Good morning and welcome to the Aldeyra Therapeutics Full Year 2020 Financial Results Conference Call. After the speaker's presentation, there will be a question-and-answer session. [Operator Instructions] At this time, I would like to turn the call over to Mr. Joshua Reed, the company's Chief Financial Officer. Please go ahead sir..

Thank you and good morning everyone. On the call with me is Dr. Todd Brady, President and Chief Executive Officer. Dr. Brady will begin with an overview of our recent highlights and expected upcoming clinical milestones. I will discuss our full year 2020 financial results and then we'll take your questions.

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 statements regarding the timing of planned clinical trial initiations, Aldeyra's possible or assumed future results of operations, expenses, and financial position, business strategies and plans, research development and commercial plans, or expectations, trends, market sizing, competitive position, industry environment, and potential growth opportunities among other things.

These statements are based upon the information available to the company today. As a result of the COVID-19 pandemic, clinical site availability, staffing, and patient recruitment have been negatively affected and the timeline to complete our clinical trials may be delayed.

Aldeyra assumes no obligation to update these statements as circumstances change. Future events and actual results could differ materially from those projected in the company's forward-looking statements, including the current and potential future impact of the COVID-19 pandemic on our business, results of operations, and financial position.

Additional information concerning factors that could cause results to differ materially from our forward-looking statements are described in greater detail in the company's press release issued this morning containing financial results for the year ended December 31, 2020 and the company's filings with the SEC.

And with that, I'll turn the call over to Dr. Todd Brady, our President and Chief Executive Officer. .

Thank you, Joshua and good morning everyone. Our year-end call is an opportunity to share with you the progress we've made in advancing our lead clinical programs and equally important, the strategic vision for Aldeyra as we move to the next stage in our development. Over the past several quarters, we have focused on three primary objectives.

First advance reproxalap into two Phase 3 trials in a clinically relevant sign of dry eye disease, ocular redness, augmenting the statistically significant symptom improvement we achieved in previous Phase 2 and Phase 3 trials and positioning our compound as a novel rapidly acting potential first-line therapy.

Second, complete enrollment in our pivotal Phase 3 INVIGORATE trial in allergic conjunctivitis, facilitating the advancement of reproxalap as the first novel entrant for this disease in decades. And third, begin to explore the therapeutic potential of our retinal and systemic disease assets highlighted by ADX-2191 and ADX-629.

I'm pleased to report that we have succeeded on all fronts. In February, we finalized the design of our Phase 3 TRANQUILITY Trial of reproxalap as the treatment of dry eye disease. As we have previously announced, the trial is expected to enroll approximately 150 patients per arm.

The primary endpoint of TRANQUILITY is ocular redness over 90 minutes in a dry eye chamber with tier RASP levels, Schirmer's test, and dry eye symptoms as secondary endpoints. The protocol will replicate the two-day dosing paradigm, dry eye challenge design, and enrollment criteria of the run-in cohort.

Although in a relatively small number of dry eye disease patients in the run-in cohort, reproxalap achieved statistical significance in ocular redness as well as all assessed symptoms in the chamber. Symptom improvement was observed after a single day of dosing. And in the dry eye chamber as soon as five minutes after a single dose.

Likewise, improvement in redness also occurred within minutes, following dosing. Reproxalap was observed to act prophylactically preventing exacerbation of signs and symptoms as well as therapeutically reducing signs and symptoms following dosing in the middle of the dry eye chamber exposure.

TRANQUILITY and the confirmatory Phase 3 TRANQUILITY-2 trial are on schedule to begin enrollment in the first half of this year with top line results expected in the second half of the year.

Based on demonstrated symptom control in clinical trials and differentiated mechanisms of action, reproxalap has the potential to provide first-line ocular symptom control for dry eye disease patients. There is no dry eye disease therapy today that acts rapidly.

And health care providers at times must persuade patients to remain on therapy for weeks, even as little or no benefit is experienced.

I'm also pleased to report that enrollment has been completed in the Phase 3 INVIGORATE trial, a two-way randomized crossover trial assessing the safety and efficacy of reproxalap compared to vehicle, and subjects with allergic conjunctivitis.

Patients undergo 3.5 hours of continuous allergen exposure in an allergen chamber with dosing administered five minutes before and 90 minutes after chamber entry. The primary endpoint is statistical significance in ocular itching on a 9-point scale and a majority of 11 time points between 110 and 210 minutes in the chamber.

Top line results for INVIGORATE are expected in the first half of this year. Progress in our lead retinal program also remains on track. Completion of enrollment to part one of the Phase 3 GUARD trial of ADX-2191 for the prevention of proliferative vitreoretinopathy or PVR, is expected by the end of this year.

PVR is a serious site threatening retinal disease with no approved treatment. ADX-2191 has been granted orphan drug status and fast-track designation from the FDA for the prevention of PVR.

With regard to our systemic disease programs, we continue to expect top line results from our Phase 2 clinical trials of ADX-629, the first orally available RASP inhibitor by the end of the year.

The Phase 2 trials follow a successful Phase 1 clinical trial of ADX-629, which demonstrated statistically lower RASP levels in drug treated subjects relative to controls and no treatment-related adverse events at any dose tested.

As part of our longer-term clinical development strategy, we are also readying new compounds for retinal and systemic disease. The lead molecules of which could be in the clinic as early as next year. A strong and well-capitalized balance sheet is obviously an important asset in our industry.

With the completion in January of our underwritten public offering, which raised gross proceeds of nearly $75 million for Aldeyra, we began 2021 in great shape financially. We believe our current cash will be sufficient to fund our anticipated operating expenses and execute on our current operating plans through the end of 2023.

We were gratified by the strong support from the existing and new institutional investors that participated in the offering. With that, I'll turn the call back over to Joshua to review our financial results for 2020..

Thank you, Todd. As Todd noted in January, we announced the closing of an underwritten public offering of 7,868,421shares of common stock at a price of $9.50 per share. The offering included 1,026,315 shares, representing the full exercise of the underwriter's option to purchase additional shares.

And generated gross proceeds of $74.7 million and net proceeds of approximately $70 million after deducting offering discounts, commissions and estimated expenses. Cash and cash equivalents as of December 31, 2020, were $77.9 million.

Based on our current operating plan and including the net proceeds from the underwritten public offering completed in January 2021, we believe that existing cash and cash equivalents will be sufficient to fund currently anticipated operating expenses through the end of 2023, including the completion of the Phase 3 TRANQUILITY and TRANQUILITY-2 trials in dry eye disease, the completion of the Phase 3 INVIGORATE trial in allergic conjunctivitis, the Phase 2 clinical trials of ADX-629 in psoriasis, atopic asthma and COVID-19 and the completion of Part 1 of the adaptive Phase III GUARD trial in PVR.

Turning now to our full year financial results. Research and development expenses were $24.7 million for the full year 2020, compared with $44.4 million for the full year 2019.

The decrease of $19.7 million in R&D expenses primarily reflected a reduction in clinical research and development expenditures, partially offset by an increase in non-cash compensation costs related to a portion of a contingent acquisition milestone.

Acquired in-process research and development expenses were $1.8 million for full year 2020, compared with $6.6 million for full year 2019. The $4.8 million decrease is related to lower in-process research and development expenses associated with the 2019 acquisition of Helio Vision.

General and administrative expenses were $10 million for full year 2020, compared with $12.2 million for the full year 2019.

The decrease of $2.2 million in G&A expenses primarily reflected lower personnel costs, legal costs, public company costs related to continuing compliance with the Sarbanes-Oxley Act of 2002 and miscellaneous administrative costs.

The net loss for full year 2020 was $37.6 million, or $1.11 per share, compared with a net loss of $60.8 million or $2.24 per share for full year 2019. With that, I will turn the call back to Todd for closing comments..

Operator, I think, we'd like to open the line for questions at this point..

[Operator Instructions] Your first question will come from the line of Yigal Nochomovitz with Citigroup. Please, go ahead..

Hi, Todd and team. Thanks for taking the questions.

Could you just expand a little bit on the rationale for choosing ocular redness as the primary endpoint in TRANQUILITY, given, obviously, that in the running cohort RASP peer levels was the primary endpoint? And then related to that, if you could explain the rationale around choosing ocular redness as a secondary endpoint, not a primary in INVIGORATE? Thank you..

Yigal, good morning and thanks for the excellent question. We have a bit of an embarrassment of riches when it comes to reproxalap in terms of objective signs of dry disease that we can select for approval. In the running cohort, we had activity in ocular redness and Schirmer's test and in RASP, as you know.

Any of those three could be used as a pivotal endpoint for the TRANQUILITY trials. We selected ocular redness for a couple of reasons. One is, the data are very strong. We achieved statistical significance in a relatively small number of patients, I think, 23 total in the running cohort.

The second reason is that, this is the second time we've demonstrated activity in ocular redness. Ocular redness was also achieved in the Phase 2 allergen chamber trials. And as you know, allergy is closely related to the dry eye disease.

And I think the third and most important reason redness was selected is that, there is a considerable commercial advantage to having ocular redness in the label of the drug. Ocular redness is the only sign that patients care about. And therefore, it's probably the most important signs to the vast majority of physicians that treat this disease.

Many physicians as we've announced previously have complained that patients are concerned about ocular redness and thus a drug that can improve ocular redness, especially, a drug that can improve ocular redness quickly could be quite advantageous and therefore beneficial to patient care.

Your question about the selection of ocular redness as a secondary endpoint in the allergy trial is a really good one. For approval in allergic conjunctivitis, ocular itching is generally the only endpoint that is used, that is the primary symptom of allergic conjunctivitis.

Ocular redness is also the primary sign of allergic conjunctivitis, but it's not required for approval and therefore, we've designated ocular redness as a key secondary endpoint for INVIGORATE.

I do think based on my prior comments about ocular redness that there is considerable commercial advantage to having ocular redness in the allergy label as well. All of us are concerned when our eyes appear red and the amelioration of redness does add to patient care. .

Thank you. That's super, super helpful. And just one other question. Could you provide us a little bit more detail with respect to the enrollment criteria for the COVID-19 trial? Are these patients hospitalized not hospitalized severe, moderate, mild.

Can you just help us understand the requirements there?.

Of course. The COVID enrollment criteria are centered around patients with moderate disease. These days many of those patients are not hospitalized. So we anticipate a mix of hospitalized and outpatient populations for the COVID trial.

My guess is based on the way things are going and the current status of COVID treatment care most of the patients will be treated as outpatients. .

Okay. Thank you very much, Todd..

Thanks, Yigal..

Your next question comes from the line of Louise Chen with Cantor Fitzgerald. Please go ahead. .

Hi. Congratulations on all the progress this quarter and thanks for taking my questions. So first question I had was back on the TRANQUILITY trial.

Just curious if you've had a chance to speak to the FDA about your primary endpoint and what they might think of that? And then secondly, the dry eye disease market is getting crowded with many different companies developing different mechanisms for dry eye disease.

I'm just curious if your product is approved where do you expect it to fit into the treatment paradigm? And then last question I have for you is, just how should we think about operating expenses for 2021? Thank you..

Louise, good morning and thank you for the question. I'll address the first two questions and turn the third over to Joshua to address the financials. The Type C meeting we held with the FDA in the middle of last year was designed specifically to clarify the agency's position on our potential primary endpoints for TRANQUILITY.

You can rest assured that we clarified with the agency that redness can be used as a primary endpoint. Other companies have used redness as a primary endpoint at least as redness relates to an objective sign of dry eye disease. So we're quite comfortable that redness will be acceptable in our case.

As you know the agency also clarified that RASP the target of reproxalap and ADX-629 can be used as an objective sign of dry disease. And as you also know Schirmer test is also a possible signs. All three of those will be assessed in the TRANQUILITY trial with redness being the primary endpoint.

One of my favorite topics is where does reproxalap fit in the treatment paradigm for dry eye disease. As I mentioned in my prepared remarks, one of the major issues, if not the major issue in dry eye treatment today is that the available therapies do not work quickly. Xiidra and RESTASIS often take weeks to months for patients to feel better.

In 2019, if paper was published indicating that the median discontinuation times for Xiidra and RESTASIS are between one and three months. There is nothing more challenging for a health care provider then having to convince patients to stay on drug when there is no perceived benefit to the patient.

And that is precisely what is happening in the dry eye therapeutic landscape today.

Reproxalap therefore is a true paradigm shift and solves many of the problems that I've just described because the drug acts rapidly that is within minutes as was demonstrated not only in the run-in cohort of TRANQUILITY, but also in the Phase II allergen chamber trial reproxalap offers a manner of treating the disease rapidly.

In theory, patients could present to a healthcare provider a dose of reproxalap could be administered in the office of the healthcare provider. And assuming the patient has a red eye and is currently experiencing dry eye symptoms, which is often the case for patients that present to healthcare providers.

That patient could in theory feel and look better before leaving the health care provider's office. For all of these reasons we believe that reproxalap represents a first-line therapy. In summary, the key advantage is rapid onset and we believe rapid onset solves the primary problem with dry disease therapy today.

Josh do you want to talk about the financials?.

Of course. Thanks for the question Louise. With our planned activity in 2021 including TRANQUILITY, TRANQUILITY-2, INVIGORATE advancing our systemic program ADX-629 and development in ADX-2191 you should expect our spend particularly in R&D to increase versus 2021.

As far as timing goes as you know that can be a bit variable, but I would anticipate that our spend would increase quarter-over-quarter as the year progresses. .

Okay. Thank you very much..

Thanks Louise..

Your next question comes from the line of Kelly Shi with Jefferies. Please go ahead. .

Thank you for taking my questions and congrats on the great progress. I have a question for [indiscernible] filings expected by this year and for both dried and the conjunctivitis. Beyond the top line data what are other things you are and willing to work on for getting the package ready? That's my first question.

And the second question is how should we think about the marketplace of these two ocular indications? Do you see overlapping area where you can actually do promotion of reproxalap, given that they share the same working -- the mechanism of action? And also now you also share like one primary endpoint? Thank you..

Kelly, good morning. Good to hear your voice and thank you for the questions. There are many aspects of a successful new drug application submission which you allude to only one of them are -- is your efficacy trials.

Obviously, we're very optimistic about INVIGORATE and we're very optimistic about TRANQUILITY based on the Phase II trials in allergy and the running cohort of TRANQUILITY not to mention the prior trials in dry disease that have demonstrated activity of reproxalap and symptoms and signs. The other components of NDA submission concern safety studies.

Safety studies are a requirement for NDA submissions. In addition to safety studies is the magnitude of the safety database, which is really a summation of all the patients that have been exposed to drug throughout the clinical program from the beginning starting in Phase 1.

We have now over 1,100 patients that have been exposed to a reproxalap at concentrations higher than 0.25%, which is our concentration we intend to take forward or are taking forward. And at dosing frequencies that exceed the dosing frequencies that we are currently using, we have experienced or observed no safety events.

Which typically concern visual acuity, fundoscopy, slit lamp exam of the front of the eye, intraocular pressure and adverse events. I think it's remarkable that so many subjects in clinical trials have been exposed to drug and we have no reports of clinically relevant safety issues.

The third aspect of NDA submission concerns chemistry manufacturing and controls, as there the FDA is primarily concerned with the manufacturing process, the commercial process and the stability of the commercial batch. And I'm happy to say that we believe we're in very good shape with regard to all those standards as they relate to C&C.

The only thing I'll add is that the safety trial for dry eye disease is ongoing. The FDA requires that for NDA submission we have a certain number of patients with six months of exposure to drug. And we believe that we're on track to reach that milestone by the end of this year, Kelly.

Regarding your second question in terms of other opportunities for reproxalap. I think, one of the benefits of being an immunology company is that if products in the immune mediating space have broad applicability. Many if not most diseases have some inflammatory component to them.

And therefore, the potential applications for drugs that are active immunologically are broad. Allergic conjunctivitis and dry disease as you know, Kelly, are probably, if not certainly, the two largest and anterior segment inflammatory diseases of the eye, but there are other diseases.

We've announced trials previously in anterior uveitis, cyclitis, there are scleritis. There are many other diseases that involves inflammation of the anterior segment. And I think like the use of corticosteroids, the potential for broadly acting drugs like reproxalap is considerable.

Our plan currently however is to focus on dry eye disease and allergic conjunctivitis, but as you allude to the potential application of reproxalap down the road is significant..

Thank you very much for the color. Congrats again..

Yes. Thanks Kelly..

Your next question comes from the line of Justin Kim with Oppenheimer. Please go ahead..

Hi. Good morning. Thanks for taking the question. Maybe just one on TRANQUILITY.

When you think about the size and scope of the studies, could you share any thoughts on how you think about the powering for the primary and the key secondary end points?.

Yes, happy to Justin. We take statistical powering very seriously. Our company policy is to power at 90%, which is generally the most conservative threshold that biotech companies use for enrolling clinical trials. There are several different ways to power. As you know, we pick the most conservative threshold for powering to get to 90%.

And the powering is all based on ocular redness. In the TRANQUILITY run in cohort, the differences between groups were approximately 0.2 units. We use slightly less than that difference to power the main cohort of TRANQUILITY. I'll also comment briefly on powering for RASP.

I believe or we believe, at this point that, the powering for redness includes powering for RASP that is we should be at 90% power to detect differences in RASP based on the data from the running cohort. So those two end points, I believe are well covered in terms of powering..

Got it. Thanks.

Maybe then just as we think about sort of the patient population in dry eye disease, which endpoints may have more or less variability sort of inter patient? I mean is there some color you could offer us there based on sort of the study that you did and the measurements that you were taken in the running portion?.

A really interesting question, Justin, because variability in dry eye disease as everyone knows is considerable. And the variability among the endpoints specifically is considerable. We're hoping that RASP provide a very objective measure of disease severity. Although, the assay for RASP is somewhat complex.

Tears must be extracted, frozen, shipped to a central lab, an analysis must be performed and so forth, requiring much more time than the standard, the dry eye disease assessments.

Redness, we believe we've controlled for by including a central reader for the TRANQUILITY studies, redness is assessed with digital photography, such that light levels hue, color, intensity, saturation, contract, et cetera are all rigorously controlled. And then as we mentioned, those digital photographs are read by a central reader.

So we're hoping that the variability that we see with some dry eye endpoints will be limited by the controls that we've outlined for ocular redness..

Got it. Got it. Just a final question.

Could you just expand for us a little bit on the Phase 3 INVIGORATE study endpoint and how we should think about sort of the hurdle rate with respect to maybe the regulatory hurdle as well as maybe the commercial hurdle there?.

The FDA stance on allergic conjunctivitis is interesting and that they're particularly interested in assessing the onset and duration of a therapy in allergic conjunctivitis. The allergen chamber is particularly well suited to assess onset and duration because patients are continuously exposed to allergen over 3.5 hours.

And the particular primary endpoint as I mentioned in my prepared remarks is the achievement of statistical significance between drug and vehicle over a majority, or I should say, at a majority of time points in a prespecified range.

As you can see in our corporate deck, we specified a range that in Phase 2 was highly statistically significant between drug and vehicle. Within that range, the FDA will be looking not only for the achievement of majority of endpoints or time points but also the onset of the drug and how long the drug acts within that range.

Based on the Phase 2 data, we would expect the onset to be the first time point and the duration to be the last time point. But that is sort of the rubric that the FDA is using to assess the drug..

Got it. Thanks so much..

Thanks, Justin..

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

Hey, guys. Good morning and congrats on another quarter of progress. Just a couple of housekeeping questions for me today.

So first off, can you remind us how much lead time you'd expect between the initiation and completion of TRANQUILITY 1 versus 2? I guess given the overlap in design, would you anticipate that these will start and end more or less in lockstep for the first and second half of this year, or is there any kind of intermediary step between these two studies, we should be considering as we're thinking about time lines for the year? And then the second one I had was kind of similarly for ADX-629 and these three different indications being studied in Phase 2, is there anything you can say about the pacing of enrollment between these three? Are any of them kind of clearly advancing more quickly, more slowly, or may read out more quickly this year by virtue of the endpoints that you're examining? Just trying to get a better sense of how these may complete throughout the remainder of the year and distinguish themselves from one another? Thanks.

.

Thanks, Matt. Good morning. The difference between TRANQUILITY-1 and TRANQUILITY-2 in terms of protocol is zero. The intent is to replicate TRANQUILITY-1 with TRANQUILITY-2. There is an intentional stagger in timing between TRANQUILITY-1 and TRANQUILITY-2.

The reason for the stagger is that we want to have some time to analyze the results of TRANQUILITY-1 prior to database lock of TRANQUILITY-2. This allows us if need be to adjust the statistical analysis plan accordingly.

I do not expect any significant changes in analysis between TRANQUILITY-1 and TRANQUILITY-2, but the stagger is there as a conservative measure just to make sure that no changes are needed. Regarding the Phase 2 trials for 629, too early to say in terms of timing.

I would say the trials for psoriasis and asthma and COVID are more or less in lockstep at this point, but the exact timing of the results for all three of those Phase 2 trials will depend on enrollment and how the enrollment is affected by COVID and other factors over the summer. .

Got it. Appreciate the info and time. Thanks again..

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

Hi. Good morning. Congrats now there is some progress and thank for taking my question. First, I'm wondering how we should be thinking about the read-through from your upcoming allergic conjunctivitis data to the TRANQUILITY trials keeping in mind both are in chamber settings beyond involving different conditions albeit with significant overlap.

Are there any other nuances or differences worth highlighting here between trials especially pertaining to the redness data you're collecting in each?.

Per usual Julian, an excellent point about the read-through between the allergen chamber trial and the dry eye chamber trial. I do think there is read-through. And in our TRANQUILITY run and data release slide deck, we had a slide that included all four symptom and sign readouts across the allergen chamber and the dry eye chamber trial.

The point of that slide is that whether it's a dry eye chamber or an allergen chamber and whether it's symptoms or redness, reproxalap seems to behave the same way that is activity within minutes. So I do think that there is read-through between INVIGORATE and TRANQUILITY both our challenge studies both are using a chamber.

And both are enrolling a population of patients that do have some pathophysiological overlap. As I mentioned in my answer to Yigal's question there is about a 50% overlap between dry eye patients and allergic conjunctivitis patients, specifically about half the patients that complain an itching, which is the symptom of allergy.

Also complain of dryness. And about half the patients the complaint of dryness also a complaint of itching. And there are many other overlaps between these two patient populations including pollen. Pollen obviously exacerbated allergy, but it's also probably the key exacerbator of dry eye disease.

And to make matters worse as you know, Julian, the therapies for allergy including antihistamines make your eye dryer and at least one of the therapies for dry eye disease seems to induce ocular itching the key symptom of allergy.

So I would say not only do the trials themselves INVIGORATE and TRANQUILITY have overlap in terms of protocol and methods. But also the patient population is overlapping in terms of anterior segment inflammatory the pathophysiology. And to boot reproxalap seems to behave the same way in terms of improving symptoms and signs rapidly in these chambers..

Got it. Okay. Thanks. That's helpful. And then sorry if I missed it on the vitreoretinal lymphoma program. I'm wondering, when we should expect an update on the path forward.

Are you still anticipating the possibility to file an NDA without the need for any clinical trials?.

The answer is, potentially, I think you will hear more from Aldeyra on our plan path forward with lymphoma and other retinal diseases that can be treated with ADX-2191 shortly..

Okay, great. Thanks very much..

Your next question comes from the line of Esther Hong with Berenberg. Please go ahead..

Hi, good morning. So as the programs for reproxalap move forward, can you speak about the commercial strategy for reproxalap that will potentially be approved for both dry eye disease and AC? Thanks..

Hi, Esther, good morning. The commercial strategy is something that we've historically thought a lot about. As you point out as reproxalap nears NDA submission, the commercial and go-to-market strategy is particularly important.

As I mentioned in previous answers, we believe that reproxalap is well-positioned in the market today given that as I mentioned the current therapies take a long time to work and reproxalap seems to work quickly. A question we often get is, is reproxalap going to be marketed or launched by Aldeyra.

I think the good news is that we have considerable optionality around a do-it-alone launch versus a partnered launch.

On one hand, many of the health care providers that prescribe dry eye disease therapies are spread across the continuum of patient care from optometrists to nurse practitioners to general ophthalmologists to general practitioners, the anterior segment ophthalmologists.

So there's a wide prescriber base that probably is best served by a large company with a significant commercial footprint. On the other hand, small ophthalmology companies have and are launching anterior segment drugs on their own. So it's certainly feasible that Aldeyra could do so as well.

I believe that based on what other companies are currently executing on the standard sales force for a front of the eye launch is in the range of 100 to 300 sales representatives, which again is feasible for small companies. In summary, I think that we have many options as it relates to launching reproxalap.

Regarding Retina, I do think that Retina is something a small company not only can do but maybe even should do because the prescribing base for rare retinal diseases is very limited.

In not only Aldeyra's case, but probably other companies' cases that are working on rare retinal diseases, the physicians that prescribe these drugs are the ones running the clinical trials. And so that prescriber base is very familiar to the company..

That’s very helpful. Thanks..

Thanks, Esther..

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

Thanks for taking my questions. Congrats on the recent progress. I have a quick one on ADX-629, the primary compound for your systemic strategy. Can you briefly talk about the bio design of the Phase 2 study in psoriasis, for example, the primary endpoint and the size of the study? Thank you..

Thanks for the question, Edwin, and I'm particularly thrilled to talk about ADX-629, because I think it represents a transformative event for our company as we've previously been focused primarily on anterior segment ocular disease, ADX-629 represents a transition from ocular disease to systemic disease.

As you know the number of systemic diseases that relate to immunology is considerably larger than the number of diseases in the eye that are immunologically based, and thus we are particularly thrilled with the launch of the Phase 2 trial for ADX-629. There is a systematic, well thought out approach to testing ADX-629.

As you know, there are different kinds of inflammation. In particular, they sit on a continuum between allergy and autoimmune disease. Different kinds of cytokines, different cytokine profiles, and other pro-inflammatory mediators exist along the continuum, and our idea is to assess the activity of ADX-629 in both camps.

And thus, we're able to guide the future development of 629 in Phase 2b clinical testing next year. I'm happy to comment on all of the trials generally in terms of protocol for asthma, the psoriasis, and COVID these are all Phase 2a proof-of-concept trials. In the case of asthma and COVID, these will be controlled trials.

In the case of psoriasis, a single-arm trial, the numbers of patients in each trial is between 10 and 30 patients. The idea is that by the time the results are available for each of the trials we're able to assess the biomarker response of ADX-629. There are no primary endpoints, because these are proof-of-concept studies.

Obviously, safety and adverse events will be a key metric, but really our focus as I mentioned is on the biomarker activity affected by ADX-629. In particular, we're looking specifically at cytokine profiles and RASP levels. We have other biomarker assessment specific to certain of those trials.

But in general, I think, the street will have a very good understanding of the kind of cytokine profiles affected by ADX-629 by the time the three Phase 2 readout at some point this year..

Very helpful. Thank you..

Thanks a lot, Edwin..

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

Hi. Good morning and thanks for taking my questions. I think you mentioned that some new molecules might enter the clinic next year. Could you give more color on the mechanism of these compounds? Will they also be based on the RASP? And for these molecules, what indications might be of interest? Thank you..

Thanks. Prakhar. This is an excellent transition to the future of Aldeyra. One of our core strategies is to continue to develop new molecules, as part of pipeline progression. I see many biotech companies and the focus is on a single asset, or a series of assets with very little behind the initial pipeline.

We do not intend strategically to focus on a certain number of assets and those assets only. Instead, we intend to develop a – almost ever green source of new compounds. The answer to your question about RASP is yes. These compounds are RASP inhibitors. There is a large chemical composition space available to us regarding RASP inhibition.

As you know, we seem to be the only company focused on RASP, and we have developed what we believe to be truly foundational compositional structures around RASP inhibition, and thus have what we believe is a considerable freedom to operate. I'm particularly excited about these new compounds.

Many of them are from a RASP inhibition standpoint more potent than reproxalap and ADX-629. Others have specific advantages as they relate to PK, blood-brain barrier penetration, metabolism, dosing formulation, solubility, et cetera.

So we've had – we've undergone specific efforts to not only discover new RASP inhibitors, but prioritize new molecules for advancement. As I mentioned, we anticipate being in the clinic, with a compound, one compound at least next year. And those compounds will be targeted to retina and/or systemic diseases..

Our final question will come from the line of Yale Jen with Laidlaw & Company. Please go ahead..

Good morning, Todd. And I add, my congrats, on the progress. My first question is, regarding the INVIGORATE trial -- this come from investors. That is it a nine-point scale each for the current study. But if I remember correctly, the prior study was four-point scale.

Could you provide some color for the differences?.

Yeah. Good morning, Yale. And thanks for the question. It's just a matter of semantics. It's the same scale. The reason it's a nine-point scale is because, it's a zero to four, scale with half unit increments. So if you add up zero to four and you include 0.5 and 1.5, et cetera, you'll get nine points. It's the same scale.

It's sometimes called a four-point scale and sometimes calls a nine-point scale. But in the end, we're talking about precisely the same thing..

Okay, great. That's very helpful. And maybe one more question here, which is for 2191.

Could you reiterate what is the study design at this moment? And what's the endpoint, you anticipate for the first part of the study?.

Right.

You're speaking Yale, of PVR?.

Yes, yes..

Yes, yes. The GUARD trial is designed to assess retinal detachment rates over six months of therapy. And compare retinal detachment rates of standard of care which is essentially monitoring to those of ADX-2191 intravitreal injections. The problem with PVR is retinal detachment. Retinal detachment occurs, surgeons can replace the retina.

But then, there is scarring behind the retina, that's PVR. And that scarring, leads to two issues. One is loss of sight. And two is further retinal detachments. As the scar grows, the retina is pushed back off the eye.

And that's why the FDA has agreed that, retinal detachment rates or the proportion of patients with retinal detachment can be used as a primary endpoint to compare standard of care in reproxalap. The GUARD trial we expect to be enrolled this year. Because it's a six-month follow-up results from that trial would be expected next year.

And of course, once those results come in, we'll visit with the FDA again to talk about next steps..

Maybe one more sort of question here which is, is the study placebo-controlled, or you're look -- compared with historical status?.

The control is standard of care. Patients are randomized one-to-one to either receive the series of ADX-2191 injections or, standard of care. And as I mentioned, standard of care means monitoring. The standard of care, today, is to repair the retina and not, to treat PVR. There is no treatment, other than, ADX-2191 that's used today for PVR.

So thus, standard of care is essentially, repair of the retinal detachment and monitoring..

Okay, great. Thanks a lot. I appreciate it and congrats..

Yeah. Thank you, Yale..

At this time, I'll turn the call back over to Dr. Todd Brady for any closing remarks..

Well, thank you, operator. We have a number of virtual events coming up, including a presentation this afternoon, at the OIS dry eye innovation showcase and next Tuesday, at the Oppenheimer Annual Healthcare Conference. As always, we look forward to connecting with you. And keeping you updated on our progress..

Ladies and gentlemen, that will conclude today's call. Thank you all for joining. And you may now disconnect..