Ladies and gentlemen, thank you for standing by and welcome to the Aldeyra Therapeutics Second Quarter 2022 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 Interim Chief Financial Officer, Mr. Bruce Greenberg. Please, go ahead, sir..

Good morning, everyone. With me today is Dr. Todd Brady, our President and Chief Executive Officer. This morning we issued a press release reporting our financial results for the quarter ended June 30, 2022, and recent corporate highlights. A copy of the press release is available on the Investor & Media section of our website at www.aldera.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 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 result from clinical trials or portions of clinical trials may not accurately predict the results of future trials for the same or different indications and Aldeyra's continuing review and quality control analysis of clinical data.

As a result of the COVID-19 pandemic, clinical site availability, staffing and patient recruitment have been negatively affected and the time lines to complete our 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 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 in our filings with the SEC. I will now turn the call over to Dr. Brady..

Thank you, Bruce, and good morning, everyone. In reflecting on our accomplishments so far in 2022, a couple of things stand out to me. The first is the exceptional progress our team has made in advancing our lead investigational new drug reproxalap to a planned new drug application submission in the second half of 2022.

We've amassed what we believe is the most comprehensive regulatory package ever for a dry eye disease drug candidate and based primarily on what we believe to be an unparalleled rapid onset of action.

We're excited about reproxalap's potential to change the treatment paradigm in what is one of the world's most prevalent ocular surface diseases which today is suboptimally addressed with drugs that require at least weeks of administration for even modest improvement.

With the recent completion of the crossover and Phase III TRANQUILITY-2 trials, we believe we put ourselves in a position to submit a thorough and extensive NDA based on robust symptomatic improvement, and the achievement of three objective sign endpoints of dry eye disease; ocular redness, Schirmer test and the Schirmer test greater than or equal to 10-millimeter responder analysis.

As I previously stated, the key outcome of the crossover trial is affirmation of the potential rapid onset of activity of reproxalap, which based on the results of the trial included observed improvement within minutes in ocular redness tear production and symptoms, including discomfort, dryness, burning and stinging.

For the primary endpoint of Schirmer test on day one and ocular redness in the dry eye chamber on day 2, the superiority of reproxalap was statistically significant with a p-value of 0.0004 for ocular redness and 0.0005 for Schirmer test.

I think the other important takeaway from our crossover trial results is the strength of reproxalap's safety and tolerability profile. Our clinical experience with reproxalap now encompasses more 1,800 patients. The drug has been well-tolerated with no observed safety signals in any patient.

Consistent with all of our prior trials and consistent with most topically administered ophthalmic drugs the most common adverse event is transient and mild installation site irritation which in reproxalap case has generally lasted less than one minute in duration.

I think it's also worth reiterating that to our knowledge, Aldeyra is the first sponsor to evaluate investigational dry eye disease drug in adequate and well-controlled crossover trial.

As I noted on our crossover data release call, key learning from the trial is that the high degree of patient-to-patient variability that we've observed can be reduced with a crossover design.

And we believe that the crossover design is feasible not only as it relates to dry eye disease, but also for other ocular surface disease trials involving therapies with potentially rapid activity.

The effectiveness of the crossover trial design has also demonstrated the successful completion for reproxalap's Phase II and INVIGORATE Phase III allergic conjunctivitis trials. In addition, the ongoing INVIGORATE-2 Phase III trial is a crossover trials.

Looking ahead, we expect to submit our NDA in dry eye disease in the second half of the year following our Type B pre-NDA meeting with the US Food and Drug Administration later this quarter.

The other accomplishment that stands out is the progress of ADX-2191, our investigational new drug platform for rare, but serious retinal diseases with no approved therapy. The development program of ADX-2191 encompasses three such conditions.

Number one, primary vitreoretinal lymphoma, which is a near universally fatal cancer; two, proliferative vitreoretinopathy or PVR a site-threatening condition that is the leading cause of failure of retinal reattachment surgery; and number three, retinitis pigmentosa, which is a rare group of genetic eye diseases.

The FDA has granted orphan drug designation to ADX-2191 for each of these indications and ADX-2191 is the first methotrexate formulation specifically designed to be compatible with a vitreous humor the fluid in the back of the eye, and therefore, represents what we believe to be a unique potential commercial opportunity for Aldeyra.

Results from our Phase 2 GUARD trial and PVR are on schedule and are expected for the second half of this year. As a reminder, GUARD is a multi-center randomized controlled adaptive Phase 3 clinical trial of repeated intravitreal injections of ADX-2191 for the prevention of PVR. The primary endpoint is retinal detachment over a period of 24 weeks.

Relative to primary vitreoretinal lymphoma, we plan to have a pre-NDA meeting with the FDA in the second half of this year to discuss the regulatory path forward for ADX-2191.

And finally, the third key milestone for 2191 is the top line results from the Phase 2 trial in retinitis pigmentosa, which we anticipate to be reported in the first half of 2023.

Eight patients are expected to be enrolled in the trial with half receiving monthly intravitreal injections, and the other half receiving twice monthly intravitreal injections over a period of three months.

Lastly, our oral RASP modulator platform led by ADX-629 continues to advance and represents a broad expansion of our pipeline from ocular inflammatory disease to systemic inflammatory disease, which as many of you know represents in aggregate one of the largest markets in pharmaceuticals.

This year we expect to report top line results from a Phase 2 clinical trial in acute alcoholic hepatitis and to initiate Phase 2 trials in Sjögren-Larsson syndrome and minimal change disease. Top line results of the Phase 2 trial of ADX-629 in chronic cough are anticipated in the first half of 2023.

I'd say, in summary that we are full steam ahead on our programs in both anterior ocular and rare retinal diseases, with a busy and quite remarkable regulatory calendar plan for the balance of 2022 featuring two pre-NDA meetings and two planned NDA submissions.

And with two late-stage candidates in what we believe to be a clear strategic path to market, Aldeyra represents a real opportunity to positively affect patient care in both mass market and rare diseases. Now let me call -- turn the call back over to Bruce for the financial review.

Bruce?.

Thanks Todd. Cash, cash equivalents and marketable securities as of June 30, 2022 were $196.7 million.

Based on our current operating plan, we believe that existing cash, cash equivalents and marketable securities will be sufficient upon currently projected operating expenses through the end of 2023, including potential NDA submissions and initial commercialization of reproxalap in ADX-2191, if approved and continued development of Aldeyra's product candidates in ocular and systemic immune-mediated diseases.

Net loss for the three months ended June 30, 2022 was $17.8 million or $0.30 per share compared with a net loss of $14.9 million or $0.28 per share for the comparable period of 2021. 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 for the three months ended June 30, 2022 were $14.6 million compared with $11.5 million for the same period in 2021. The increase of $3.1 million is primarily related to increases in external clinical and preclinical development costs and drug product manufacturing expenditures.

General and administrative expenses for the treatments ended June 30, 2022 were $3.1 million compared with $3.1 million for the same period in 2021. Total operating expenses for the three months ended June 30 2022 were $17.7 million compared with total operating expenses of $14.5 million for the same period in 2021.

Now let me turn the call back to Dr. Brady for closing remarks. .

Thank you, Bruce. I want to let the audience know that we have a full Investor Relations calendar planned over the next several weeks which includes the BTIG Biotechnology Conference, the Wainwright Virtual Ophthalmology Conference, the Citibank Annual Biopharma Conference.

And additionally, we'll be exhibiting in a series of medical meetings in the fall including; Vision Expo West in Las Vegas, the American Academy of Ophthalmology Annual Meeting in Chicago, the 32nd Biannual Cornia Conference in Boston and the American Academy of Optometry Annual Meeting in San Diego.

As per my prepared comments today now is a particularly interesting time to get to know Aldeyra and we welcome the opportunity to meet with current and prospective stakeholders and invite you to contact our Investor Relations team to schedule a meeting. Operator we'd now like to open the call for questions. .

[Operator Instructions] The first question comes from Catherine Novack from Jones Research. Please go ahead, Catherine..

Hi, thanks so much for taking my question. I wanted to talk a little bit about the non-reproxalap programs for a second. I'm curious if you can talk about the 629-ethanol toxicity study.

Has that been initiated? And can you give a sense of what the go-forward signal would be in this indication and how clearly defined a registrational path at this point?.

reproxalap, ADX-2191 and our systemic RASP platform which is headlined by ADX-629, which is the drug that you mentioned in your question. I feel like often investors focus on bucket one, which is reproxalap and forget about buckets two and three. So, I'm really thrilled with your question.

If I think about potential value long term for those three programs. As I mentioned in my prepared remarks this morning, one of the largest markets in pharmaceuticals that exists is systemic inflammatory disease and that is subject of ADX-629 and the sons and daughters of ADX-629. We have, as you know, a robust drug discovery platform focused on RASP.

We think that platform is unparalleled. One of the most important trials we're running is what we're calling acute alcoholic hepatitis or ethanol toxicity. And this is a crossover trial.

You heard my comments about crossover trials that this morning were big fans of those trials for obvious reasons, where patients are exposed to acute ethanol challenge, like many of us were on weekends, while we were in college and either subjects received ADX-629 or placebo ahead of time.

The idea really is to see, how 629 interacts with the primary metabolite of ethanol, which is a RASP, known as acetaldehyde. Acetaldehyde is what causes cancer in alcoholics. It's what causes hangovers in alcoholics and nonalcoholics. It's what causes flushing and so forth.

So much of the bad activity associated with ethanol is really due to a RASP, known as acetaldehyde, which binds rapidly with ADX-629. The idea really is to discern some sort of signal from these trials. We're looking at a variety of symptoms and signs.

Symptoms would include sort of your typical hangover symptoms, nausea, lightheadedness, et cetera, in addition to objective indicators of intoxication. And of course, biomarkers, including liver function tests that are elevated after acute ethanol exposure.

I think, if we're able to discern one or more signals from this trial, there are two options for us going forward. One is an acute ethanol, a challenge trial, which is sort of an emergency room type trial, where patients are admitted to the hospital due to acute ethanol exposure and the endpoint would be something like a time to discharge.

The other option available to us is the classic chronic alcoholic hepatitis trial, which heretofore has involved a 90-day treatment period and the outcome is mortality. Obviously, those are much sicker patients.

So I think, one of the beauties of systemic inflammation and ADX-629 in particular and even alcoholic hepatitis is, we have a variety of different options and we're prepared to pursue those options, assuming that the results are good from this first ethanol challenge trial..

Got it. That's helpful. And continuing with the non-reproxalap questions.

For 2191 in PVRL, can you clarify FDA's feedback on the NDA submission with outperforming clinical trials? And what additional post-marketing requirements you might anticipate should you be able to submit the NDA?.

For sure. The ADX-2191 program in ocular lymphoma is particularly interesting. In that the FDA has told us at least in writing that clinical trials are not required for NDA submission in ocular lymphoma.

The reason for that is that the active ingredient of 219 which is methotrexate has been used for years, decades as an intravitreal injection to treat ocular lymphoma. So there is a tremendous amount of efficacy data available in the literature, which would form the basis for the NDA submission.

What the FDA rightly wants to see is an appropriate amount of stability and safety data on ADX-2191, which is a particular preparation of methotrexate. As I mentioned in my prepared remarks, 291 that we're aware is the only vitreous compatible formulation of methotrexate.

Today, you can compound methotrexate, which principally involves taking the intravenous form of methotrexate and injecting into the eye. There are numerous challenges with that. First of all, the concentration is wrong, a high-volume injection must be used.

As you know, Catherine the eyeball is a confined space and does not have unlimited capacity for high-volume injections. Secondly, there's always the risk for infection. So I think the agency and physicians are interested in a GMP preparation of methotrexate.

And that is exactly what ADX-2191 is designed to be, while at the same time mimicking the ph, the tonicity, the density and so forth of the vitreous..

Got it.

And then just to touch on commercial preparations for reproxalap, can you talk about what your strategy is for commercialization and plans to do it on your own or seeking a partner would be helpful to get some color on that?.

Another great question and I'm pretty sure there are no more questions from the other analysts after this series of questions Catherine. Yes. Obviously, we're committed to commercialize reproxalap. I think there are three options for any small company not just Aldeyra. One is to partner the commercialization.

I think for most small companies these days partnering is preferred. The primary reason for that has to do with contracting with payers. It does not have to do with physicians, it does not have to do with patients. It really has to do with the cost of the drug, how easy it is for patients to acquire the drug the co-pays and so forth.

Obviously for larger companies that process is easier because of leverage, because of the size of their pipelines and thus I think not only with Aldeyra but other companies partnering as preferred. Regarding partnering, I think the good news is that to our knowledge there is no other novel, late-stage or NDA-stage dry eye asset available.

And there are a number of large companies that have significant interest in the anterior segment and the topical ocular space and are interested in dry eye disease drugs and either are losing exclusivity due to the genericization of cyclosporine or have not yet marketed a dry eye drug previously.

And thus, I would say for dry eye, a compound broadly there is strategic interest. The second option is, to launch internally. The good news there is, that such launches in the ophthalmic space are easy to pull off or relatively easy to pull off. There's a limited number of prescribers.

Those prescribers are accessible and marketing efforts have generally, performed well over the years, with a limited number of sales and marketing staff. Should we decide to launch on our own, we'll be prepared three to four months ahead of launch, with a sales and commercial operations group.

The third option, is a hybrid of the first two options, which generally involves partnering with what used to be called a contract sales organization, or an external group that handles back office and front office that is sales efforts.

And often those companies, will offload some of the cost, which gets paid back via revenues and there's a variety of different examples of that in the industry at least as it relates to small biotech companies. I would say, overall, we have optionality. We're prepared to move forward. As Bruce said today, we're financed to move forward.

And all in all, I think that puts us in a very good position..

Got it. Thanks so much..

Thank you, Catherine.

The next question comes from Yigal Nochomovitz from Citigroup. Please go ahead. .

Thanks. Hi, Todd and team. Hope you guys are doing well. On dry eye I'm just curious regarding the pre-NDA meeting for dry eyes.

How much of this meeting is purely administrative, as you've characterized in the past? And how much of this meeting is actually needed to get answers from the agency to outstanding question, to guide your filing strategy? And if so, what are those outstanding questions? Thank you very much.

Yes. Thank you, Yigal. That question is top of mind for us. Obviously, that meeting is imminent.

If you look at the regulations the Type B pre-NDA meeting is designed primarily to be -- meaning to discuss format, to discuss submission details and so forth, but we never waste opportunity to ask the agency interesting questions and I think the agency is generally receptive to that.

I think the primary question, from our end is, given what we've characterized as an unprecedented breadth of data, how does the FDA view our submission, to fulfill the efficacy requirements? As I said in my prepared comments, as I said in the crossover data release, as I said in the TRANQUILITY-2 data release we're submitting with a package that I think, has really never been submitted in terms of symptoms plus three different signs.

We're obviously very eager to hear the agency's response to that question. I would say they're very familiar with Schirmer test. If you look at the labels and dry disease that exists today, Schirmer test is on most of them particularly the responder analysis.

And I think the reason for that is the responder analysis is correlated with symptomatic improvement. So from the agency's perspective, the Schirmer test responder analysis is an all in one.

It's a sign and a symptom at the same time or at least correlates with the symptom at the same time and that's something they're going to be very interested in seeing. But we've posed the question about the breadth of submission. Obviously very eager to hear what they have to say along those lines..

Great. Thank you very much..

Thanks Yigal..

Next we have a question from Kelly Shi from Jefferies. Please go ahead, Kelly..

Thank you for taking my questions. So for 2191 in PBR, if I remember correctly the Phase III GUARD trial applied to more frequent dosing than Phase I.

Any impact there has been observed on the rate and discontinuation rate, as well as the impact on the efficacy end point, the real attachment to success rate? And also, what should be the regulatory bar on the efficacy endpoint? Thank you..

Good morning Kelly. Happy Friday. Your question is particularly interesting because what's happened since we started GUARD is that more and more data continue announced in the form of publications and presentations and posters.

With dosing regimens that are less frequent than what we're using in the GUARD trial, I think there are about 13 injections in the GUARD trial. The reason for is that we're enrolling a variety of severities in terms of the disease. And, obviously, the more severe the disease that is the more severe the detachment.

the greater number of prior PVR episodes and so forth would require in theory more dosing. I think in practice, what we may see is dosing that's less frequent than 13 injections. But that will have to be worked out systematically over time. We're quite comfortable with the number of injections we're giving in the GUARD trial.

Our discontinuation rate has been acceptable, but we really haven't seen too much of an issue with discontinuations. And I think the reason for that Kelly is that patients know they're going to lose their sight.

Just to remind everyone what happens when the retina detaches is sort of like a dark curtain coming down over your eyes such that in a matter of minutes you lose sight in one eye, which is quite frightening I would suspect. And thus patients are really motivated to prevent that from occurring again.

Because if it keeps reoccurring, there can be permanent loss of vision. And often that recurrent retinal detachment is due to PVR. In terms of the regulatory bar another interesting question back to what I said previously, the amount of data now that have been released in the public forum continues to grow.

And I think assuming we see positive results from GUARD in the second half of this year, we'll have a Type C meeting with the agency. We'll discuss the safety and efficacy results from GUARD. And what the regulatory bar is, I think will be the outcome of that discussion.

My guess Kelly is that the FDA will consider the published literature, the posters, the presentations, the data that have more or less come from real-world experimentation of methotrexate and PVR, in addition to the GUARD results. As I mentioned earlier, the GUARD results will provide key safety data that the FDA want to see.

The primary endpoint of GUARD is detachment rate or I should say re-datachment rate of the retina relative to standard of care, which is about 40%. If you go to the literature, there have been two or three large studies that have looked at. Detachment rates in PVR and typically those are re-detachment rates are about 40%.

So our aim is to be statistically lower than 40% in the treatment arm of GUARD. We'll also look at the treatment arm of GUARD versus the non-treatment arm of GUARD. However, we're really under powered to detect any differences there. I think those differences are primarily going to be summarized at a high level.

The idea being that it's becoming increasingly difficult to convince surgeons to randomize the patient to no treatment given all the data now that's available for methotrexate to treat..

Super helpful. Thanks Todd, and happy Friday too..

Thanks..

Thank you. Thanks for the glasses [ph]..

Next we have a question from Tom Shrader from BTIG. Please go ahead, Tom..

Good morning. Congratulations. I guess we'll stay on the 2191 theme. Just quickly, are you certain that it will be the same formulation and dosing for everything? And are the price points equivalent? I mean you have a cancer drug and you also have a prophylactic drug.

So, is it going to be one formulation with more or less on price? Just commercially what do you think we're looking at?.

Good morning, Dr. Shrader. Yes, the answer is yes. How's that for you? Same formulation, same concentration -- yes. I probably should. The dosing regimen is different. As I mentioned to in response to Kelly's good question about the dosing regimen in PVR. How that evolves over time, I think, is to be determined in the GUARD trial that's 13 injections.

Now, in lymphoma, many patients are dosed monthly, but more or less for the rest of their lives. To some extent, the dosing regimen of lymphoma depends on the physician and the patient. So I would say, -- the answer is yes in terms of formulation for sure.

And again that relates to the vitreous compatibility, which we think is unique and advantageous for this one. In terms of pricing, I think that's to be determined. Part of pricing depends on which indication is approved first.

And obviously, we're in the throes of market research and other methods to determine pricing with our research groups and our access groups here internally..

All right. Great. Thank you. We were happy with yes..

Thanks Tom..

Next is a question from Justin Kim from Oppenheimer & Co. Please go ahead..

Hi, good morning Todd and team. Thanks for taking the questions. Maybe just to talk a little bit more about 629. Can you discuss some of the blocking and tackling leading up to clinical trial initiation for? Just very curious what work needs to be done ahead of getting those studies up and running..

For sure Justin. Good morning And I want to give you credit personally in a public forum for your support of ADX-629 over the years and the systemic -- the platform.

You were one of the first analysts to really pick up on the applicability of RASP modulation beyond the eye and obviously we're appreciative of that and big believers of the expansion of our program systemically.

629 is currently the subject of what I would say is a four-pronged approach in Phase II right now two large diseases, alcoholic hepatitis and chronic cough and then two rare diseases. The two that you mentioned Sjögren-Larsson syndrome and minimal change disease. We're interested in particular in diseases that affect children.

And one reason for that is the safety profile that's been exhibited with reproxalap has been exhibited with ADX-629. RASP modulation because it does not directly inhibit or activate a single protein in theory, has significant safe advantages.

We think of RASP modulation instead of turning things on or off as sort of an analog approach where you're turning the volume down from a seven to two. And that should award safety advantages. And when we think safety, we think children.

MCD, minimal change disease is a renal inflammatory condition that primarily affects kids, but the problem is corticosteroids are often needed to treat those children and some of them cannot wean off corticosteroids.

Steroids have significant toxicities, especially in growing that children stunted growth, hormonal dysregulation, glucose dysregulation, bone growth dysregulation, and so forth. So, the idea is to get children off steroids as soon as possible and ADX-629 may be a mechanism to do that. So, we're obviously very excited about that trial.

Sjögren-Larsson, a similar story, a neuro cutaneous disorder that primarily affects children although there are some adults with Sjögren-Larsson Syndrome as well. No therapy approved for MCD or SLS. Each of these requires an IND submission.

The IND for Sjögren-Larsson syndrome is an investigator IND put forth by Bill Rizzo who really discovered the biochemical molecular and genetic basis for SLS and has I think one of the largest SLS cohorts in the world.

And then minimal change disease is an IND that will be sponsored by Aldeyra and we're just absolutely thrilled with the response we've received so far from the renal community on that..

Great. Great.

Maybe just as a follow-up there, do you think that steroid-sparing is sufficiently meaningful clinical benefit for MCD patients? Just sort of curious, maybe in light of recent M&A activity as well with similar potential approaches and other indications?.

Yes. I think it depends on the indication. For many years biotechnology companies have focused on steroid-sparing. To your point, I think with variable results. Steroids are inexpensive, they're effective. They're a little bit like a hammer, in treating many of these diseases.

The challenge is the unintended side effects of steroids, which may not matter for diseases that are treated acutely with steroids or for severe adult patients and so forth. But they do matter for children.

If one of my children had to take steroids, my goal would be to get them off steroids as soon as possible while maintaining some control of the disease and that's exactly what we're going for with ADX-629 and Minimal Change Disease..

Understood. Maybe just lastly I'll stick one in for reproxalap. Just any updates on the dry eye safety study.

And whether it remains on track for the sort of filing time lines? And whether it's sort of on the critical path, let's say?.

The safety trial does remain on track. One of the questions we'll be asking at the pre-NDA meeting is how does the agency want to see those data, in what format and so forth. But at this point prior to that meeting, we're quite thrilled actually with the progress of the safety trial. It's always good news when patients are on drug for 12 months.

And they stay on drug. It's often difficult to keep patients on anything for 12 months, particularly with diseases like dry eye which are episodic. As you know, dry eye gets better in the summer, because it's more humid. It gets worse in the spring. And it gets worse in the fall, to some extent in the winter.

But to our knowledge, we've been able to maintain a healthy number of patients on reproxalap for 12 months which is always a very good sign. Safety aside, it's always a good sign. So we're pleased with the progress. And again heading into the pre-NDA meeting we think we're right on track with the safety trial..

Great. Thanks for taking my question and congrats on the progress..

Yeah. Thank you, Justin..

Next our question comes from Marc Goodman from SVB Securities. Please go ahead, Marc..

Hi. Good morning. This is [indiscernible] for Mark. I just was wondering, if you can give us some color on the regulatory pathway for reproxalap and allergic conjunctivitis.

And now after the filing the NDA and more specifically about the timeline and whether do you think there will be any limiting steps? And could you also remind us of your filing strategy of ATX-2191 in PVR? Thank you so much..

Perfect. Perfect questions [Indiscernible] I thank you for asking about allergic conjunctivitis. Dry disease has received a ton of interest at Aldeyra and other companies. And I think, there's a variety of reasons for that mostly dry disease is untreated. It affects tens of millions of people.

It's been nicely promoted by the companies that have come before us in developing dry disease drugs. What people forget about is allergic conjunctivitis, which affects about one-third of the world and is growing in prevalence. And it's growing in prevalence for a couple of reasons. One is pollution continues to increase unfortunately.

And the second reason is the level of pollen is increasing. And the reason, the level of pollen is increasing is because of global warming. That essentially the growing season for grasses and weeds, and other pollen-producing plants is growing and is increasing in duration, which means more pollen.

As I mentioned some time ago, I saw a headline that said, if you think your allergies are getting worse, it's because they are. And that's for the reasons that, I just mentioned. Reproxalap is unique in that, it affects both dry eye and allergic conjunctivitis.

That I'm aware aside from corticosteroids, which you can only use on a short-term basis due to toxicity reproxalap is the only drug that has that kind of optionality. Now, what's interesting about that optionality is that, there's a 50% overlap between dry eye disease and allergic conjunctivitis.

It was a paper – another paper released this year out of Asia detailing that overlap is a very real comorbidity that exists between dry eye disease and allergic conjunctivitis. At this point, our idea is to submit allergic conjunctivitis as a supplemental – supplemental NDA or sNDA following the potential approval in dry eye disease.

The timing of INVIGORATE 2 as we have said is 2023. If the dry eye disease NDA is successfully submitted this year then a 2023 results for INVIGORATE two would make sense as it relates to an sNDA for allergic conjunctivitis.

Regarding PVR another interesting question, I think the Type C meeting that I referenced earlier once the GUARD data come out we'll have a Type C meeting, with the FDA. That Type C meeting will be informative in terms of the regulatory path forward.

And as I mentioned previously, our suspicion without having talked to the FDA our suspicion is that said NDA for PVR would be a combination of real-world data existing literature publications and so forth as well as the results from the GUARD trial..

Thank you so much. That was helpful..

Thanks..

The next question is from Yale Jen from Laidlaw & Company. Please go ahead..

Good morning, and thanks for taking the questions.

I recall that earlier time, when you did the SLS study mainly as a single center study and should we anticipate the current study and maybe even the pivotal study will be also mainly at the center or that could be multicenter studies?.

Thank you, Yale. That's a great question and that I think many investors have forgotten that we've previously worked with Dr. Rizzo on Sjögren-Larsson syndrome.

Many years ago, we treated Sjögren-Larsson patients topically with a dermatologic formulation of reproxalap long before we had data in dry eye disease and allergic conjunctivitis which was that by and large effective. The challenge with that though is that these Sjögren-Larsson patients aren't that just burdened with dermatologic disease.

Many of their symptoms are neurologic. In fact, Sjögren-Larsson Syndrome is the most common neurocutaneous disorder. That disorder is caused by mutations in fatty aldehyde dehydrogenase, which is an enzyme that metabolizes aldehydes and the relationship to an aldehyde inhibitor is therefore obvious.

In a sense, ADX-629 is sort of a pharmacologic enzyme replacement therapy. ADX-629 binds aldehyde including fatty aldehyde and some of that work has been published by Dr. Rizzo and others.

And therefore, we think a systemic approach to treating SLS with ADX-629 would benefit not only the neurologic signs and symptoms potentially, but perhaps even dermatologic the size of symptoms. The number of centers is at this point restricted to Dr. Rizzo Center. As I said earlier, Dr.

Rizzo has what we believe is one of the largest cohorts of SLS patients in the world. The reason for that is he discovered the physiologic basis of the disease. So we're thrilled to continue to work with Dr. Rizzo. I can tell you that he is excited about this particular approach. We'll have data from this trial next year.

And predictably, I can't wait to see the results..

Okay. Great. That's very helpful.

And the next question is probably a follow-up from the previous one which is in the PVL discussion you will have with the FDA are mostly centered around the PK and the maybe PD to see the equivalency -- something of equivalency or something of that nature to decide what the sort of filing pathway or process maybe?.

Yale, I don't think it's a PK/PD question. I think it's more of a safety question. We're well aware of the PK/PD of compounded methotrexate.

The concentration is obviously different for ADX-2191, but the amount of drug should be roughly the same because we're injecting less volume at a higher concentration versus the intravenous compounding that's injected into the eye is more volume at a lower concentration. The net result is the same amount of drug on a weight basis.

So don't really think PK/PD is going to matter. What I think will matter is safety. Because the formulation is novel in that to our knowledge methotrexate has never been formulated to mimic the vitreous. Now I would say, the formulation doesn't have fancy bells and whistles that I think would raise eyebrows at the agency.

At the same time, as I mentioned, the various characteristics of the vitreous that have been matched pH being one, density being another, tenacity being another that are important with regard to intravitreal injection. And my guess is the agency just wants to confirm the safety of that formulation.

In my opinion, a priority, there should be no safety concerns with those kinds of changes and in fact if anything such a formulation may have safety advantages. But nonetheless, the agency's job is to confirm to just to confirm safety and I think that's what they'll focus on here, Yale..

Okay. Great. And maybe the last question here a little bit forward looking that if both 2191 and the reproxalap approved and that you chose to market it yourself.

Just curious, are the typical call point for the sales would that be the same or overlap or quite separate for two drugs in fact?.

There are some synergies on the sales side for reproxalap and 2191, particularly in the back office and distribution access, et cetera. I don't believe that the front office is the same. That is there are few ophthalmologists that treat both retinal diseases and anterior segment diseases.

Typically, retinal surgeons focus on the retina for good reasons. They're not the kind of physicians that would be approached to engage awareness around dry eye disease drugs vice versa.

The good news, I think, though about 2191 in particular, there's a very limited number of retina surgeons that inject methotrexate on a regular basis as you might imagine. We're talking about rare diseases in terms of ocular lymphoma and PVR and retinitis pigmentosa.

There aren't hundreds and hundreds of surgeons that treat patients by injecting methotrexate intravitreally. And thus, I think, 2191 in terms of sales is really about distribution that is getting ADX-2191 in the offices and hospitals of the surgeons that treat patients with rare retinal disorders..

Okay. Great. That's very helpful. And congrats on the all the progress..

Thank you, Yale. Always the pressure. .

[Operator Instructions] We currently have no more questions registered, so I'll hand it over to Dr. Todd Brady. .

Thank you very much. I appreciate all your time this morning. And as always, that we look forward to keeping you updated on our progress, as we continue to endeavor to improve the lives of patients with significant unmet medical need..

This now concludes today's call. Thank you all for joining. Please disconnect your lines..