Aldeyra Therapeutics, Inc.

Ladies and gentlemen, this is the operator. Today's conference will begin in approximately two minutes. Until that time, your lines will again be placed on music hold. Thank you for your patience. Thank you. Thank you. Thank you. Thank you. Ladies and gentlemen, thank you for standing by and welcome to the Aldera Therapeutics Conference Call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question and answer session. I would now like to turn the conference over to your Chief Financial Officer, Joshua Reed. Please go ahead, sir.

Joshua Reed Good morning, everyone. With me is Dr. Todd Brady, President and Chief Executive Officer of Aldera. This morning we issued a news release reporting top line results from the Phase III Invigorate Clinical Trial of Reproxilab and Allergic Conjunctivitis. A copy of the news release is available on the Investors and Media section of our website, www.aldera.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 two. This presentation and various remarks, which may be made during this presentation, contain forward-looking statements regarding Aldera and investigational drug candidate Raproxilab. Forward-looking statements involve known and unknown risks, uncertainties, and other factors that may cause Aldera'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 Aldera'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 Aldera's product candidates and systems-based approaches. The risks that results from clinical trials or portions of clinical trials may not accurately predict results of future trials for the same or different indications, and Aldera'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. Aldera 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 FCC. Now, beginning with slide three, 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 three 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 three trial for Reproxilab and allergic conjunctivitis, and the third positive trial of Reproxilab demonstrating improvement versus vehicle of signs 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 Aldera clinical staff that worked so hard on the Invigorate trial over the past two 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. Reproxilab represents true innovation in allergic conjunctivitis, a novel drug with a novel mechanism for the first time in decades. The results of Invigorate suggest substantial utility of Reproxilab in a disease that affects approximately one-third of the U.S. population and more than one billion people worldwide, as is described on slide four. 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 five, Reproxilab 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 Reproxilab, lead to a chronic, self-perpetuating inflammation that results in persistent symptoms occurring over hours to days. Reproxilab 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 Reproxilab's safety profile and clinical results observed now across 14 clinical trials, we believe that Reproxilab, 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 the 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, Reproxilab is the first late-stage investigational therapeutic that has been rigorously tested in an allergen chamber. Slide 7 outlines the two-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 three and a half hours. Subject-reported ocular itching and tearing scores, as well as investigator-assessed ocular redness scores, were recorded approximately every 10 minutes. Droger 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 Reproxilab in preventing the development of 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 NNRM 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 pre-specified 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 tiering 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 roproxilab over vehicle 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 pre-specified 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 Reproxilab-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 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 was less in reproxilab-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 across arms. Importantly, Any noticeable change in redness, which is by definition what the 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 sign of the disease, hence the designation of redness as the key secondary endpoint. As with ocular itching scores, both prophylactic and treatment effects of drug were demonstrated. The slope of 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 in drug-treated patients versus slightly higher in vehicle-treated patients. Similar statistically significant results were achieved for the secondary endpoints of patient 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 disturbing and persistent symptom that diminishes quality of life for allergic conjunctivitis patients. and represents the second most bothersome symptom besides itching. The activity of Reproxilab 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 utility of Reproxilab 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. Reproxilab 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, Riproxilab has demonstrated success across a robust development program of allergic conjunctivitis trials across two different allergen challenge models. In combination with Alleviate, the Invigorate trial represents the second large, well-controlled trial to achieve statistical significance for the primary endpoint of ocular itching. including the run-in cohort of the Tranquility Trial and Dry Eye Disease, Invigorate also represents the third chamber trial in which Reproxilab 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 three common culprits of ocular surface disease, pollen pollutants and parched environments, make the etiologies of dry eye disease and allergic conjunctivitis difficult to untangle for healthcare providers, necessitating novel therapies for chronic use that can treat both conditions. The potential importance of the relationship of Reproxilab 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, two hallmark symptoms of ocular surface disease, across different challenge models featuring pollen and dry air irritants, and across patients with allergic conjunctivitis and patients with dry eye disease. The striking consistency for improvement over vehicle and reduction of ocular redness is illustrated on slide 17. As mentioned previously, ocular redness may represent the only objective sign of anterior ocular inflammation that is of importance to patients and, by extension, to 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 US Food and Drug Administration shortly. Slide 19 summarizes the potential commercial advantages of Reproxilab in allergic conjunctivitis and dry eye disease. Reproxilab appears to improve symptoms and signs within minutes, and the symptomatic activity of Reproxilab appears to be broad. In sum, Reproxilab 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.

Certainly. If you would like to ask an audio question, please press star 1 on your telephone keypad. Again, that's star 1 to ask an audio question. Your first question comes from the line of Mark Goodman with SVB Lee Rink.

Yes. Good morning, guys. Two questions. One is for the filing, can you tell us what is left to do with respect the safety, the long-term safety. How many more patients? What do we need to do if you were only going to file for this indication? And then second of all, just, you know, you mentioned some thoughts, but maybe you could just give us, you know, your level of confidence now in the dry eye studies, just given what we know here. Thanks.

Yeah, thanks, Mark. And we're thrilled you're involved. We know that you've 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 filing. 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, 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. In allergic conjunctivitis, that is a six-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 and allergic conjunctivitis probably at this point depend in terms of timing on the safety trial. Your second question about 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 two 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, three and a half 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 erproxilab 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 four times, and then day two is the dry eye chamber. Like with the allergen chamber, drug is administered just prior to the dry eye chamber, and then 45 minutes into the chamber. So in sum, the patients in Tranquility will receive more drug 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 sum, I would argue that the data today in ocular redness from Invigorate bode well for the potential of tranquility where ocular redness is the primary endpoint.

And just to follow up, the six-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, Mark.

Thank you.

Yes, thank you.

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

Thanks for taking my questions here. 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 six-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? Thank you.

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 and 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 two labels are negotiated at the same time. It could be in series. And I would say more or less, we at Aldera 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 will 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 disease and the market in dry disease, I think, is more optimal than that of allergy. And we'd like to get on formularies with a dry disease label first before allergy. But, again, the timing of the NDAs 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, Luis. So given our previous guidance regarding filing an NDA potentially at the end of this year, yes, we'll begin our planning on building out the organization for commercialization. With that said, however, we are committed to making Reproxilab 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 the potential to use the dry eye safety study, or will they just be separate?

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

Okay, thank you very much.

Thanks, Louise.

Your next question comes from the line of Ilgal Novakovic.

Yeah, hi, this is Ilgal Novakovic. Nice to talk to you, Todd and Josh. I just had one question on the label. Is this label going to be broad in the sense that it will just state for the treatments 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 that the riproxilab is for prophylaxis or for the onset of treatment, for the onset of symptoms once symptoms appear?

Thanks. Good morning, and this is a question. that is particularly relevant to us these days and has a lot to do with label negotiations. To some extent, the answers to your questions will depend on the NDA and 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 two 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 the broader indication as it relates to ocular allergy. And, of course, we would love to have the ocular redness data from allergy in the label because, as I mentioned, redness is very meaningful to patients, and healthcare providers 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 the position that we are qualified to receive an indication for treatment of signs and symptoms. However, as I mentioned, I don't think commercially the 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 that's too detailed?

That's an interesting question, Igor, because typically antihistamines have been approved in what I would argue is a prophylaxis model, which is treatment with drug or vehicle prior to conjunctival exposure to allergen. I think by definition that is a prevention model. However, the labels do not reflect that terminology. So I am, because Raproxilab 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.

Just one other housekeeping question. Was there any particular reason that you did not analyze RASP in this study? Was it just efficient 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 hyperlacrimation, 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.

Understood. Thank you very much, Todd.

Yep. Thanks, Egal.

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

Hi, good morning. Congrats on the terrific data. My first question is regarding the way through to dry trial. So are the steps designed the same from conjunctivitis to dry trial on the ocular redness endpoint? And my second question is how to position Reprexilab in conjunctivitis market. So we know antihistamine drug class is preferred as a frontline treatment. And topical steroid may be considered in patients with refractory symptoms. So how do you position Reprexilab in future marketplace? And also, what are the key drug attributes for Reprexilab to enable breaking into conjunctivitis market? Thank you.

Thanks for the questions, Kelly. And I'm glad you asked the question about statistics, which is near and dear to our hearts. All of us ultimately in biotechnology are in the p-value business, and we take statistics very seriously. I've never understood why companies pick time points. Rather, it is more powerful to assess all time points in aggregate, and that's precisely what we've done with ocular redness and tiering 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 ANCOVAs 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 timeframe for the primary endpoint of Invigorate based on FDA guidance. And we selected a timeframe 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 vehicle-treated patients. And we're just thrilled about the consistency of the data and the highly statistically significant differences in results. As he mentioned, we intend to continue to use overall assessments of the results, which include 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 and are de facto antihistamine recalcitrant, meaning antihistamines 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 Reproxilab. 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 Reproxilab, in theory, could offer a potential solution to that gap between antihistamines and corticosteroids. Does that answer your questions, Kelly?

Yes, very insightful. Thank you very much and congrats again.

Thanks so much, Kelly.

Your next question comes from the line of Justin Kim with Oppenheimer and Company.

Hi, good morning. Congrats on the results and thanks for taking the question. Just maybe one first to begin. When you revisit 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. Good morning, Justin, and thanks for the question. That's correct. In the Phase 2 trial, I think over this timeframe, we had nine time points, and in the Phase 3, 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 two allergen chamber trial, whereas in 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 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 two winters. As you recall, Allergen chamber trials cannot be run during pollen season, which is essentially spring through fall. So the trial must be run at least in allergen chambers over winters. This was essentially a two-year trial. As a result, the second year modestly hampered by COVID, like most clinical trials. But other than that, the two 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 antihistamines ahead of a potential 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. As is illustrated on slide five, the histamine release is acute. Histamine sits in mast cells. It's pre-made. Once an allergen binds to IgE on the 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 histamine. And therefore, the combination of an antihistamine with a more durable, chronically acting drug like roproxilab may be attractive. And that's something we've thought about and are continuing to think about. I think regarding the marketplace, it's fairly obvious that healthcare providers, if roproxilab is available and on the market, would combine the two therapies to sort of get that immediate effect of antihistamine in combination with the subacute effect and chronic effect of roproxilab.

Okay, got it. Just the 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 two 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 two patient populations to eliminate any confounding variables that overlap the two diseases. Your thought about running a trial in combinations of patients is really interesting. In fact, we've announced previously in our dry eye trials effects of roproxilab 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 activity of erproxilab 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.

Understood. Thanks for taking the questions, and congrats again.

Yeah, thanks, Justin.

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

Hi, good morning. Congrats on the data, and thank you for taking my question. 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 at minute zero, at least for the run-in portion of Tranquility. But this really didn't seem to be a possibility for Invigorate. Thanks.

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 zero, 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 Trial features day one dosing, which is four doses, so that subjects before entering the chamber receive five doses of drug, four doses on day one, one dose prior to the chamber, And that, we believe, explains the difference at time zero between drug and vehicle in the tranquility run-in cohort, as you can see on slide 17. I agree with you that 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.

Excellent. Thank you.

Thanks, Julian.

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

Hi, all. Good morning and 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 wanting to clarify whether there was, you know, what additional work would be necessary to kind of make those claims. Is that contingent on the six-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 overlap and combination use with antihistamines, Just to clarify, do you feel you're really limited or will primarily be using Reproxilat for AC as an antihistamine refractory population? Or given that you're also, you know, potentially marketing for dry eye and, you know, 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, you know, really up front when patients are beginning treatment for allergy treatment? 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 the kind of marketing potential and how restrictive that might be. Thanks.

Thanks, Matt. Well, I could go on for an hour talking about these two 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 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 these this bimodal distribution with these two 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 disease is a chronic condition. So there could be a use of Raproxilab chronically, that is over many months, ostensibly 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 Ruproxilab 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 six months of data. That really allows Ruproxilab to be used chronically. Whether patients have dry eye chronically, whether 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, Reproxilab is steroid-like. It's anti-redness. It's anti-inflammatory. We've demonstrated it. Multiple cytokines that are inflammatory or reduced. We've demonstrated an increase in IL-10. Really behaves from an efficacy standpoint as a steroid. However, Reproxilab 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 disease that is limited in the indication statement of the label to two weeks. So Reproxilab may have a major advantage in terms of chronic therapy, particularly given the overlap of dry disease and allergic conjunctivitis, 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 Reproxilab is if those patients aren't satisfied and those patients see a healthcare provider, they're already status post antihistamines. They're sort of de facto antihistamine resistant. And that's when the healthcare provider today needs to make the difficult decision. Am I going to put this patient on corticosteroids and risk an intraocular pressure spike and risk a referral to a glaucoma physician? Or in the future, perhaps, am I going to try Reproxilab? So I really do think that Reproxilab, as I mentioned, fills a large unmet medical need practically mad. between antihistamines and steroids.

Got it. Thanks, Todd. No, I tend to agree, and certainly, you know, broad-spread use of antihistamines, but I don't think that necessarily means that it works consistently for many of us out there dealing with it. So glad to have something like Reproxilab hopefully coming to market soon. So thanks for all the answers here. Appreciate it.

Yep. Thanks, Matt.

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

Hi. Thanks for taking my questions. 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, including the patient baseline characteristics?

Good morning, 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 zero, 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 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 roproxilab and a slight trend up for vehicle. I will say, I just want to reiterate that the 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 0.0001. You just say 0.001. Here, the actual p-value, according to R, is 7.9 times 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?

Ah, yes. So we intend to publish the full data at a 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 two which, as you know, is half the scale. Now, an increase of two 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 six-month safety trial. But I just want to know if these efficacy trials and data are adequate for filing in AC. Thank you.

Correct. As we mentioned in our prepared comments, we have never seen a potential filing for an investigational allergic adjunctivitis a drug that is as robust as this filing in terms of the breadth of models, at least not recently, where Raproxilab 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 Reproxilab across two 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.

Thanks, Todd. Congrats again. Thanks, Edmund.

Your next question comes from the line of Esther Hong with Beringberg.

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

Hi, Esther. Good morning. Those are both really 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 most healthcare providers, and I'm talking about community-based physicians, optometrists, nurse practitioners, generalists, internists, et cetera, spend the time to Shermer test patients, to stain 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 two diseases, it's just simply not worth it to most healthcare providers. And that's why Reproxilab truly does represent a paradigm shift, because healthcare providers can... without spending the time with complex diagnostic tools that may or may not relate to symptomatology to distinguish these diseases. Reproxilab 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. Thank you. Congratulations.

Thank you, Esther.

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

Hi. Good morning and 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 pair management between the two 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 disease and allergic conjunctivitis if partnership discussions do not pan out by the time of launch? Thank you.

Prakash, as usual, those are good questions, and I'm glad you brought up the commercial implications as it relates to the size, the opportunity of allergic conjunctivitis. As I mentioned earlier today, one-third of the world has allergic conjunctivitis. In the United States, that's 100 million people. Approximately one-third 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 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 patients that have not responded to antihistamines? 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 dry eye patients in the United States. Some of those we'll see healthcare providers We have only two 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 in 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 ruproxilab in allergic conjunctivitis. Launching alone, maybe I'll turn it over to Joshua for that answer. Thanks, Prakhar.

As mentioned, we will begin preparing the organization for potential commercialization, and we do believe that If necessary, we can launch a loan. But as I stated earlier, we're committed to maximizing the value of Reproxilab, and that may mean partnering out the asset.

Your next question comes from the line of Yeo Jin with Laidlaw and Company.

Congrats, Pat and the team. My first question is that with understanding the difference between hunger and dry disease, and in the data, the secondary endpoint for the dry disease, you reduce the redness, whereas in the AC, you have reduced the tearing. Could you explain a little bit in terms of a mechanism what makes the differences in the outcome of these two different indications?

Good morning, Neil, and thanks for the question. I know you've been following this story for some time, and it's great that you've seen all of the progress we've been fortunate enough to make. This paradox that you point out between hyperlacrimation 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 two 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 disease. The hyperlacrimation, or the excessive tearing, 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 hyperlacrimation and allergic conjunctivitis and lack of tears and dry 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 a very helpful insight as well. Maybe just a speculation from you, which is that it seems that the chamber challenging study in these two indications seems to work very well Do you anticipate this become more of a norm or more of the preferred method to use going forward of these indications, maybe other eye indications as well?

Yeah, 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 have 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 Reproxilab, 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 Raproxilab. I also think the same is probably true about dry eye chambers, but again, finding dry eye drugs that work acutely is difficult. Fortunately, Reproxilab is squarely in that situation, and thus a chamber model highlights, I think, the advantages of Reproxilab. 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, Ken. You're right. This is a long journey and certainly 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.

Thanks a lot.

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.