Aldeyra Therapeutics (ALDX) Q4 2021 Earnings Call Transcript

Aldeyra Therapeutics (ALDX 0.51%)
Q4 2021 Earnings Call
Mar 17, 2022, 8:00 a.m. ET

Contents:

• Prepared Remarks
• Questions and Answers
• Call Participants

Prepared Remarks:

Operator

Ladies and gentlemen, thank you for standing by, and welcome to the Aldeyra Therapeutics full year 2021 financial results conference call. [Operator instructions] I would now like to hand over the conference to the company's chief financial officer, Mr. Joshua Reed. Please go ahead, sir. 

Joshua Reed -- Chief Financial Officer

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 not 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 position, 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 that are 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 our clinical trials or portions of clinical trials may not accurately predict the 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 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 our 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.

Todd Brady -- President and Chief Executive Officer

Thank you, Joshua, and good morning, everyone. 2022 promises to be an exciting year for Aldera, 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 and dry 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 intend 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 29th, during which we plan to announce topline data from our Phase two proof of concept trials of ADX-629, our first-in-class oral RASP Modulator in psoriasis, asthma, and COVID-19. The goals 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 of 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 in systemic disease and complementing our late stage retinal and topical ocular programs. In addition to describing the initial phase two 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 potenciators 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 three TRANQUILITY-2 trial of Reproxalap and 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 and dry disease patients, we plan to submit an NDA for Reproxalap and 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 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 the 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 a Reproxalap has the potential to be that treatment.

The clinical benefits of a Reproxalap are supported by a growing body of scientific research. In January, we reported the results of a phase two dry eye chamber trial, comparing patient reported ocular discomfort and ocular itching symptom 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. In 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.

Allergic conjunctivitis, the phase three 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 three INVIGORATE trial, the results of which were announced in April 2021. INVIGORATE trial demonstrated statistically significant superiority of Reproxalap over vehicle in 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 two trial of ADX-2191 and Retinitis Pigmentosa, an incurable, potentially blinding disease with no approved therapy. This single-center-open-label trial will evaluate the safety and tolerability of ADX-2191 in 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 one of the phase three 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 estimate -- estimated 5% to 10% of retinal detachments. Results from part one 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 the vitreous, the fluid in the back of the eye. Thus, ADX-2191 represents a unique commercial opportunity. For example, off label methotrexate [Audio gap] 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.

And each indication ADX-2191 has received the U.S. FDA 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.

Joshua Reed -- Chief Financial Officer

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 and initial commercialization of approximately if approved, and continued development of our product candidates in 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.

Todd Brady -- President and Chief Executive Officer

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?

Questions & Answers:

Operator

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

Yigal Nochomovitz -- Citi -- Analyst

Hi, Todd and Josh, thank you very much for taking the question. On 629, I'm just curious, you're looking at three diseases; psoriasis, asthma and COVID-19. Just wondering if you have a sense as to where the best evidence is for potential therapeutic effect across these 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 this study? Thank you.

Todd Brady -- President and Chief Executive Officer

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 disease, which is more of an autoimmune TH1 type condition? And at the time I didn't really know [Inaudible] been demonstrated consistently Reproxalap worked across the board. ADX-629 is a close 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 for Reproxalap and ADX-629 as RASP modulators affect inflammation proximally 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 in that -- that is an infectious disease.

Yigal Nochomovitz -- Citi -- Analyst

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 could give your -- 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?

Todd Brady -- President and Chief Executive Officer

Yigal, your point is a good one. The 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. 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 eye 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 eye disease data. It depends on a 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.

Yigal Nochomovitz -- Citi -- Analyst

Great. Thanks, Todd. 

Todd Brady -- President and Chief Executive Officer

Thanks, Yigal. 

Operator

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

Unknown speaker

Hey, Todd. This is Hal on for Kelly Shi, and thanks for taking my questions. So -- my first one is really for the Schirmer test results in the [Inaudible] trial. It was very fast [Inaudible] that basically one day you see the efficacy.

So do you think there's any [Inaudible] point of view that you can explain the fast onset of action? And then do you think the effect is durable and if FDA need to acquire some evidence for the disability of the effect?

Todd Brady -- President and Chief Executive Officer

Great. Thanks for the question, Hal, and those are important questions to consider as we approach NDA submission for dry eye disease. I want to build on [Inaudible] questions 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 work so quickly is because the mechanism of the drug involves the chemical reaction, that is the binding of Reproxalap to RASP as we've presented in our corporate deck and discussed previously. That reaction is exceedingly fast. Occurring within minutes and 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 a very rapidly.

The FDA's position on signs, at least per our discussions with the agency, is that the signs of dry eye 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, with being 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 the developer of Reproxalap, to demonstrate very rapid activity, at least from a science standpoint of the drug.

Unknown speaker

Thank you, Todd. That's very helpful. Just a quick follow up. So for the phase two trials, that's optimizing [Inaudible] measurements.

Just want to check the status of that one. And also, you mentioned about across all the trial and Schirmer test one day trial in your opening. Just to get a little bit understanding about the timing and trial design, if possible.

Todd Brady -- President and Chief Executive Officer

Right. The wrath 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 eye disease of 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. A crossover dry eye chamber trial is unique heretofore and TRANQUILITY and 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 and allergic conjunctivitis. As you know, the INVIGORATE trial and the ongoing INVIGORATE-2 trial and a phase two allergen chamber trial, which has recently been published in clinical ophthalmology, are subjecting subjects -- and have subjected 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, that 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, Hal, that if both trials, if successful, will support the NDA submission, though may not necessarily be needed for the NDA submission pending the outcome of TRANQUILITY-2.

Unknown speaker

Great. Thank you, Todd. 

Operator

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

Marc Goodman -- SVB Leerink Partners -- Analyst

Yes. Hi, 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, if 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 -- just give us an update on how the safety is going, the numbers that you need. Also, CMC just making sure that the next study is 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, as question number one. And 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 backups just in case this other one TRANQUILITY doesn't work? What other purpose does it serve? Thanks.

Todd Brady -- President and Chief Executive Officer

Thanks, Marc, and thanks for the excellent question. I think, as I've said many times before, investors often forget about the requirement for safety trials 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 and registration batches, stability, and etc.

The safety trial is a significant undertaking for chronic drugs, generally, a 12-month safety trial is required per FDA dry eye disease guidance. As you know, 100 subjects are or 100 patients are required to be exposed to the drug for a 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 mid-year for dry eye disease based on the current enrollment in the safety trial.

Across the industry, not only in dry eye 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 move through various phases of COVID. But as is the case with COVID broadly, I think 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 ones. 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 eye disease chamber crossover trial, which, as I mentioned in response to Hal'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.

Marc Goodman -- SVB Leerink Partners -- Analyst

Thanks. 

Operator

[Operator instructions] Our next question comes from Thomas Shrader of BTIG. Thomas, your line is now open. 

Unknown speaker

Hey. Good morning. And this is [Inaudible] on for Tom. So, as we await data read-out for TRANQUILITY-2 from TRANQUILITY-1.

One of the concern was patients going into the trial had low baseline ocular redness, and I was just wondering if you guys had an earlier read on the -- for the TRANQUILITY-2 patients? Thanks.

Todd Brady -- President and Chief Executive Officer

Hi, [Inaudible], and good morning. Yes, we expressed or described, I would say two major differences with the TRANQUILITY trials 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, it can confound ocular surface disease and assessment of 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 two trial demonstrated statistical significance across Reproxalap and vehicle for ocular redness. One reason for that may have been the use of antihistamines or use of piezo constrictors or use of artificial tears, which of course are restricted in clinical trial settings, but nonetheless occasionally occurs among patients that are suffering from allergies and other effects that 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-2 the baseline, scores look better or higher than they did in in the prior phase two trial. But obviously, the result that matters is the unblinding of the trial and the differences between groups.

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

Unknown speaker

Great. Thank you. 

Operator

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

Matthew Cross -- Alliance Global Partners -- Analyst

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

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

Todd Brady -- President and Chief Executive Officer

That's an interesting question, Matt. Thank you. Generally, the FDA considers dry eye disease distinct from allergic conjunctivitis, notwithstanding the overlap that [Inaudible] 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 redness reduction of allergic conjunctivitis will be a primary consideration when assessing the sign activity of Reproxalap and 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 a 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 a 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 than dry eye disease, where subjects to some question must have a redness not only in the dry eye disease chamber to enter the trial, but generally -- as as drug is dosed and they enter the chamber for redness assessment. So due to different protocols highlighted by the difference in pollen and the nature of the diseases.

Matthew Cross -- Alliance Global Partners -- Analyst

Got it. Thanks. I appreciate the thorough answer there. And then just a related points around INVIGORATE-2.

Obviously, you already conducted a positive second study in the form of ALLEVIATE. I just wanted to, now that you've discussed plans officially to go ahead with the INVIGORATE-2 which is largely a repeat of INVIGORATE. I wanted to confirm whether you had received any additional feedback from the FDA, confirming or that maybe would explain to some degree better why they had opted to request. And I don't know if this was the FDA request or maybe your answer can clarify that.

But to repeat the similar design and what was the shortcoming ALLEVIATE?

Todd Brady -- President and Chief Executive Officer

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, with primarily designed to assess antihistamines. Obviously, Reproxalap is not an antihistamine and thus, the FDA wanted to adequate and well controlled trials 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 two trial now recently published in the allergen chamber that was highly statistically significant for patient reported ocular itching and ocular tearing and investigator assessed redness. And also because the INVIGORATE trial was highly statistically significant across itching, redness, and tearing.

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 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, they've said today, the NDA submission for allergic conjunctivitis would occur subsequent to that of dry eye disease.

Matthew Cross -- Alliance Global Partners -- Analyst

Understood. OK. That's all very helpful. Thanks, Todd for the data and the rest of the year.

Todd Brady -- President and Chief Executive Officer

Thank you, Matt.

Operator

Thank you. Our final question for today comes from Yale Jen of Laidlaw and Company. Yale, your line is now open. 

Yale Jen -- Laidlaw and Company -- Analyst

Thanks for taking the question, Todd. Just as you mentioned that you don't want to start and continue [Inaudible] chamber study readiness to be in the pollen season, should we assume that you were about to complete patient enrollment for the study?

Todd Brady -- President and Chief Executive Officer

I think that is an excellent assumption. As I said previously today, as we've discussed during the TRANQUILITY data call, pollen is a confounding factor, not only in terms of dry eye disease development, but also in terms of the assessment of dry eye 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 mid-year timeframe.

Yale Jen -- Laidlaw and Company -- Analyst

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?

Todd Brady -- President and Chief Executive Officer

That's another interesting question. Yale. 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 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 care, which essentially is nothing. It's a watch and wait approach.

There is no approved therapy for PVR. And thus, the risk is that 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 will 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 -- of the future FDA meeting that would occur after the GUARD results, assuming that guard results are positive.

Yale Jen -- Laidlaw and Company -- Analyst

OK. Great. That's very helpful, and best of luck for all the success over there. Thanks.

Todd Brady -- President and Chief Executive Officer

Thank you, Yale.

Operator

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

Todd Brady -- President and Chief Executive Officer

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

Operator

[Operator signoff]

Duration: 49 minutes

Call participants:

Joshua Reed -- Chief Financial Officer

Todd Brady -- President and Chief Executive Officer

Yigal Nochomovitz -- Citi -- Analyst

Unknown speaker

Marc Goodman -- SVB Leerink Partners -- Analyst

Matthew Cross -- Alliance Global Partners -- Analyst

Yale Jen -- Laidlaw and Company -- Analyst

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