Aldeyra Therapeutics, Inc.

that of standard of care antihistamines. In addition to durability, the rapid onset of response will be highlighted in a poster presentation next week at the American Academy of Ophthalmology 2020 virtual annual meeting. The poster features new data from responder analyses of our phase two allergen chamber trial, as well as new data on ocular tearing and post-chamber activity of drug after exposure to allergen has ceased. The data further support the clinical utility of Reproxilab, suggesting the possibility of rapid efficacy in reducing redness and itching in allergic conjunctivitis. For these reasons, we remain particularly excited about the potential of Reproxilab as the first novel mechanistic approach for late-stage allergic conjunctivitis in decades. Turning to the posterior segment of our ocular disease pipeline, we expect to complete enrollment in part one of the phase three GARD trial of ADX2191 for the prevention of recurrent retinal detachment due to proliferative vitreoretinopathy, or PVR, by the end of 2021. PVR is the leading cause of retinal detachment surgery failure, affecting roughly 4,000 patients per year in the United States and nearly twice as many in Europe and Japan combined. Recruitment for the GARD trial is underway at more than 20 clinical sites across the United States. And as I noted in our Q2 call, the pace of enrollment has been slower than anticipated, particularly due to delays caused by COVID-19. ADX2191 may also have the potential to treat primary vitreoretinal lymphoma, or PVRL, a rare aggressive high-grade cancer that affects approximately 2,900 people in the United States, with about 600 new cases diagnosed annually. There are no approved treatments for this severe type of ocular cancer. As for our systemic disease programs, in September, we received a study may proceed letter from the FDA clearing the way to start phase two testing of ADX629, our orally available RASP inhibitor, for the treatment of adult patients hospitalized for COVID-19. We continue to expect the trial to begin by year end. This quarter, we also plan to initiate Phase II clinical trials of ADX629 for the treatment of severe inflammation associated with Th2 type cytokine production represented by atopic asthma and Th1 type cytokine production represented by psoriasis. As I noted on our Q2 call, testing in an animal model of cytokine storm suggested that RASP inhibitors have the potential to act as immunological switches that may broadly modulate immune systems from pro-inflammatory states to anti-inflammatory states. Target engagement of ADX629 was confirmed in our Phase I clinical trial, in which reduction in the commonly described pro-inflammatory RAS malandialdehyde was observed in treated subjects. ADX629 was well tolerated, and no treatment-related adverse events were observed in the trial. We head into the final two months of the year in excellent financial condition. Based on current operating plans, we believe we are well capitalized and expect our cash runway to fund operations through 2022, including potential NDA submissions for reproxilab and dry disease and allergic conjunctivitis, assuming positive clinical trial results and regulatory review. Now I'll turn the call over to Joshua for the third quarter financial review.

Thanks, Todd. For the quarter ended September 30, 2020, we reported a net loss of $8.9 million compared with a net loss of $18.7 million for the quarter ended September 30, 2019. Net loss per share was 23 cents for the quarter ended September 30, 2020, compared with 69 cents for the same period in 2019. 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 $6.1 million for the quarter end of September 30, 2020, compared with $16.2 million for the same period in 2019. The decrease of $10.1 million is primarily related to a reduction in clinical research and development expenditures and lower personnel-related costs, partially offset by increases in manufacturing and preclinical development costs. General and administrative expenses were $2.3 million for the quarter ended September 30, 2020, compared with $2.8 million for the same period in 2019. The decrease of $500,000 is due to lower personnel-related costs and other miscellaneous administrative costs. For the quarter ended September 30, 2020, total operating expenses were $8.4 million, compared with total operating expenses of $19 million for the same period in 2019. Cash, cash equivalents, and marketable securities were $86.2 million as of September 30, 2020. Based on current operating plans, our cash, cash equivalents, and marketable securities as of September 30, 2020 are expected to be sufficient to fund operations through the end of 2022, including potential NDA submissions for raproxylapin, dry eye disease, and allergic conjunctivitis, pending clinical trial results, regulatory review, potential disruptions due to COVID-19, and other factors that may not be in our control. Use of cash, cash equivalents, and marketable securities are also expected to include part one of the phase three GAR trial in PVR, and Phase II clinical testing of ADX629, an orally administered RASP inhibitor in inflammatory diseases. Now I'll turn the call back to Todd for closing comments.

Thanks, Joshua. As you can tell, we have a busy several quarters ahead, highlighted by significant clinical development milestones beginning this quarter and throughout 2021. We look forward to keeping you updated on our progress as we execute on our strategic plan to bring forward potential best-in-class immune-modulating therapies that improve the lives of patients with serious unmet medical needs. This month, we will be participating in the Jeff Reeds Virtual London Healthcare Conference and the Alliance Global Partners Virtual Healthcare Symposium. Please check the events and presentation section of our website for details. In addition, I would encourage you to register for tomorrow's Icelerator 2020 virtual conference. Icelerator is a new partnership between the American Academy of Ophthalmology and the American Society of Cataract and Refractive Surgery. Aldera is one of a number of companies participating in the event at Icelerator.com. With that, Josh, Dave, and I will be happy to take your questions. Operator?

Ladies and gentlemen, as a reminder, if you would like to ask a question, please press star 1 on your telephone keypad. And your first question comes from the line of Eagle Nokomofich with Citi. Please go ahead.

Hi, this is Samantha. I'm for Eagle. Thank you very much for taking our questions. A couple from me. Todd, thanks for the details on the RAS trial. Just curious, what are the gating factors before you start that trial later this quarter? And it seems like you're sort of combining both the late chronic setting with the 28 days and the more keep setting. Just curious if the FDA has a preference on which of those settings is more important to them, or are they equally important?

Good morning, Samantha, and thanks for the question. There is no preference from the FDA as to the chronicity of dosing. In fact, we clarified with the agency that single or multiple doses could be used to demonstrate statistically significant changes in signs between drug and vehicle. I don't think there are any gating factors in particular regarding the start of the pivotal trial. We do intend, as I mentioned in my prepared comments today, to complete analysis of the natural history study in dry eye patients where we extracted peers from about 20 dry eye subjects, and those peers will be analyzed for RASP levels to confirm the RASP assay and confirm parts of the pivotal trial protocol. However, at this point, we are comfortable with our guidance that not only will the pivotal trial It began this year, but it will be in a position to complete the 20-patient run-in phase of that trial by year end.

Okay, great. And you're going to run two BRAS trials, right? Is it fair to assume that both of them are going to have the same design?

I think the design of the second trial depends on the outcome of the first trial. and particularly the outcome of the 20-patient run-in of the first trial. If, for example, we're able to demonstrate changes in RASP over two days of dosing, it doesn't make sense in the second trial to treat patients for 28 days. I think there are probably some other protocol design changes that we may choose to make depending on the outcome of the first trial. So I think we'll have to wait and see, um, for the data to arrive before we can comment in particular on that second protocol design.

Okay. Got it. That makes sense. And then I remember we had some conversations in the spring about the allergen chamber for allergic conjunctivitis, given the context of COVID-19. And now that you're using a similar chamber design for the RASP trial, are you implementing testing prior to entry into the chamber? And how are you thinking about that for both dry eye disease and allergic conjunctivitis going forward?

Testing is required for entry to either chamber, either the dry eye chamber or the allergen chamber. Patients must meet certain criteria at baseline. for example, a history of either dry eye disease or allergic conjunctivitis. And I think now with COVID-19, there's a variety of other measures that must be met prior to trial entry. The other thing I would note is that for patients to qualify in either the dry eye disease trial or the allergic conjunctivitis trial, at baseline, certain criteria must be met. patients must exacerbate in the chamber. In the case of dry eye disease, patients must exacerbate after a dose of vehicle in the dry eye chamber. So we're quite careful about precisely who we enroll in the trial, and obviously we're attempting to optimize screening criteria such that the differences between drug and vehicle are expanded.

Okay, great. That's helpful. And then just one last one from me. I'm curious if you have any updates on where you stand for ADX2191 in primary vitreorectinal lymphoma. I believe last we spoke on this, you said you were looking to see what data you would need in order to, I believe, file with the MDX or, excuse me, SDI. Is that any updates you have there that would be helpful?

You're absolutely correct, Samantha, that Methotrexate is the standard of care for the treatment of ocular lymphoma. There really is no other therapy that's routinely used to treat the condition. However, there is no methotrexate formulation that's approved for intravitreal injection to treat the disease. So thus, there is a tremendous unmet medical need Today, physicians treat that condition by compounding methotrexate, which has a long series of issues associated with it, including potential infection, the standardized drug doses and so forth that are very difficult to control with compounding. This is why our interest in ocular lymphoma is quite strong. And you are correct that at this stage, we're in the process of discussing how best to advance ADX2191 in ocular lymphoma with the FDA. And we look forward to guiding on next steps, I hope, early next year.

Okay, great. Thanks very much for taking the questions, Todd.

Thanks, Samantha.

Thank you. And your next question comes from the line of Louise Chen with Cantor Fitzgerald. Please go ahead.

Hi, this is Jennifer Kim on for Louise. Thanks so much for taking our question. My first question, I just wanted to clarify the phase three trial that's being initiated for Reproxilab this quarter, is that the first of the two planned RAS trials you've talked about before? So are top line results for that trial still expected by the end of 2020? And then I was wondering if... Do you have any updates on the timing of the second trial?

Hi, Jennifer. Good morning. Yes. The first of the trials for the objective sign and dry disease, the first of the pivotal trials will begin this year. By the end of the year, we will have results from the first 20 patient run in, which is important for the reasons that I explained earlier in the call. in that that 20-patient run-in will, A, give us an indication as to how well the RASP assay is working. It will confirm a protocol for the remainder of the trial. It will confirm the statistical power for the remainder of the trial. And it will probably indicate the protocol for the second pivotal trial.

Got it. And maybe one other question. Considering that the phase two trials for ADX629 are starting by the end of 2020, and then Rapoxilab is also starting by the end of 2020, I'm just wondering, how should we think about the impact of the timing of those trials on R&D costs for maybe the fourth quarter and going to 2021? And then on a similar note, SG&A costs, it's been managed pretty well. I'm just wondering how should we think about that as we get into 2021 as well?

Thanks for the question. So with respect to SG&A, you should continue to expect that to be relatively consistent in the way that you see in a quarter over quarter. And you're right, given the trial initiations later this year and into 2021, you should expect to see an increase in R&D costs this quarter in Q4 and into next year.

Okay, helpful. Thank you. Thank you. And your next question comes from the line of Justin Kim with Oppenheimer. Please go ahead.

Hi, good morning. This is Jackie. I'm for Justin. Thanks for the question. So my first question is, do you have any additional updates on how you think about RASP as an endpoint? and how you plan to measure it in upcoming clinical studies based on any additional assay work or feedback from the agency. Thank you.

Hi, good morning. And thanks for the question. I think as we've discussed in prior calls, there are two main methods to measure RASP level, depending on the kind of RASP that are measured. RASP exists in free form. They also exist in protein-bound forms. So the typical method to measure free levels of analytes is mass spec, and the typical method to measure protein-bound analytes is ELISA, which is an antibody-based approach. So both of those methods are what we are assessing currently with the dry eye disease natural history trial where we've taken tear samples from dry eye disease patients. That's an in vitro assessment that's occurring and will indicate, I think, the precise method that we use in the pivotal trial, the top line results of which, as I mentioned, we expect by year end.

Got it. Thank you. And then perhaps for Dave, as you contemplate a label that would hypothetically describe activity unrest and ocular discomfort score, ODS, in combination with treatment of allergy, how do you think about the commercial launch and what features would drive adoption of ReprofiLab?

Yeah, thanks for that question. It's a great one. When I think about Reproxilab and our target product profile, you're right, there's a lot of different legs of differentiation. At the core of the profile is differentiation on the dry eye disease front. And in the marketplace, this is a symptom-driven disease. And so the aspects of Reproxilab that are really exciting are the early and broad improvement in symptoms. We think it's remarkable what we've seen with Reproxilab, where with this product that can treat the chronic inflammation you can also see improvement in symptoms at one week. If we're successful, you'll have for the first time a safe and effective anti-inflammatory addressing the core of the disease that you're able to use to treat the condition chronically, but that can also benefit the patient very rapidly. In addition, we see in our profile the ability to reduce or improve the symptom that the patients are experiencing across the spectrum. And so that broad advocacy, we believe, is indicative of how it will translate into more patients and more doctors having a positive experience with the product itself. Those are two things that we know that the market is looking for. The current solutions aren't a great fit and they don't meet those needs, and so they are unmet currently. Dry disease is an ocular surface disease. It's not the only one. It's one of three big ones. One of the biggest ones is allergic conjunctivitis. And allergic conjunctivitis and dry disease overlap tremendously. And all you have to do is some market research to learn and see how these two conditions overlapping can make the effective treatment of these patients difficult for physicians and can make it very frustrating for patients. What's currently available is not a great fit for that overlap. And here with ReproxLab, we have, again, a unique solution. We've seen the ability of this drug not only to address the signs and symptoms of dry disease, but also allergic conjunctivitis. And so we're seeing this future where you would have one product that simplifies a lot of things for the doctors and for the patients. And while the profile of the marketplace is different for dry disease and allergic conjunctivitis, we're developing Reproxilab with our first focus on dry eye disease and then allergic conjunctivitis as an added differentiator to that profile. Our development programs are such that we, as announced today, we anticipate that we will be able to submit a concurrent NDAs for both indications.

Great. Great. This is super helpful. Maybe if I may, my last question is just, given a resurgence recently seen in COVID-19 cases, can you talk about specific criteria or conditions that would make site initiation or program initiation? And again, thanks for all the questions.

We have not heard from our CROs that COVID is going to dramatically impact enrollment at this point. As you mentioned, The caseload around the world is increasing, and it is certainly possible that COVID-19 infections could impair enrollment. But at this point, we have not heard from CROs that COVID-19 will dramatically impact either the rate of enrollment or the ultimate number of patients. I will say that many sites, including sites we're working with, are testing for COVID. This has been viewed as a benefit in some cases by potential subjects in clinical trials because the COVID test is essentially free and that it's required for entry to the trial. I expect that kind of testing to continue. And our hope is that even as cases rise, around the country and around the world that enrollment continues per plan.

Thank you.

Thank you. And your next question comes from the line of Matthew Cross with Alliance. Please go ahead. And Mr. Cross, your line may be muted.

Apologies, thank you. Hey guys, thanks for the progress update and looking forward to seeing you at the conference later this month. Just had a couple of quick questions. First off, in terms of the kind of sign trial design changes here, or updates rather, just wanted to confirm whether the decision to include multiple signs here was, in fact, FDA-directed or was, you know, maybe kind of more internally devised. and whether you could comment on how those may be handled statistically, considering RASP, redness, and SHRMRS. Do you need to kind of hit on all of these? If there will be some kind of composite endpoints, just any kind of thoughts at this stage.

Matt, good morning, and thanks for the question. The activity of riproxilab is broad, so it made sense to us to test a variety of signs. is the short answer. The FDA did not require multiple sign assessment. I do not expect to take statistical penalties or adjust for multiplicity as a result of testing multiple signs. I think the reason for testing signs is to continue to generate evidence for the broad activity of ruproxilab and dry eye disease. There is Good reason, I think, to believe that Reproxilab will have an effect on redness. Those data we have released from allergen chamber studies for quite a while now. You will see more redness data at the American Academy of Ophthalmology poster shortly. That is one reason we're testing at least redness in dry eye disease after acute dosing. As you recall, our Shermer test results were very good in our Phase IIb trial released back in 2018 in dry eye disease. Those are the reasons we're looking at a variety of additional signs, particularly because I think the breadth of activity of proxilab is a major differentiator for this drug within the dry eye disease landscape.

Yeah, no, I wholeheartedly agree, and that makes complete sense. Thanks for the clarity there. And then just another one around the, it looks as if the path forward for dry eye is adaptive in a number of different ways. I guess one starting with this kind of run-in portion and the natural history study analysis prior to the actual full second trial. I guess just wanted to get a little bit of understanding of whether post-run-in by the end of this year, At that point, even in the first of these RASP trials, you may take a second to adjust some of these parameters. I know we've discussed the approaching bound versus freely circulating RASP assessments, single versus multi-dose. But is it fair to assume that once the run-in is gone on and certainly completed, you would kind of, you know, at that point commit to one form of method of measuring RASP and one kind of treatment protocol? or if that may change mid this first study post-run.

Matt, as usual, you are absolutely correct. We have intentionally designed a couple of clinical data outputs to help us plan the pivotal aspect of the trial. The first of those is the natural history study, which I've mentioned a few times this morning. which is really functioning as an in vitro phase three to assess RASP levels in the tears of dry eye patients. And as I mentioned in my prepared comments, the tears from those patients will be tested at baseline. They'll also be tested after exposure to drug and vehicle. After the dry eye disease natural history study, we'll have a very good idea of how well the assays I've described earlier are working. The 20-patient run-in serves a very similar function, which is to confirm the RASP assays and the protocol design before the main cohort of the pivotal trial is initiated. To your point, the protocol may change somewhat depending on the results of both the natural history study and the run-in. The good news is RASPs are the first new novel sign in dry disease in decades. The bad news is this has not been done. And so I think that part of the rationale for the natural history study and part of the rationale for the run-in phase of the pivotal trial is to confirm the protocol and the assays and so forth in an area that I think is very novel and exciting.

Perfect. Yeah, another very creative design from you guys, so I appreciate you confirming that and looking forward to the very forthcoming progress for the end of the year. Thanks, Todd. Thank you very much, Matt.

And ladies and gentlemen, again, as a reminder, if you would like to ask an audio question, please press star 1. And your next question comes from the line of Julianne Harrison with BP IG. Please go ahead.

Hi. Good morning. Thank you for taking my questions, and congrats on the quarter. On the assays, I was wondering if you could talk a little about your experience measuring RASP with ELISA and mass spec so far beyond the natural history study and how you're applying any learnings there to your ongoing efforts.

Julian, thanks for the question. And I'm glad you asked. I think it's important to remind everyone that back in Phase IIa in dry eye disease, we demonstrated statistically significant changes from baseline after drug treatment of RASP in dry eye disease, which is another reason why ELISA is part of the assay mix. not only for the natural history study but also for the pivotal trial eliza is an interesting approach because protein bound rasp again which we showed change after drug treatment in beta 2a are chronic indicators of inflammation and and change over time i think what is also possible based on the literature and based on the Phase IIa trial is that RAS protein-bound RAS levels may also change acutely. And so as part of the natural history study and part of the run-in, we'll be using ELISA for both acute and chronic assessments of RAS changes alongside MassSpec, which is primarily designed to measure acute changes in RAS.

Okay, great. Thank you. That's very helpful. And then, sorry if I missed it, but on the safety requirement for the dry eye disease NDA, how much can you lean on prior data and what work still needs to be done there?

The safety package, which is part of every NDA submission, as you know, generally needs to be quite extensive. As I mentioned in my prepared comments, proxilab has been tested in more than 1,000 patients We have no serious adverse events. We have no safety findings that relate to biomicroscopy or fundal assessment or visual acuity or intraocular pressure or any other toxicity that would be significant. So we're quite confident in our safety package. Those 1,100 patients or so that have been exposed to ReproxLap are added to the number of patients in the safety trial And that will comprise the safety population assessment for the NDA submission. I think with any indication, there is a dialogue between the sponsor and the FDA as to precisely how many patients are required for the safety portion of the NDA. That is a function of the number of patients that have been exposed in your prior clinical trials and the number of patients that you intend to test in your safety trial. I think, though, we're in an excellent position with Reproxilab, given the safety results and what amounts to be the complete lack of safety issues that we've observed across numerous clinical trials in over 1,000 patients to date. Great. Thanks very much. Thanks, Julia.

And our final question comes from the line of Kelly Shee with Jefferies. Please go ahead.

Hey. Thank you for taking my question. The first question is also on the trial design of a RASPR trial. We use a lot of patients by same criteria as for renewal part one and also the phase two study that has generated for the data set on RASP reduction. And specifically, we use a lot of patients based on the baseline level of RASP and what is the impact of the baseline level of RASP on the trial outcome. Thank you.

Kelly, thanks for the question. Good to hear your voice. I think that the criteria are, if not identical, substantially similar for enrolling patients in RENEW and the upcoming pivotal trial. There is more or less a standard group of enrollment criteria across all dry eye disease trials. Patients must have certain symptoms and certain signs to qualify. as dry eye patients and thus be enrolled in clinical trials. Our intent is not to deviate from those more or less standard criteria extensively. Your question about baseline RASP levels is particularly fascinating to us. I do not expect at this point we will require certain RASP levels for enrollment in our trial. That may change depending on the results of the natural history study and the results of the run-in phase for the pivotal trial. But at this point, I expect we will enroll all comers as it relates to tier RASP levels. We'll know a lot more towards the end of this year. regarding the answer to your question, what effect does baseline RASP level in tears have on the ultimate activity of drugs? A priori, I do not expect the effect to be dramatic for two reasons. One is that from our Phase IIa trial, we know that essentially all dry eye subjects have elevated RASP levels. RASP are a hallmark of inflammation. We know that dry eye disease is an inflammatory condition, and thus RASP should theoretically be elevated in all patients. The second reason I don't think baseline levels will play a major role in the activity of drug is that the levels of RASP in tears, as has been published, is probably in the low micromolar range at most, maybe higher for bound levels of RASP. The drug is millimolar in concentration. So as we've expressed previously, administration of a single drop of roproxilab to the anterior surface of the eye essentially represents a thousand-fold or more of excess of drug relative to levels of RASP. So whatever the baseline concentrations of RASP are in the micromolar range, are unlikely to be affected by the large excess of Reproxilab. Recall that Reproxilab binds to RASP in a one-to-one stoichiometry. So I think after acute administration of drug, there should theoretically be a near total elimination of RASP, whatever the baseline level.

Thank you very much. It's very helpful. And I also have a second question regarding the CQ study. And do you expect any specific requirements from FDA since the Reproxilab ever holds a novel mechanism of action from other dry drops?

I do not. The novel mechanism of action of Reproxilab RASP inhibition has been discussed with the agency extensively from the very beginning across dry disease and allergic conjunctivitis. I think the fact that the agency awarded RASP as an objective sign endpoint in dry disease speaks to the agency's confidence in RASP as a RASP inhibition as a beneficial mechanism for the treatment of ocular inflammation. We have heard from the agency no specific concern about RASP inhibition as it relates to safety. And again, based on my prior comments and the number of patients that have been tested with the PROXLAT, I do not expect that to change.

Great to hear. Thank you very much. That's all from me.

Thank you very much, Kelly.

Ladies and gentlemen, thank you for your questions. Now I would like to turn the call back over to Dr. Brady for any closing comments.

Well, thank you again for joining us. And on behalf of everyone at Aldera, please stay safe and healthy during the holidays. And as always, we look forward to keeping you updated on our progress.

Ladies and gentlemen, thank you for your participation. This does conclude today's conference call. You may now disconnect.