Ladies and gentlemen, thank you for standing by, and welcome to the Aldeyra Therapeutics’ Full Year 2021 Financial Results Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session.

I would now like to hand over the conference to the company's Chief Financial Officer, Mr. 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 press release reporting our financial results for the year ended December 31, 2021. A copy of the press release is available on the investors and media section of our website, www.aldeyra.com.

Please note that this morning's conference call contains forward-looking statements regarding future events and the future performance of Aldeyra.

Forward-looking statements include but are limited to statements regarding submission of potential new drug applications, potential commercialization, the anticipated timing of results from our clinical trials, our projected cash runway, our possible or assumed future results of operations, expenses and financial positions and potential growth opportunities.

These statements are based upon the information available to us today and reflect our current views concerning future events. They 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 results 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 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 our press release issued this morning and our filings with the SEC. I will now turn the call over to Dr. Brady..

Thank you, Joshua. And good morning, everyone.

2022 promises to be an exciting year for Aldeyra as we enter a catalyst rich period that will highlight not only what we hope will be the successful completion of clinical development for reproxalap in dry eye disease, but also the emergence of our RASP modulator platform for the treatment of systemic autoimmune and inflammatory diseases and late-stage regulatory milestones for ADX-2191 for the treatment of certain rare retinal diseases.

We believe that our systemic and retinal platforms are broadly underappreciated and underexposed, and we therefore attend to aggressively build awareness of these platforms throughout 2022 and beyond. Our plan to increase recognition of our systemic immune modulating platform is indeed near term.

The Aldeyra Therapeutics R&D Day will occur on March 29 during which we plan to announce topline data from our Phase 2 proof-of-concept trials of ADX-629, our first-in-class oral RASP modulator in psoriasis, asthma and COVID-19. The goal of the ADX-629 proof-of-concept trials are threefold.

First, to demonstrate an acceptable safety and tolerability profile for what represents the first time a RASP modulator has been orally administered to humans. Second, to indicate pharmacodynamic activity of ADX-629 across a variety of biomarkers related to inflammation.

And third, to elucidate signals with clinical activity consistent with what might be expected from small trials with varying levels of doses, durations of therapy, trial designs and disease states.

ADX-629 and related molecules from our RASP modulator platform have the potential to be transformative for Aldeyra creating a broad range of new commercial opportunities and systemic disease and complementing our late-stage retinal and topical ocular programs.

In addition to describing the initial Phase 2 outcomes for ADX-629 and potential future clinical indications, we're particularly excited to welcome Dr. Geoffrey Thiele as the featured speaker for R&D Day. Dr. Thiele is the Umbach Professor of Internal Medicine in the Division of Rheumatology at the University of Nebraska Medical Center.

He is a leader in the research of malondialdehyde, acetaldehyde and other RASP as potentiators of the inflammatory response. Dr. Thiele brings a unique understanding of the science behind our RASP programs.

We look forward to his perspectives on ADX-629, and the potential for RASP modulation broadly as a novel approach for the treatment of inflammatory diseases.

Our next set of catalysts relate to reproxalap a first-in-class RASP modulator for the treatment of dry eye disease and what we believe has the potential to be the next novel entrant in the dry eye disease marketplace. Results from the Phase 3 TRANQUILITY-2 trial of reproxalap in dry disease are expected during the middle of this year.

Pending the outcome of TRANQUILITY-2 and enrollment in the 12-month safety trial of reproxalap in dry disease patients, we plan to submit an NDA for reproxalap in dry disease after the completion of TRANQUILITY-2.

The endpoint of the TRANQUILITY-2 trial will be met if either Schirmer test or ocular redness demonstrates statistical significance in favor of reproxalap over vehicle.

We've also initiated two additional trials, a crossover dry eye disease chamber trial and a one-day Schirmer test trial either of which could serve as pivotal trials in support of an NDA submission.

In recent months, we've met with a number of ophthalmologists and optometrists across the United States to learn more about the substantial unmet medical need associated with treating dry eye disease, which we estimate affects 39 million or more adults in the United States.

Nearly 20 years since the approval of the first prescription drug for dry eye disease, the market remains significantly underserved, a point supported by the millions of patients who report that first-line therapies are ineffective.

Many of dry eye disease professionals express a keen interest in a rapid and durable treatment that can be used chronically and enables improved patient outcomes compared with the current standard of care. We believe reproxalap has the potential to be that treatment.

The clinical benefits of reproxalap are supported by a growing body of scientific research, in January we reported the results of a Phase 2 dry eye chamber trial, comparing patient-reported ocular discomfort and ocular itching symptoms scores of reproxalap versus Xiidra, an approved drug for the treatment of dry eye disease.

For both endpoints, reproxalap demonstrated statistically significant symptom improvement compared to Xiidra and a separate study published last year in clinical ophthalmology the reproxalap eye drop experience, including a broad assessment of ocular sensations over one hour following administration was superior to that of Xiidra.

In allergic conjunctivitis, the Phase 3 INVIGORATE 2 allergen chamber trial was initiated in the first quarter of this year. INVIGORATE 2 was a randomized, double-masked crossover trial. The trial design is substantially similar to that of the Phase 3 INVIGORATE trial, the results of which were announced in April 2021.

The INVIGORATE trial demonstrated statistically significant superiority of reproxalap over vehicle and reducing ocular itching and redness the key symptom and sign of allergic conjunctivitis, respectively.

To avoid the confounding effects of pollen in the environment, allergen chamber trials are conducted exclusively in winter, and often require two winter seasons to enroll sufficient numbers of patients as was the case with the INVIGORATE trial. Therefore, we expect results from INVIGORATE 2 in 2023.

In addition to Aldeyra's advancement to systemic disease, we are committed to a significant development effort in retinal diseases. Many of these diseases lead to loss of sight and are poorly treated today, especially retinal diseases that are rare.

Along those lines, I am pleased to report the initiation of the Phase 2 trial of ADX-2191 in retinitis pigmentosa, and incurable potentially blinding disease with no approved therapy.

This single-center open-label trial will evaluate the safety and tolerability of ADX-2191 and patients diagnosed with retinitis pigmentosa due to specific genetic mutations animal models of which responded to methotrexate treatment.

The trial, which will be conducted at Duke University Medical Center is expected to enroll eight patients, four patients receiving monthly and four patients receiving twice monthly intravitreal injections of ADX-2191 over a period of three months. Results are expected during the second half of this year.

In January, we announced the completion of enrollment in Part 1 of the Phase 3 GUARD trial of ADX-2191 in patients with proliferative vitreoretinopathy or PVR, another rare retinal disease that can lead to loss of vision yet has no approved therapy.

PVR is the leading cause of primary retinal detachment after surgical failure occurring in an estimated 5% to 10% of retinal detachments. Results from Part 1 of GUARD are expected in the second half of this year.

To our knowledge, ADX-2191 is the first methotrexate formulation specifically designed to be compatible with vitreous, the fluid in the back of the eye. Thus, ADX-2191 represents a unique commercial opportunity. For example, off-label methotrexate injections are standard of care for the treatment of ocular lymphoma.

Together with retinitis pigmentosa and PVR, the current indications for our ADX-2191 platform span three rare retinal diseases. In each indication, ADX-2191 has received the U.S. FDA’s orphan drug designation.

Now, I’ll turn the call back over to Joshua for the financial review, after which I will summarize our recent clinical progress and our future potential in developing novel platforms for the treatment of immune-mediated disease..

Thank you, Todd. Cash and cash equivalents as of December 31, 2021, were $229.8 million.

Based on our current operating plan, we believe that existing cash and cash equivalents will be sufficient to fund currently projected operating expenses through the end of 2023, including potential new drug application submissions, initial commercialization of reproxalap, if approved, and continued development of our product candidates and ocular and systemic immune-mediated diseases.

Now, let me review the P&L for the 12 months ended December 31, 2021. Net loss was $57.8 million or $1.07 per share compared with a net loss of $37.6 million or $1.11 per share for the comparable period of 2020.

Losses have resulted from the cost of clinical trials and research and development programs as well as from general and administrative expenses. Research and development expenses were $44.9 million, compared with $24.7 million for the same period in 2020.

The increase of $20.2 million is primarily related to increases in our clinical research and development expenditures. General and administrative expenses were $11.3 million, compared with $10 million for the same period in 2020. The increase of $1.3 million is primarily due to increases in legal, insurance and consulting costs.

Total operating expenses were $56.2 million, compared with total operating expenses of $36.4 million for the same period in 2020. Now, I’ll hand the call back to Todd for closing comments..

Thanks, Joshua. We enter 2022 from a position of financial strength and clinical success across a variety of therapeutic platforms.

Interestingly, while we believe that the investor community is aware of the potential of reproxalap to be the next dry eye disease market entrant and a novel therapeutic approach that addresses many of the shortcomings of currently available therapy.

We also believe that our systemic and retinal disease platforms are under recognized and present a unique opportunity for value accretion in Aldeyra as we expect to announce new clinical data and regulatory progress in systemic and retinal indications beginning at R&D Day this month and continuing throughout the remainder of 2022 and beyond.

I am pleased to state without reservation that we continue to execute on our mission to develop novel therapies for the treatment of immune-mediated diseases. We believe our future is catalyst-rich. Our potential remains strong, and our commitment is unwavering. With that, Joshua and I will be happy to take your questions.

Operator?.

Thank you. [Operator Instructions] Our first question for today comes from Yigal Nochomovitz of Citigroup. Yigal, your line is now open..

Hi, Todd and Joshua, thank you very much for taking the questions. Todd, on 629, I’m just curious, you’re looking at three diseases, psoriasis, asthma, COVID-19. Just wondering if you have a sense as to where the best evidence is for potential therapeutic effect across the three inflammatory diseases.

In other words, do you think one of them is more likely to work than the others? Or is it really unclear and thus this is why you’re running these studies? Thank you..

Good morning, Yigal, and thank you for the question. It’s something we thought a lot about, I remember years ago, a similar question about reproxalap.

Did we expect reproxalap to work better in allergic conjunctivitis, which is obviously a TH2 allergic type condition, or we expect reproxalap to work better in dry eye disease, which is more of an autoimmune TH1 type conditions. And at the time, I didn’t really know as has been demonstrated consistently, reproxalap worked across the board.

ADX-629 is a closed relative of reproxalap. It is also a RASP modulator. And I think my answer to your question would be the same as it was for reproxalap, which is although we’re not entirely clear until the data are presented. I think we have reason to believe that RASP modulation is proximal. It is upstream.

It therefore has the potential to influence all kinds of inflammation. And I have a reasonable amount of optimism that we’ll see activity in both psoriasis and asthma. Now, COVID-19 is a different animal. COVID is, A, an infectious disease; and B, involves both arms of the immune system, TH1 and TH2. That is a new experiment for us.

I’m eager to present the data. But if we believe that both reproxalap and ADX-629 is RASP modulators affect inflammation approximately upstream, then it is likely that we would see some kind of effect in COVID-19 as well, notwithstanding the fact that COVID-19 is different from psoriasis and asthma and that is an infectious disease..

Got it. That’s very, very helpful. And then I just wanted to get your latest thoughts on allergic conjunctivitis, meaning, obviously, there’s a very heavy overlap in symptomology between dry eye and AC. And so, I know you’ve thought about this in the past, but I’m just wondering if you can give a latest perspective.

From a commercial perspective, do you think you even need to file an AC to get physicians to prescribe reproxalap for this condition?.

Yigal, your point is a good one. The overlap between dry eye and allergic conjunctivitis is indeed substantial. I often wonder if dry eye disease and allergic conjunctivitis are variants of the same disease, the variants of ocular surface inflammation that are very closely related.

I think many healthcare providers both ophthalmologists and optometrists recognize that these two diseases are related, the differential diagnosis process when a patient presents with ocular surface inflammation between dry disease and allergic conjunctivitis is complicated and often not clear.

And therefore, I think many healthcare providers believe that patients will have elements of both conditions and that prescribing for one condition is similar to prescribing for another condition.

Now whether we file for allergic conjunctivitis, whether we submitted NDA for allergic conjunctivitis, which would occur subsequent to the NDA for dry disease, I think is a different question. I think it depends on the dry disease data.

It depends on potential partnership that we may or may not have with a different company in launching reproxalap, and we’ll have to answer that question later on in the future..

Great. Thanks, Todd..

Thanks, Yigal..

Thank you. Our next question comes from Kelly Shi of Jefferies. Kelly, your line is now open..

Hey, Todd, this is Hao [ph] for Kelly Shi. And thanks for taking my questions. So, my first one is really for the Schirmer’s test result in the TRANQULITY trial, it was very fast onset, basically one day, you see the efficacy.

So, do you think there’s anything from MOA point of view that you can explain the fast onset of action? And then do you think the effect is durable and if FDA may require some evidence for the durability of the effect..

Great. Thanks for the question, Hao [ph] And those are important questions to consider as we approach NDA submission for dry eye disease.

I want to build on Yigal’s question about the upstream nature of RASP inhibition not only is RASP modulation, something that is broad and can affect a variety of different signs and symptoms of inflammatory diseases, but it is also rapid.

And to your question, one reason why we believe that reproxalap works so quickly is because the mechanism of the drug involves a chemical reaction that is the binding of reproxalap to RASP.

As we presented in our corporate deck and discussed previously, that reaction is exceedingly fast occurring within minutes in vitro situations and our guess is that that’s exactly what’s happening in the ocular tissue that there is a rapid chemical reaction, which then can effect changes in signs and symptoms very rapidly.

The FDA’s position on signs, at least per our discussions with the agency is that the signs of dry disease need to be demonstrated in part to prove that your drug is not an anesthetic that the drug is not simply numbing the surface of the eye and has a physiologic component that is beneficial for the treatment of disease.

Based on our conversations with the FDA, the chronicity, the duration of modulation of signs is not important. What is important is that we can prove that the drug has physiologic activity beyond anesthesia.

And accordingly, we’ve been able to run a series of chamber trials and dry eye chambers, which allow us to demonstrate beneficial effects on signs, both redness and now Schirmer test very rapidly. I think the advantages of chamber trials are multifactorial. They are fast. They are relatively inexpensive.

And most importantly, from a commercial standpoint, they allow us as a developer of reproxalap to demonstrate very rapid activity, at least from a signed standpoint of the drug..

Thank you, Todd. That’s very helpful. Just a quick follow-up. So, for the Phase 2 trial that’s optimizing RASP measurement, just want to check the status of that one? And also, you mentioned about the crossover trial and Schirmer’s test one-day trial in your opening.

Just to get a little bit understanding about the timing and the trial design, if possible..

Right. The RASP assessment is occurring in all of these trials. The current plan is to organize the RASP data in aggregate and present that data later, the RASP assessment, as I have described previously, is more complex than clinical assessment and more complex than the standard assessment of dry disease signs.

So, RASP data upon completion of TRANQUILITY-2 and the two other trials that you just brought up will be announced separately in the future. I’m glad you asked about the crossover trial and the Schirmer test trial, those are slightly alternative methods of measuring signs in dry eye disease.

The crossover dry eye chamber trial is unique here to for in TRANQUILITY and in TRANQUILITY-2, we have assessed patients and dry eye chambers in a parallel group manner. That is each patient either receives vehicle or drug. A crossover trial is different in that each patient will receive vehicle and drug at different times in a random order.

We’ve been highly successful with crossover chamber trials in allergic conjunctivitis.

As you know, the INVIGORATE trial and the ongoing INVIGORATE 2 trial and a Phase 2 allergen chamber trial, which has recently been published in clinical ophthalmology are subjecting subjects and half objective subjects to each test article prior to entering a chamber.

This is a powerful approach statistically because it eliminates subject to subject variability. That is each subject is his or her own control. We have, to our knowledge, but never seen a crossover dry eye disease chamber trial.

We’re thrilled to be the first company that’s running such a trial, obviously, based on the allergic conjunctivitis results, we’re optimistic about the dry eye disease results, and we look forward to describing those results later this year for the investor community.

The Schirmer test trial is a one-day trial, again, highlighting the rapidity of onset for reproxalap. Essentially, the trial is similar to the TRANQUILITY and TRANQUILITY-2 trials where subjects are dosed four times on a single day, unlike TRANQUILITY and TRANQUILITY-2, there is not a dry eye chamber on the following day.

The Schirmer test is taken in and around the fourth and final dose on day one for the upcoming trial. We believe, as I mentioned in my prepared comments how that both trials, is successful, will support the NDA submission, though may not necessarily be needed for the NDA submission, pending the outcome of TRANQUILITY-2..

Great. Thank you, Todd..

Thank you. Our next question comes from Marc Goodman of SVB Leerink. Marc your line is now open..

Yes. Todd, first of all, can you just give us an update on – you had mentioned the safety data and the timing of filing for dry eye, which would be the study works in the middle of the year, we get the data. And then if the safety data is there and then you can file. Just give us an update on how the safety is going, the numbers that you need.

Also, CMC, just making sure that when that study kind of completes, we can get an idea of how soon after you would be able to file? And are you planning on having a meeting with the FDA before you file? Just give us a sense of all that timing kind of as question number one.

And then question two here, just so we’re clear, can you tell us what is the purpose of doing the crossover chamber trial, the Schirmer test trial that you just mentioned? I mean, is this just backup just in case the other one TRANQUILITY doesn’t work what other purpose does it serve? Thanks..

Thanks, Marc, and thanks for the excellent questions. I think, as I’ve said many times before, investors often forget about the requirement for a safety trial and the CMC requirements, both of which are obviously critical for NDA submission. I’m thrilled to report that our CMC progress to our knowledge is superb.

We’ve discussed CMC, specifically with the FDA. And at this point, I don’t foresee any issues regarding CMC as it relates to commercial or registration batches, stability, et cetera. The safety trial is a significant undertaking for chronic drugs generally a 12-month safety trial is required per FDA dry disease guidance.

As you know, 100 subjects are 100 patients are required to be exposed to the drug for 12 months at least. The NDA can be submitted prior to the completion of the safety trial, but by the – generally, by the 120-day update, all the final safety data, that is the 12-month data for those 100 patients that needs to be submitted in addition.

I think at this point, we remain on track to be able to submit the NDA midyear for dry disease based on the current enrollment in the safety trial, across the industry not only in trial disease or in ocular diseases, but broadly, we are experiencing some challenges in retaining patients in trials.

Enrollment has not been as difficult as we moved through various phases of COVID. But as is the case with COVID broadly, I think that many people are evaluating life choices differently than they have in the past and retention, again, across the biotech industry and the clinical trial industry broadly is a challenge.

Notwithstanding those comments, I still believe we’re on track for a midyear NDA submission. Your questions about the crossover and the one-day Schirmer test trial are good wins. For sure, I think either trial could serve as a backup.

But really, we’re running those trials because they answer slightly different questions than what we’ve asked previously, in particular, the dry disease chamber crossover trial, which, as I mentioned in response to How’s question to our knowledge, has never been done before.

As you know, the FDA considers the preponderance of evidence – our position in submitting this NDA is that with reproxalap will come one of the most comprehensive NDA packages ever submitted for dry eye disease, the crossover trial, the Schirmer test trial are two examples of our efforts to expand the package to demonstrate the breadth of activity of the drug across not only a large number of patients, but different models and different trial designs..

Thanks..

Thank you. [Operator Instructions] Our next question comes from Thomas Shrader of BTIG. Thomas your line is now open..

Hey good morning, Todd and Josh. This is Sung on for Tom. So, as we wait data readout for TRANQUILITY-2 from TRANQUILITY-1, one of the concerns was patients going into the trial had a low baseline ocular redness. And I was just wondering if you guys had an earlier read on that for the TRANQUILITY-2 patients? Thanks..

Hi, Sung, good morning. Yes, we expressed described, I would say, two major differences with the TRANQUILITY trial relative to prior trials that we’ve run. One of them is that the TRANQUILITY trial was primarily run during pollen season in the spring.

Pollen, as you know, is not only allergic or pro-allergen in many cases, but even if subjects aren’t allergic to pollen, pollen is a mechanical irritant and therefore, can confound ocular surface disease and the assessment of the ocular surface disease.

The other major difference that you highlighted in your question is that the baseline redness scores going into TRANQUILITY were paradoxically lower than they were with the previous Phase 2 trial that demonstrated statistical significance across reproxalap in vehicle for ocular redness.

One reason for that may have been the use of antihistamines or use of vasoconstrictors or use of artificial tiers, which, of course, are restricted in clinical trial settings. But nonetheless, occasionally occurs amongst patients that are suffering from allergies and other effects are evident during allergy season or pollen season.

I would say so far, as we monitor the baseline scores on a blinded basis for TRANQUILITY to the baseline scores look better or higher than they did in the prior Phase 2 trial, but obviously, the resulted matters is the un-blinding of the trial and the differences between groups.

And as I mentioned in my prepared comments, we remain on track for a midyear data announcement for TRANQUILITY-2..

Great. Thank you..

Thanks, Tom..

Thank you. Our next question comes from Matthew Cross of Alliance Global Partners. Matthew, your line is now open..

Hi guys. Good morning and thanks for taking a couple of questions for me here. So, pressing ahead in AC with INVIGORATE 2, I was wondering if you could expand upon the measurement of redness in that chamber study.

I guess could you confirm that the same baseline redness score of at least two, I think, that was used and INVIGORATE will also be required in INVIGORATE 2 given the design similarity you noted.

And is there any possibility of referencing data from INVIGORATE in the kind of overall data package for filing in DED, given the kind of overlap and disease characteristics that we've covered here..

That’s an interesting question Matt. Thank you. Generally, the FDA considers dry disease distinct from allergic conjunctivitis, notwithstanding the overlap that Yigal and others have highlighted on this call between allergic conjunctivitis and dry eye disease.

I suspect that in reviewing the dry eye disease NDA, the FDA will consider the reduction of redness in allergic conjunctivitis, though I doubt that retinas reduction of allergic conjunctivitis will be a primary consideration when assessing the sign activity of reproxalap in dry eye disease.

The allergen chamber trial protocols are somewhat different than the dry eye disease chamber protocols. As I mentioned in my prepared comments, the allergy trials can only be run in the winter. And the reason for that is if you have pollen in the environment, it confounds the allergen response in the chamber, which has Aerosolized Pollen in it.

Patients to your point before entering an allergen chamber trial must demonstrate an increase in itching and redness to qualify for the trial. But prior to entering the chamber after dosing drug or a vehicle prior to entering the chamber, patients must have essentially no redness, and the redness has to build in the chamber.

That is different in dry eye disease where subjects to Sung's question must have a redness not only in the dry disease chamber to enter the trial, but generally as drug is dosed, and they enter the chamber for redness assessment. So, two different protocols highlighted by the difference in pollen and the nature of the diseases..

Got it. Thanks. So, I appreciate the thorough answer there And then just kind of a related point around INVIGORATE 2. Obviously, you've already conducted a positive second study in the form of ALLEVIATE, just wanted to – now that you've kind of discussed plans officially to go ahead with INVIGORATE 2, which is largely a repeat of INVIGORATE.

I wanted to confirm whether you would receive any additional feedback from the FDA kind of confirming or that maybe would explain to some degree better, why they adopted to requests, and I don't know if this was an FDA request or maybe your answer can clarify that, but to repeat a similar design and what was kind of the shortcoming of ALLEVIATE?.

Based on our discussions with the agency, ALLEVIATE, which was a conjunctival challenge trial, that is pollen is directly administered to the surface of the eye and patients are assessed over an hour or so after that. Was primarily designed to assess antihistamines, obviously, reproxalap is not an antihistamine.

And thus, the FDA wanted two adequate and well-controlled trials in a different model, which is the allergen chamber model.

I think, I've expressed a considerable amount of optimism regarding INVIGORATE 2, mostly because we have a Phase 2 trial now recently published in the allergen chamber that was highly statistically significant for patient reported ocular itching and ocular tiering and investigator-assessed redness and also, because the INVIGORATE trial was highly statistically significant across itching, redness and tiering.

I don't expect anything different from INVIGORATE 2, one reason for that is that the protocol for INVIGORATE 2 is substantially identical to that of INVIGORATE. And obviously, we've discussed the protocol and the assessment with the agency previously. The timing of INVIGORATE 2, as we've described today will likely be 2023.

That's because we can only run these trials in the winter. It often takes two winter seasons to enroll a sufficient number of patients. But in response to other questions, as I said today, the NDA submission for allergic conjunctivitis would occur subsequent to that dry eye disease..

Understood. Okay. That's all very helpful. Thanks, Todd, look forward to the data and the rest of the year..

Thank you, Matt..

Thank you. Our final question for today comes from I-Eh Jen of Laidlaw & Company. I-Eh, your line is now open..

Thanks for taking the questions. I just as you mentioned that you don't want to start – continue to dry chamber study registered in the pollen season.

Should we assume that you were about to complete the patient enrollment for the study?.

I think that is an excellent assumption.

As I said previously, today, and I think we've discussed during the TRANQUILITY data call, pollen is a confounding factor, not only in terms of dry disease development, but also in terms of the assessment of dry disease, the issues with pollen are apparent with patients that are allergic to pollen and they're apparent with patients that are not allergic to pollen.

One goal, as you pointed out, of TRANQUILITY-2 is to perform the trial outside of pollen season, which, as you know, is about to start.

And so, I think your assumption is reasonable that we will not continue enrolling very much longer and that at some point in the relatively near future, we'll have completed enrollment, and then we look forward to reading out the results again in the midyear time frame..

One follow-up question here is that for 2191 in the PVR, should you have a positive data to be reported in second half of this year? What might be the follow-up on that indication?.

That's another interesting question, I-Eh. The PVR trial, the GUARD trial, completed enrollment late last year. And the follow-up is six months. So, one might reasonably assume that the last patient last visit in the trial is somewhere around midyear this year, and the data would come out subsequent to that.

I think then we need to discuss with the agency the next steps, which are interesting in that since we have started GUARD, methotrexate has been recognized at conferences and in papers that you can access online as a potential treatment for PVR.

If that's the case, then it becomes difficult to enroll a trial like GUARD, where patients are randomized to either receive ADX-2191 or standard of care, because surgeons don't want to risk a patient being randomized to standard of care, which essentially is nothing. It's a watch-and-wait approach.

There is no approved therapy for PVR, and thus, the risk is a patient is enrolled in the trial and randomized to watch-and-wait and does not receive therapy, which now in terms of methotrexate is more and more regarded as an effective therapy. Thus, I don't think GUARD is practical – a trial like GUARD is practical to repeat.

My guess is we'll end up discussing the GUARD results with the agency, we'll end up discussing the literature that has emerged on methotrexate for the treatment of PVR, a subsequent to starting GUARD and that potentially, we can negotiate an NDA submission that involves a combination of real-world data published data and GUARD data.

But that remains the subject of a future FDA meeting that would occur after the GUARD results, assuming the GUARD results are positive..

Okay, great. That’s very helpful and the best luck for the success over there. Thanks..

Thank you, I-Eh..

Thank you. We have no further questions. So, I will hand back to Dr. Brady for any closing remarks..

Well, thank you all for joining us today. And as always, we look forward to keeping you updated on our progress..

Thank you for joining today's call. You may now disconnect..