation between groups of minute 0, at least for the running portion of TRANQUILITY, but this really didn't seem to be a possibility for INVIGORATE.

Right, Julian, and I must admit, I had not thought of that until just now, but you are 100% correct. The separation, as you can see on Slide 17, the rightmost panel, the separation between drug and vehicle in the run-in cohort of TRANQUILITY and dry eye disease was evident already at time 0, which, to your point, Julian, looks like 90 minutes or so if you compare that to the INVIGORATE redness results. I also think your supposition about why that's happening is correct. As I mentioned in a prior answer, the TRANQUILITY features day 1 of dosing, which is 4 doses, so that subjects before entering the chamber received 5 doses of drug, 4 doses on day 1, 1 dose prior to the chamber. And that, we believe, explains the difference at time 0 between drug and vehicle in the TRANQUILITY run-in cohort as you can see on Slide 17. I agree with you that it -- the differences between a drug and vehicle early on, in the TRANQUILITY chamber, the dry eye chamber, are due to different dosing paradigms, namely more dosing in the dry eye trial.

Your next question comes from the line of Matthew Cross with Alliance Global Partners.

Congrats on a very welcome result in AC. As I sit here rubbing my eyes like I'm not supposed to, due to all the oak pollen around right now. I had a couple of questions about the commercial potential here in AC, I guess, given how generally straightforwardly positive the data from INVIGORATE looks. The first was around chronic use, which I know, Todd, you mentioned in your release. And I wanted to clarify whether there was -- what additional work would be necessary to kind of make those claims? Is that contingent on the 6-week safety study that we focused on here in any way or just the totality of data across the development strategy? And then secondly, as we're thinking about the kind of market and overall in combination use with antihistamines. Just to clarify, do you feel you're really limited or will primarily be using reproxalap for AC as an antihistamine refractory population? Or given that you're also potentially marketing for dry eye and complete lack of side effects we've really seen here in allergic conjunctivitis, might there be more of a marketing campaign directed at the use of this really upfront when you -- when patients are beginning treatment for allergy as opposed to having to fail antihistamines and then see a physician to get that? I know there's an OTC advantage, but just wanted to think about kind of marketing potential and how restrictive that might be?

Thanks, Matt. Well, I could go on for an hour talking about these 2 very good points especially since you and I both suffer from ocular surface inflammation. Let me first discuss chronicity. In allergy, because we have used seasonal allergens, our label will be -- will highlight seasonal allergy. And seasonal allergy is by definition episodic, particularly in the spring and fall. If you look at prescribing patterns for the old antihistamines before they went OTC, you saw this bimodal distribution with these 2 large peaks, one in the spring and one in the fall because of the incidence of pollen, but why your question about chronicity is so interesting is the overlap of allergy and dry eye and the relationship of pollen to dry eye. There was data at ARVO some years ago indicating that pollen actually may be the most important factor regarding dry eye exacerbations, not humidity. So that you see peaks in dry eye disease that seem to follow seasons as well, but we know dry eye disease is a chronic condition. So there could be a use of reproxalap chronically, that is over many months extensively for the treatment of dry eye disease, but that would also cover this bimodal distribution of seasonal allergy that peaks in the fall and the spring. I think it's important for reproxalap that a long-term safety study is run, and that's exactly what's being done for dry eye disease, that's a 12-month study. Though we believe we can file on 6 months of data. That really allows reproxalap to be used chronically, whether patients have dry eye chronically, whether the patients have allergic conjunctivitis chronically or multiple times a year, probably doesn't matter as much as the fact that the drug is active in both diseases. And from a safety standpoint, can be used chronically. This is really quite unique. In many ways, from an efficacy standpoint, reproxalap is steroid-like. It's anti-redness, it's anti-inflammatory. We've demonstrated multiple cytokines that are inflammatory are reduced. We've demonstrated an increase in IL-10, really behaves from an efficacy standpoint as a steroid. However, reproxalap does not have the toxicity liabilities of corticosteroids, which as I mentioned in my prepared comments, are significant. In fact, I think there was a recent steroid approved for dry eye disease that is limited in the indication statement of the label to 2 weeks. So reproxalap may have a major advantage in terms of chronic therapy, particularly given the overlap of dry eye disease and allergic conjunctivitis productivities, which is why your question, Matt, is so interesting. Your second question is, are we going to be limited to antihistamine refractory patients? I don't know from a payer perspective, but from a practical perspective, I do think that most patients who are severe enough, will go to the drugstore, will go to the shelves that feature allergy eye drops and try antihistamines. What's now, in a way, sort of nice for reproxalap is if those patients aren't satisfied, and those patients see a healthcare provider, they're already status post antihistamine. There's sort of de facto antihistamine resistant. And that's when the healthcare provider today needs to make a difficult decision: Am I'm going to put this patient on corticosteroids and risk and intraocular pressure spike and risk a referral to a glaucoma physician or in the future, perhaps am I going to try reproxalap? So I really do think that reproxalap, as I mentioned, fills a large unmet medical need practically, Matt, between antihistamine and steroids.

Got it. No, I tend to agree. And certainly, broad spread use of antihistamines, but I don't think that necessarily means that it works consistently for me -- us out there dealing with it. So glad to have something like reproxalap, hopefully, coming to market soon.

Your next question comes from the line of Edwin Zhang with H.C. Wainwright.

Congrats on the positive data. Could you give us some more details on ocular redness over the duration of the allergen chamber, for example, what does it look like in the first 90 minutes? Do you also see statistical significance at 90 minutes? When do we expect to see the full data improving the patient baseline characteristics?

Edwin, thanks for the question, and thanks for your support. The redness question about the timing. Of the separation of drug versus vehicle is one that we anticipated. And obviously, we're quite interested in, given that particularly in dry eye disease, the drug seems to have a very rapid anti-redness effect. I believe at 72 minutes, there is statistical separation. Now I have to caveat that statement because remember, subjects entering the chamber don't have much redness. In fact, I believe if subjects have more than half a unit or a unit of redness at time 0, they're excluded or they have to come back another day for a different chamber test. So redness takes a while to develop in the allergen chamber in contrast to the dry eye chamber where the insult is much more severe. In the allergen chamber redness evolves more slowly. And thus, of course, it's difficult to distinguish groups if redness is, but not particularly evident in the beginning of the trial. However, I think in the TRANQUILITY data, you can see that there really is an acute effect in that model. And in terms of allergy, an effect prior to the second dose. As I mentioned in my prepared comments, the slopes of the lines between the first and second doses in redness are different. The slope of the drug-treated patients is lower, which indicates a prophylactic effective drug. And from the peak redness score, there's a slight trend down for reproxalap and a slight trend up for vehicles. I will say, I just want to reiterate that the consistency of the data here is remarkably strong. We actually used R to calculate a p-value for redness, typically for something less than 0.000 -- you just say 0.001. Here, the actual p-value according to ours is 7.9 x 10 to the negative 24th. So this is a highly statistically significant near definitive difference in redness and I think the good news, as you point out is that occurs even prior to the second dose of drug.

Great. Thanks for the color. When do we expect to see the full data?

Yes. So we intend to publish the full data at the conference or at least release the full data at a conference and/or a manuscript shortly. An example of the kind of data set we intend to generate was released last year, I believe, in December, at the American Academy of Ophthalmology Annual Conference. That is really an excellent data set that features all kinds of interesting results from the Phase II allergen chamber trial, including clinical utility results. And there, we measured time to itching and redness scores of 2, which as you know, is half the scale. Now an increase of 2 points is well beyond what typical clinical trials and physicians would consider clinically meaningful. So this is a conservative measure of clinical utility, but you can see those graphs in the AAO release from last year, and we would intend to do something similar for the INVIGORATE results, and I expect that they'll be at least as robust as they were in Phase II.

If I may, one more question. For allergic conjunctivitis, you have done both allergen chamber and allergen challenge studies. I guess you will submit all this data in this package. I understand you need to do an additional 6-month safety trial. But I just want to know if these efficacy trials and data are adequate for filing in AC?

Correct. As we mentioned in our prepared comments, we have never seen a potential filing for an investigational allergic conjunctivitis, a drug that is as robust as this filing in terms of the breadth of models, at least not recently, where reproxalap has generated positive data with direct allergen challenge. That's the conjunctival challenge used in ALLEVIATE as well as the environmental real-world challenge that we see in the allergen chamber for the Phase II trial and INVIGORATE. My suspicion is that activity of reproxalap across 2 different models is particularly attractive to regulators and physicians that are in the business of assessing probable response for their patients. That, in combination with the highly statistically significant changes, both in ALLEVIATE and in INVIGORATE, I think, are particularly compelling.

Next question comes from the line of Esther Hong with Berenberg.

Congratulations. Two questions. So given the overlap between dry eye disease and allergic conjunctivitis, can you remind us how patients are diagnosed is one patient -- either AC or maybe dry eye disease easier to identify or diagnose? And then my second question is, I'm just curious about the duration effect beyond 210 minutes, if there's anything there?

Those are both really good questions. I was speaking with a key opinion leader late last night. And this is someone who treats anterior ocular inflammation regularly. The difficulty in distinguishing dry eye disease from allergic conjunctivitis is real. It is a common problem that healthcare providers face. I do not think that, that most healthcare providers, and I'm talking about community-based physicians, optometrists, nurse practitioners, generalists, internists, et cetera, spend the time to Schirmer test patients to sustain the corneas of patients to assess tear film breakup time to rule out dry eye disease. Mostly, I think what those healthcare providers do is try artificial tears, suggest over-the-counter antihistamines if those haven't been used and then resort to prescription drugs. The difficulty in distinguishing these 2 diseases is just simply not worth it to most healthcare providers. And that's why reproxalap truly does represent a paradigm shift because healthcare providers can, without spending the time that -- with complex diagnostic tools that may or may not relate to symptomatology to distinguish these diseases, where reproxalap can be used in both conditions. Regarding the duration of effect after 210 minutes, we actually did measure, I believe, for another hour or so, symptom scores and redness after departing the chamber. Like with the Phase II trial, those results will be reported subsequently at a major medical meeting, and then after that in a manuscript, you can get a very good feel for how those curves look in the AAO data that I mentioned previously that were released last year. As a teaser, I can tell you that the groups remain separated for some time despite the fact there is not continuous allergen exposure.

Great. Congratulations.

Your next question comes from the line of Prakhar Agrawal with JonesTrading.

Congratulations on the data. I had a few commercial questions. Firstly, could you comment on the size of the opportunity in allergic conjunctivitis related to dry eye disease? And are there any differences in payer management between the 2 diseases? Secondly, given the pricing in allergic conjunctivitis tends to be lower at roughly $200 per month versus closer to $600 in dry eye, could you remind us how you are thinking about pricing right now? And lastly, are you prepared to launch alone in dry eye disease and allergic conjunctivitis if partnership discussions do not pan out by the time of launch?

Prakhar, as usual, those are good questions, and I'm glad you brought up the commercial implications as it relates to the size of the opportunity in allergic conjunctivitis. As I mentioned earlier today, 1/3 of the world has allergic conjunctivitis. In the United States, that's 100 million people, approximately 1/3 of that group is what we would call antihistamine recalcitrant. That is those patients have disease, there are noticeable signs and symptoms and antihistamines are not satisfactory to those subjects. So that's roughly 30 million people in the United States. Some proportion of those patients approximately half visit healthcare providers. I think the other half probably toughs it out during allergy season. But that half, that 10 million to 15 million patients that visit healthcare providers face, in terms of the healthcare provider's perspective, this difficult conundrum we talked about previously, what do I do with these subjects? These are patients that have not responded to antihistamine, am I prepared as a healthcare provider to prescribe a corticosteroid, which is potentially toxic. So that's sort of a breakdown of the allergy market. Now relative to dry eye, that market may be smaller on a patient numbers basis. We believe in more than 30 million in dry eye patients in the United States, some of those will see healthcare providers. We have only 2 drugs that are used prolifically that aren't corticosteroids that are used prolifically for chronic treatment and I think it's fairly clear amongst patients and physicians that those drugs are considered to be broadly inadequate. So I think there's a major need in dry eye disease. I also think there's a major need in allergic conjunctivitis, but to your next question, our intent would be to enter formularies with dry eye pricing to serve that large unmet population and dry eye disease and then I continue to believe, even at those prices, the use in allergic conjunctivitis would be significant because, again, the cost of treating a patient with glaucoma or the cost of treating patients with ocular infections and so forth, exceeds the cost of reproxalap in allergic conjunctivitis. Launching alone, maybe I'll turn it over to Joshua for the answer.

Thanks, Prakhar. As mentioned, we will begin preparing the organization for potential commercialization and we do believe that if necessary, we can launch alone, but as I stated earlier, we're committed to maximizing the value of reproxalap, and that may mean partnering out the asset.

Our next question comes from the line of Yale Jen with Laidlaw & Company.

My first question is that with the understanding the difference between allergic conjunctivitis and the dry eye disease. And in the data, the one of secondary endpoint that you for the dry eye disease, you have reduced the redness, whereas in the AC, you have reduced the tearing. Could you explore a little bit in terms of a mechanism, what makes the differences in the outcome of these 2 different indications?

Yale, and thanks for the question. I know you've been following the story for some time, and it's great that you've seen all the progress we've been fortunate enough to make. This paradox that you point out between hyper lacrimation in allergic conjunctivitis and a lack of tearing in dry eye disease is interesting, especially because we know there's about a 50% overlap between the 2 diseases. I think, however, that there are a lot of allergic conjunctivitis patients that use antihistamines, which then cause dry eye. Antihistamines are well-known in the scientific literature to have anti-muscarinic effects, which lead to ocular dryness. And that in turn exacerbates this comorbidity with dry eye disease. The hyper lacrimation or the excessive tiering in allergic conjunctivitis occurs acutely in response to allergen exposure. As I mentioned in my prepared comments, that is disturbing, and it is indeed the second most bothersome symptom behind ocular itching in allergic conjunctivitis patients. So I'm particularly thrilled about the ocular tearing data that we posted here today with INVIGORATE. But I think you can answer the paradox between hyper lacrimation in allergic conjunctivitis and lack of tears and dry eye disease with a simple difference between acute tear production after exposure to allergen and chronic dryness in allergic conjunctivitis, especially once subjects or patients start using antihistamines.

Okay. That's very helpful, insightful as well. Maybe just a speculation from you, which is -- it seems that the chamber challenging study in these 2 indications seem to work very well. Do you anticipate this to become more of a norm or more of the preferred method to use going forward of the indication, maybe other eye indications as well?

Yes. We were just discussing that concept right before the call. We're thrilled that there is now a robust chamber model in ocular allergy. Chambers has been around for decades, particularly allergen chambers but I think the standardization of those chambers has been questioned, and there really haven't been acutely active drugs to test in those chambers aside from antihistamines. So to have a drug like reproxalap, which is not an antihistamine and complements antihistamines, be so active in a chamber for ocular allergy is particularly thrilling. And I agree, Yale, I think that ocular -- I'm sorry, that allergen chambers will be used much more prolifically going forward, especially for investigational drugs that have acute onset within minutes like reproxalap. I also think the same is probably true about dry eye chambers but again, finding dry eye drugs that work acutely is difficult. Fortunately, reproxalap is squarely in that situation and thus a chamber model highlights, I think, the advantages of reproxalap. In the end, I'm thrilled for those of us that are working on chambers. There's a lot to say about challenge models, the standardization that I mentioned in the prepared comments, combined with the so-called real-world exposure to ocular irritants like allergens and dry eye is particularly powerful. And I think, quite helpful in distinguishing the activity of drugs from vehicle.

Okay. Great. I really appreciate that, and again, you're right. This is a long journey and it certainly had a pretty good goal at this point and congrats.

Thank you, Yale. Yes, I'm happy for all of us at the company and the investors that have been with us for a long period of time, but I'm mostly happy for patients and physicians, as I mentioned, that have faced these difficult choices in allergic conjunctivitis over the years.

At this time, there are no further questions. I would now like to turn the call back to Dr. Brady for any additional or closing remarks.

Thank you, operator, and thank you all for joining us this morning. As always, we look forward to keeping you updated on our progress towards our mission at developing novel immune-mediated therapies to satisfy unmet medical need. Thanks again.

Thank you for participating in today's conference call. You may now disconnect your lines at this time.