Thank you for your patience on today's call. We are looking to start at approximately one minute past the start time. Thank you for your patience. Hello and welcome, everyone, to the Aldeyra Therapeutics 2025 Research and Development Update webcast. My name is Becky, and I'll be your operator today. All lines will be muted throughout the presentation portion of the call, with a chance for Q&A at the end. If you wish to ask a question at this time, please press star, followed by one on your telephone keypads. I will now hand over to your host, Laura Nichols, Associate Director of Investor Relations, to begin. Please go ahead. Thank you, and good morning, everyone. Today, we issued a press release announcing the expansion of Aldeyra's RASP platform into central nervous system diseases and providing an update on reproxalap, our NDA stage product candidate for the treatment of dry eye disease. A copy of the press release is available on the Investor and Media section of our website, www.aldeyra.com. The press release contains important information and should be read and considered in conjunction with the slides presented and prepared remarks made on today's call. With me today to discuss the research and development updates is Dr. Todd Brady, President and Chief Executive Officer of Aldeyra, and Dr. Adam Lazorchak, Director of Translational Sciences in Nonclinical Development. Turning to slide two, this presentation and various remarks which may be made during this presentation contain forward-looking statements regarding Aldeyra, Aldeyra's RASP modulator pipeline, the investigational drug candidate reproxalap, and Aldeyra's plans, expectations, and opportunities, including regulatory and commercial activities. Forward-looking statements involve known and unknown risks, uncertainties, and other factors that may cause Aldeyra's actual results, performance, or achievements to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. These statements are based upon the information available to Aldeyra today and reflect Aldeyra's current views with respect to future events and are based on assumptions and subject to risks and uncertainties, including the outcome and timing of the FDA's review and approval of the new drug application for reproxalap that was submitted in June of this year, and the adequacy of the data contained therein. Aldeyra assumes no obligation to update oral or written statements made today as circumstances change. Future events and actual results could differ materially from those projected in the company's forward-looking statements, including the results of operation 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 press release issued this morning and in our filings with the Securities and Exchange Commission. I would now like to turn your attention to slide three and introduce Dr. Brady. Thank you, Laura, and thank you all for joining us this morning. We are grateful for your interest in our research and development activities, in particular because this webcast affords us the all-to-one common opportunity to discuss the future of Aldeyra as it relates to our earlier stage product candidates and the directions that we intend to pursue years henceforth. As I hope you'll appreciate today, we believe our pipeline to be robust and our future bright. Aldeyra maintains a broad pipeline of product candidates that is diversified across four elements: stage of development, molecular structure, mechanism of action, and clinical indications. As I'm sure all of you know, our lead product candidate, reproxalap, is the subject of a new drug application submitted earlier this year with a PDUFA date of December 16th, 2025, for the treatment of dry eye disease. Reproxalap is also under development for allergic conjunctivitis, having completed, we believe, phase three clinical testing. Reproxalap represents the first generation of a new class of potential therapeutics known as RASP modulators, which affect a large number of proteins simultaneously in a systems-based approach that we believe represents the future of pharmacology. Late last month, we reported the conclusion of proof-of-concept clinical testing for a relative of Reproxalap, ADX-629, with positive results in alcohol-associated hepatitis, some of which I'll review in more detail during the webcast. Although second-generation RASP modulator, ADX-246, is in development for the dry form of age-related macular degeneration, which is the precursor to geographic atrophy, today we will focus primarily on another second-generation RASP modulator, ADX-248, a novel, potent, once-daily, orally-administered product candidate that has demonstrated activity in a variety of preclinical models and is currently undergoing phase I clinical testing. We're pleased to announce the advancement of ADX-248, already in development for atopic dermatitis and metabolic inflammation, to immune-mediated diseases that affect the central nervous system. I'm also pleased to introduce Dr. Adam Lazorchak, our new Director of Translational Sciences, who will review for us the compelling data from ADX-248 and preclinical models of neuroinflammatory disease. Our pipeline also includes ADX-2191, which is, that we are aware, the only intravitreal formulation of methotrexate designed for intraocular injection. By the end of this year, we anticipate initiating pivotal phase three clinical testing of ADX-2191 in primary vitreoretinal lymphoma, a rare and often fatal retinal cancer with no approved therapy. We also anticipate initiating phase two-three clinical testing of ADX-2191 in retinitis pigmentosa, an orphan disease that invariably leads to progressive loss of vision, in the first half of 2026. We look forward to discussing ADX-2191 in more detail in the future. Importantly, we believe that we are well-capitalized to continue to execute on our pipeline. Based on our prior guidance, current cash, cash equivalents, and marketable securities of over $75 million as of September 30th are expected to support operations into the second half of 2027. Our prior cash runway guidance does not include partnership or product revenue associated with reproxalap. Turning now to slide five, RASP, or reactive aldehyde species, are a class of small-molecule drug targets that affect a large number of proteins, particularly proteins that promote inflammation through a series of well-described interactions. Thus, by binding RASP, RASP modulators such as reproxalap and ADX-248 in theory affect a myriad of pharmacologic actions at once, thereby affording a systems-based approach that does not focus on inhibiting or activating single protein targets. The possible advantages of modulating RASP are illustrated on slide six, which suggests that, as opposed to turning on or off single targets, which are generally not consistent with normal biological function and therefore can lead to unwanted side effects, modulating RASP is akin to lowering a master volume control, a gentler but also more comprehensive approach to pharmacology. As I've said many times before, it seems to me that our children and grandchildren and their children will not be treated with drugs that do just one thing. Instead, they'll be treated with just a few drugs that do many things, potentially allowing for the treatment of many conditions at once in concert with the maintenance of normal physiological balance. Moving to slide eight, as I mentioned in my opening comments regarding the signal-finding RASP modulator, ADX-629, we've completed our proof-of-concept phase II suite of clinical trials designed to assess the feasibility of improving the signs and symptoms of immune-mediated diseases by modulating RASP. Across seven phase II clinical trials in aggregate, ADX-629, which is a first-generation RASP modulator that was administered orally twice daily, was deemed to be safe and well-tolerated, and in each trial, evidence of activity in decreasing the signs or symptoms of inflammation was observed. The final ADX-629 clinical trial was conducted in patients with alcohol-associated hepatitis, an inflammatory condition that in severe cases can lead to death. As is illustrated in the lower left-hand corner of slide nine, the results of the clinical trial in alcohol-associated hepatitis were consistent with those of other ADX-629 clinical trials in patients with immune-mediated diseases, including atopic dermatitis, psoriasis, and chronic cough. The model of end-stage liver disease, or MELD score, which is an objective blood-based measure of liver function comprised of bilirubin, creatinine, and clotting function, and is predictive of mortality and other clinical sequelae of alcohol-associated liver disease, decreased in a consistent and statistically significant manner relative to baseline in patients with alcohol-associated hepatitis. As is illustrated in the lower right-hand corner of slide ten, lipid profiles improved with administration of ADX-629, an effect consistent with similar results observed in the phase I clinical trial following challenge with a fatty meal, as well as in clinical trials in patients with psoriasis and chronic cough. The beneficial effects with regard to lipid parameters may reflect anti-inflammatory activity in addition to the fact that RASP are precursors to lipids, consistent with the role of RASP in potentiating inflammation. Slide 11 represents the activity of ADX-629 in statistically significantly reducing another marker of inflammation, C-reactive protein, in patients with alcohol-associated hepatitis. Independent of MELD score, C-reactive protein, which is synthesized in the liver, is a major determinant of mortality and other outcomes in patients with liver disease. In broader patient populations, C-reactive protein has been associated with adverse cardiovascular outcomes, poor prognosis in cancer, and similar to liver diseases, increased risk of death. The C-reactive protein results are consistent with the results of other phase two clinical trials of ADX-629 in patients with immune-mediated diseases, and overall, we believe that ADX-629 has successfully demonstrated proof-of-concept that RASP modulation has the potential to improve the signs and symptoms of immunological conditions. Now, with the promise of RASP modulation in treating diseases associated with inflammation, I'd like to turn the call over to Dr. Adam Lazorchak, beginning on slide 13, as we move from first-generation RASP modulators such as ADX-629, which is less potent and administered twice daily, to second-generation RASP modulators such as ADX-248, which is among the most potent RASP modulators that Aldeyra has synthesized to date and is expected to be administered orally once daily. Dr. Lazorchak. Thank you, Dr. Brady. Before summarizing our results with ADX-248, I will briefly discuss ADX-246, another second-generation RASP modulator now in formulation development that is intended to be tested in patients with the dry form of age-related macular degeneration, or dry AMD. Dry AMD is a progressive, site-threatening retinal disease that is endemic in patients with advanced age. As seen in the left side of slide 13, ADX-246 is a potent scavenger of retinaldehyde, a RASP implicated in the development of macular degeneration. To the right, we show the activity of ADX-246 in an ABCR gene knockout mouse model of dry AMD. The ABCR protein is a retinaldehyde chaperone that prevents the promiscuous conversion of retinaldehyde into A2E. A2E accumulation in the retinal pigment epithelial cells leads to retinal dysfunction and is associated with low-light visual impairment, one of the first symptoms of dry AMD. As the graph on the right suggests, treatment with ADX-246 reduced levels of A2E in the eye of this mouse model. Now, moving back to our second-generation RASP modulator, ADX-248, we show on the right-hand side of slide 14 that ADX-248 potently binds the pro-inflammatory RASP 4-hydroxynonenal, or HNE. In the middle panel, the anti-inflammatory activity of ADX-248 was tested in a mouse model of acute sepsis and showed broad-based reductions in multiple pro-inflammatory cytokines. Finally, we assessed ADX-248 anti-inflammatory efficacy in a murine sensitization, hypersensitization model of atopic dermatitis. On the left-hand side of slide 48, treatment resulted in a statistically significant reduction in dermal erosion, a measure of inflammation-mediated skin ulceration and thinning. We are excited to share new preclinical results today focusing on models of Parkinson's disease, amyotrophic lateral sclerosis, or ALS, and multiple sclerosis, MS. RASP molecules are closely associated with neuroinflammatory diseases affecting the central nervous system. These reactive aldehyde species play key roles in disease pathology outlined on slide 15. In Parkinson's disease, environmental toxins can increase neurotoxic stress along with RASP in the central nervous system. Of note, the aldehyde DOPAL, a toxic RASP produced by dopamine metabolism, has been shown to promote alpha-synuclein cross-linking, leading to dopaminergic cell death. In ALS, RASP levels are elevated in the CNS of patients, and certain genetic variants associated with RASP clearance increase the disease progression risk. Finally, in MS, RASP elevation has also been observed, and pharmacologic inhibition of the RASP acrylene has been shown to reduce disease severity in preclinical models. On slide 16, we present data from ADX-629, a legacy RASP modulator tested in the experimental autoimmune encephalomyelitis, or EAE, mouse model, which closely mimics MS. ADX-629 was dosed twice daily for 28 days, beginning concurrently with disease induction. The disease severity was scored on a zero to five scale, reflecting progressive hindlimb ascending motor impairment and paralysis. ADX-629 treatment significantly reduced disease severity compared to vehicle, delaying onset and slowing progression. These results suggest that RASP modulation can meaningfully reduce neuroinflammatory disease burden in the EAE preclinical MS model. Building on this work, we developed our next-generation RASP modulator, ADX-248. On slide 17, we show that ADX-248 binds to key neurotoxic RASPs, including DOPAL and HNE, both associated with CNS inflammation and neurodegeneration. This compound shows potent RASP binding activity in vitro, forming the foundation for its therapeutic potential in multiple CNS disorders. Turning to slide 18, we begin our presentation with ADX-248 in neuroinflammatory CNS disease models with the mouse MPTP Parkinson's disease model. The story of MPTP is both out of tragedy and hope for Parkinson's patients. In 1982, Dr. J. William Langston discovered the link between MPTP and Parkinson's disease when multiple patients, each eerily locked in their own bodies yet fully conscious, were admitted to hospitals in Northern California. Dr. Langston connected these spontaneous Parkinson's cases to synthetic heroin use and an impurity in the illicit drug, MPTP. Langston's discovery, born from tragedy and detective work, sent shockwaves through the field of neuroscience, and MPTP became an important research tool that helped unlock the mechanisms of Parkinson's disease and contributed to the successful development of new Parkinson's therapies. With this history in mind, we evaluated ADX-248 in the mouse MPTP Parkinson's disease model, which reproduces dopaminergic neuron loss through toxin exposure. ADX-248 was administered concurrently with MPTP at three dose levels: 3 mg, 10 mg, and 20 mg per kg, twice daily for up to 19 days. Motor function was assessed using Rotarod performance, which measures balance and coordination, and grip strength tests. ADX-248, at the highest dose, 20 mg per kg, significantly improved motor coordination and balance, as well as grip strength compared to vehicle. These findings suggest that ADX-248 provides functional neuroprotection in this established Parkinson's disease model. At study completion, we analyzed biochemical and histological markers shown on slide 19. ADX-248 significantly increased total brain dopamine levels in a dose-dependent manner and enhanced the number of tyrosine hydroxylase positive, TH-positive dopaminergic neurons in the substantia nigra. These results suggest that in addition to improving motor function, ADX-248 may also preserve dopaminergic neurons and help restore dopamine balance in the brain. To further validate our findings, we tested ADX-248 in the 6-hydroxydopamine, or 6-OHDA, rat model, which causes unilateral dopaminergic neuron loss. As shown in slide 20, treatment began two weeks after brain lesion induction, which is a challenging test of post-injury dopaminergic neuron recovery potential. ADX-248 was dosed twice daily at 3, 10, and 20 mg per kg for 14 days. ADX-248 significantly improved wire-hang endurance, reflecting enhanced neuromuscular strength and coordination. A trend towards increased grip strength was also observed but did not reach statistical significance. This model suggests that ADX-248 may contribute to functional recovery even after neuronal damage has occurred and demonstrates ADX-248 potential efficacy in a second independent and widely accepted preclinical Parkinson's disease model. As shown on slide 21, we evaluated ADX-248 in the SOD1-G93A ALS transgenic mouse model, which develops progressive motor dysfunction leading to paralysis and death. Mice received ADX-248 at 3, 10, and 20 mg per kg twice daily for 60 days. ADX-248 significantly improved grip strength across all doses and enhanced Rotarod balance performance at 10 and 20 mg per kg. Together, these results demonstrate that ADX-248 shows robust activity across multiple neuroinflammatory disease models. As summarized on slide 22, ADX-248 sequestered neurotoxic RASPs such as DOPAL and HNE, improved motor performance in multiple Parkinson's and ALS disease models, increased dopamine levels and dopaminergic survival, and exhibited favorable exposure and safety profiles in preclinical studies. ADX-248 preclinical studies also predict that therapeutically meaningful brain concentrations in humans are achievable at doses being tested in the clinic. These favorable ADX-248 preclinical data open the door to multiple CNS neuroinflammatory disease development paths. We believe that ADX-248's safety profile supports its continued clinical development, and a phase one dose escalation study in healthy subjects is ongoing. Importantly, as is detailed in slide 23, preclinical efficacy has been achieved at doses corresponding to 50-100 mg per kg human equivalent doses. These doses are predicted to be safe with approximately tenfold safety margins based on rat and dog toxicity studies. Our ongoing phase one clinical trial supports the tolerability of ADX-248 at these levels. Exposure of ADX-248 is at least as high as reported in plasma levels of RASP in patients with immune-mediated diseases such as atopic dermatitis, and dose escalation is continuing. We expect pivotal long-term safety and toxicology studies to be completed in 2026, supporting the initiation of phase two clinical trials. I would now like to turn the call over to Dr. Brady, beginning with slide 25, who will comment on reproxalap, conclude the call, and open the line for questions. Dr. Brady. Thank you, Dr. Lazorchak. As I mentioned earlier in the webcast, one of the defining features of RASP modulation is the ability to effect a variety of clinical outcomes simultaneously, a phenomenon that is consistent with the activity of reproxalap in dry eye disease and that has been observed across a large number of phase two and phase three clinical trials. In particular, to Aldeyra's knowledge in patients with dry eye disease, reproxalap is the first investigational drug with pivotal data supportive of acute and chronic activity in reducing symptoms and the first investigational drug for chronic administration with pivotal data supportive of acute activity in reducing ocular redness, a dry eye disease sign of particular importance to patients. Said another way, when it comes to the ocular surface, many patients care as much about how they look as about how they feel. Slide 26 presents data from the sole clinical trial submitted as supportive of efficacy of reproxalap in treating the symptoms of dry eye disease, which was the only deficiency identified in the complete response letter, or CRL, from the FDA in April of this year. The trial tested patients in a dry eye chamber, which is a rigorously controlled low humidity environment designed to simulate dry eye exacerbations, representative of the bad days of a life in a dry eye patient. In order to qualify for the trial, patients were screened initially in a chamber after receiving vehicle, or placebo, eye drops. Subsequently, patients were randomized to receive either vehicle or reproxalap prior to another dry eye chamber, the so-called treatment chamber. The pre-specified primary endpoint analysis, which was highly statistically significant and resulted in a p-value of 0.002, included data from both chambers, that is, the screening chamber and the treatment chamber. In the CRL, the FDA appeared to suggest that screening chamber data from the prior dry eye chamber trial was difficult to interpret, at least relative to the treatment chamber data. Accordingly, we ran a post-hoc analysis of the chamber trial submitted to the NDA in June with just the treatment chamber data alone, which was included in the NDA submission in June, and the result of which was 0.004, also highly statistically significant and consistent with the primary analysis. The CRL also noted a baseline imbalance in the prior chamber trial submitted last year, and as reported earlier this year, there was no substantial difference in the baselines of the trial presented here that was submitted to the NDA in June. To reiterate the strength of the results from the trial reported earlier this year, the reproxalap treated patients did not meaningfully escalate from baseline in a chamber that is designed to simulate a definitively noxious environment for dry eye patients. To some extent, we believe that the dry eye chamber is more clinically relevant than field trials where patients are treated over good days and bad days since patients likely care most about their bad days, not their good ones. As we announced in our press release this morning and as it's summarized on slide 27, our drug product, that is, the filling, labeling, and packaging of the single-use eye drop vials, and drug substance, that is, the active ingredient reproxalap, manufacturing facilities have both been the subject of routine site inspections by the FDA in 2025. Both sites received voluntary action indicated, or VAI, resolutions of the inspections, and the FDA has notified the manufacturers that the inspections are closed and that no further action was necessary. The successful resolutions to the inspections of our third-party manufacturing facilities support the quality of the reproxalap product and the chemistry, manufacturing, and controls information submitted to the NDA. As a reminder, reproxalap is the subject of an option agreement with AbbVie, the terms of which are summarized on slide 28. The option expires 10 business days after FDA approval of reproxalap for dry eye disease. If AbbVie chooses to exercise after FDA approval, both upfront and FDA approval milestones will be triggered, totaling $200 million, less $6 million that has already been paid to Aldeyra. Our clinical and regulatory milestones are summarized on slide 30. In addition to the reproxalap PDUFA date, over the next several quarters, we expect a variety of trial initiations in a number of diseases characterized by inflammation, including those that affect the retina and skin, setting up a variety of important clinical data milestones in the future. Thus, over 2026 and beyond, our catalyst news flow is expected to be robust. Operator, I'd now like to open the call for questions. Thank you. If you wish to ask a question, please press star followed by one on your telephone keypad now. If for any reason you would like to remove your question from the queue, please press star followed by two. When preparing to ask your question, please ensure your device is unmuted locally. Our first question comes from Tom Shrader from BTIG. Your line is now open. Please go ahead. Good morning. Fascinating presentation. On the MS data, I'm curious when you're actually scavenging the toxin, as I'm sure you know MS is two diseases. It's a white matter inflammatory disease and then a gray matter disease that's really not understood. Do you have models, or do you know if you're affecting gray matter disease? Have you considered progressive forms of MS? A second CNS question is, the dopamine stuff is fantastic, but you're chasing the motor side of dopamine. Have you considered the depressive side of dopamine? That's another big avenue where an oral drug might be fantastic. Thanks. I have an IP question. Thanks, Tom. We appreciate your insightful questions. Why don't I turn the call over to Dr. Lazorchak to discuss the nature of the EAE model in multiple sclerosis? I know that he has extensive experience with that model and exactly what that model measures, particularly with regard to white versus gray matter. And then maybe Dr. Lazorchak, you can also comment on dopamine as it relates to depression and future animal models related to that concept. Yep. Thanks, Todd. And Tom, great questions. To provide a little context on the EAE model itself, this model is an inducible model for MS, and it's effectively induced by vaccination where we break the immune tolerance or the immune's ignorance to myelin-based protein at the motor neurons. The disease itself in this particular preclinical model is T-cell attack or T-lymphocyte attack on the spinal motor neurons. This disease progresses in the animals starting from their hind limbs and moves upwards. It's primarily in the spinal column where a large part of the disease manifests. That's largely going to be your white matter and attack on the motor functions. There is some immune infiltration in the brain in this model, but in terms of the overall presentation of disease, it's primarily manifesting in the lower motor deficits. Going on to your second question relating to dopamine and the overall other aspects of it, the models we're looking at currently are kind of our first step into the Parkinson's space. I know there are quite a few additional models that explore other elements of Parkinson's disease, even elements of alpha-synuclease accumulation, protein aggregation. I think we are definitely just at the beginning of our exploration into Parkinson's disease models. I think we've talked with KOLs and are actively engaged with leaders in the field to look at the correct models going forward that we think and the field thinks will translate into meaningful outcomes for patients. Tom, you know dopamine has made the mainstream when on my Spotify feed yesterday, an artist was singing about dopamine. One of those neurotransmitters that seems to have a lot of different activities and a sense for companies like ours is the gift it keeps giving. I could just follow up with a quick IP question. Yeah. It's always amazing given how central RASP seems to be that you haven't attracted competitors. Can you remind us, is your IP mostly around your specific molecules, or do you have some fundamental IP about the actual target? Because it still seems like you have mostly the world to yourself. Thanks. We believe, Tom, that we are the only company actively pursuing RASP modulation as a target, which is remarkable. RASP have been described for decades as potential markers of inflammation and toxicity. The fact that no other company at the moment is working on RASP, I think is quite interesting. Because RASP have been described for such a long period of time as mediators of disease, I think it would be impossible to patent RASP as targets. We are a composition of matter-based company. When it comes to IP, like many companies, we first seek to patent compositions. We are generally aware of what kinds of molecules bind to and trap RASP. It's relatively easy to bind RASP, as I mentioned earlier. That's Schiff-base reaction or Michael addition reactions. It is relatively difficult to sequester RASP. Our molecules all feature a two-click reaction process where there is a binding followed by a ring closure that effectively permanently or irreversibly sequesters RASP. Those molecules and the compositions of those molecules, including all the molecules we've mentioned today, are the subject of our compositional IP. All right. Great. Thanks for all the answers. Thanks, Tom. Thank you. Our next question comes from Catherine Novack from Jones. Your line is now open. Please go ahead. Hi. Morning, Todd. Thanks for taking the questions. Just on slide 17, what% RASP binding is ideal? Are you looking for maximum binding, or how should we think about what translates to efficacy here? Good morning, Catherine. That's an interesting question. Also, let me just describe a little bit of background as it relates to physiologic RASP. There are at least two examples of RASP, that is vitamin A and vitamin B6, retinaldehyde and pyridoxal, and pyridoxal phosphate that are required in the body for various functions. Those are highly chaperoned. Those molecules are protected. Dr. Lazorchak reviewed our dry AMD model, ABCR knockout. ABCR is a protein that protects retinaldehyde. Our drugs, therefore, are incapable of binding chaperoned RASP, which is a good thing. There's a reason why RASP, those particular RASP, are chaperoned. It's when those RASP aren't chaperoned that are problematic. 4-hydroxynonenal, malondialdehyde, choline are other examples of RASP that are de facto toxic. And they have, to our knowledge, no known function other than promoting inflammation. Your question is about how much of those do we need to bind? The answer, I think, is an empirical one. We do not particularly know any more than we know about other drugs, antibodies, say, to TNF alpha or inhibition of HMG-CoA reductase, as in the case of statins. I am not sure we completely know how much inhibition or binding is needed. I think the key outcome of what was presented today is that when administered at reasonable levels, that is, levels that we are able to achieve in phase one clinical trials in humans, ADX-248 also affects activity in animal models. Got it. And then just a question on the manufacturing. Obviously, it's encouraging to see that these facilities pass inspections. Were there outstanding issues? Can you remind us from previous NDA submissions where these facilities already inspected? How much of this is new update and how much was outstanding from prior NDA submissions? Right. The two most common questions I get from investors regarding the ongoing NDA review of reproxalap are, number one, have your drug product and drug substance vendors been recently inspected by the FDA? That is the issue we're attempting to address here and the subject of your question. The other question I get is, I've read your CRL. The FDA appears to focus on an analysis of the treatment chamber only. Have you done that analysis? What was the result? Was it submitted to the NDA? We attempted to answer both of those questions. I like to tell people that the C in CRL is complete. It's not incomplete. One of the beauties of a CRL, if there is one, is that the FDA by law tells you everything that they've found deficient. In our CRLs, the FDA has said, "We'd like to see one more symptom trial." They have not said, "We found issues with your CMC, with your drug manufacturing." Our belief, given that this NDA has been reviewed twice previously, is that there really aren't any substantive CMC issues that we are aware of. The outstanding issue was the first question from investors. That is, have your manufacturing sites been inspected recently? As we got at today, both of our manufacturing sites were inspected this year. We disclosed in our Q, our most recent 10-Q filing, that the last of those sites was inspected last quarter. Both inspections resulted in VAIs, which is the kind of result that you would want. Going forward, we're not aware of any outstanding issues. Got it. Understood. Yeah. Thanks for the color. Thanks, Catherine. Thank you. Our next question comes from Clara Dong from Jefferies. Your line is now open. Please go ahead. Hi. Good morning, Todd. Thank you for taking our question and appreciate this very informative presentation. My question is going to be on 248. On the slide, the in vivo data showing the grip strength and balance improvement, do those functional gains actually track with changes in brain tissue RASP level on the same animals? Have you tested that? For the phase one ongoing clinical study, besides safety, what other objective markers are you going to look at? What really constitutes kind of a go-forward decision for that? Thank you. Clara, thanks for your question. You nailed that the government is no longer shut down. I look forward to seeing you in London next week at your conference. Me too. Yes. I would say a couple of things to begin, and then maybe I'll turn it over to Dr. Lazorchak to address some of the specifics. RASP are notoriously difficult to measure. The reason for that is the R in RASP is reactive. RASP persists for a period of days, possibly weeks, in some cases, possibly minutes. The measurement of RASP is the subject of a large body of scientific literature and thus is notoriously difficult to nail down. Correlating back to Catherine's question, drug dose with the% inhibition of available RASP is a difficult project. Rather, we would like to focus on the activities that you mentioned, the grip strength and the balance and the rotor rod test. Maybe Dr. Lazorchak, you can talk about what those outcomes mean in a clinical sense, and then I'll, after your response, talk about phase one. Yeah. In the preclinical models, the grip strength, rotor rod performance, these are behavioral functions. We actually have a wide battery of different behavioral functions that have been described in the field where you can assess essentially what is the motor or neural behavior activity in an animal. I think that's actually one of the most important things to point out is we're trying to infer behavior and behavioral changes in mice or rats or in this case. In terms of how these particular readouts translate, I think they are relevant and they are clinically translatable. For instance, in the example of grip strength, in the context of an ALS mouse model, the disease progresses in this model and the disease manifests as a weakening in muscle strength. The model is true translationally in respect to its ability to represent that decline in grip strength and improvements or delay in that decline in grip strength can be translationally relevant from the preclinical standpoint. Similarly with the rotor rod assay, that's effectively essentially imagine yourself walking on a rotating balance beam and you're trying to maintain balance as this beam rotates. It's capturing a wide range of motor and balance and behavioral functions, which, for instance, in the case of Parkinson's disease, is quite relevant. These behaviors are compromised in Parkinson's patients who have tremors, balance problems, and motor functions which would lead them to be unstable in their gait or have inability to grasp or hold objects. The models themselves give you insights into the brain function of these animals. We can see some of the actual effects in the brain. We showed in the MPTP model, the brain dopamine levels are somewhat restored and TH-positive cells are rescued as well. We tie those behaviors with biomarker correlates to build the case that we actually are hitting not only the behavior but also the biologically relevant pathways that would translate to the clinic. Okay. To your very good question, Clara, about phase one, I am a believer in maximizing the outputs of phase one. Typically, phase ones are focused on safety, tolerability, and PK. With immune-modulating drugs, you can also add measurement of inflammatory markers. As I described for the ADX-629 phase one, we also add a fatty meal challenge. This is eggs and bacon fried in butter, a meal that is really designed to, at least from a dietary standpoint, inflame the patient. Then we measure lipid parameters after that fatty meal challenge as well as inflammatory markers. I think the good news with the ADX-248 is that so far the drug appears to be safe and well tolerated. The bad news is that requires further dose escalation. Typically in phase I, as you know, you start out with a low dose and increase the dose to the extent that the drug is safe and well tolerated. I would say we're sort of in the middle of that process. PK is also important. Back to Catherine's question about how much RASP do we need to inhibit. Per Dr. Lazorchak's comments earlier in the call, we need to have levels of drug that are capable of sequestering known levels of RASP. RASP are typically described, at least in the plasma, at low single-digit micromolar levels. I can tell you that we're in excess of that in terms of drug level. Just recall there's a one-to-one stoichiometry. Each molecule of RASP modulator binds to one molecule of RASP. Our drugs are suicide inhibitors. Once that reaction occurs, the two-click reaction that I was describing previously, there's no going back. I think the good news is we're at drug levels now, as Dr. Lazorchak mentioned, that are in excess of our known described levels of our target. In terms of inflammatory markers, we're thinking about cytokines and the typical markers like CRP that I talked at, C-reactive protein that I talked about earlier in the call with 629 that most companies examine. The challenge there is that typically phase I is performed in normal healthy volunteers. These are not people that are inflamed or supposed to be inflamed. Sometimes you can see minor decreases in inflammatory markers. I've already discussed the fatty meal challenge. We look forward to announcing the results of 248. I think it will be a comprehensive phase I, as was the phase I for ADX-629 early next year. Thank you so much. See you next week. Yep. Thanks, Clara. Thank you. Our next question comes from Yao Jin from [audio distortion]. Your line is now open. Please go ahead. Good morning, Todd. Thanks for taking the question and congrats on the progress. Just two questions here. The first one is that for the second-gen, 246 and 248, what's the specific difference between that to the 629, the first-gen compounds? I have a follow-up. Thanks, Yao. And good morning. All of our molecules have a similar pharmacophore. That is the active site of all the molecules. The site that achieves the two-click reaction that I've been describing is effectively the same or very similar across molecules. What differs across molecules, 629, 246, 248, is the backbone that supports that pharmacophore. The differences in the backbone relate to two things. One is potency in binding RASP, and the other is pharmacokinetics. As I mentioned, our first-generation RASP modulators, which include 629, were a little bit less potent, I would say, actually significantly less potent than our second-generation RASP modulators, say 246 and 248. That is number one. I think the other part that is worthy of focusing on is the PK. ADX-629, given its different backbone, was metabolized more rapidly. The half-life was lower than the second-generation molecules. Thus, ADX-629 was dosed twice a day, whereas ADX-248 will be dosed once a day, at least according to the phase I data that we've seen to date. The differences between 246 and 248, again, pharmacophores are relatively similar. I would say the backbones are different. I think 246 is designed for intraocular injection, acute administration, whereas 248 was the result of an optimization that resulted in an oral candidate. Okay. Great. Maybe just to tack on this question here, answer here. You're talking about the metabolized less rapidly. Have you guys reviewed the half-life of either 246 or 248? Absolutely. We're getting some half-life data in now for 248. Just recall that because we're in the middle of phase one, we are masked as to who is on 248, who is on placebo. Typically, phase one cohorts, at least in our experience, are six patients on drug, two patients on placebo. Excuse me, most of the data that is generated from the phase one is regarding drug. I think based on what we've seen so far, what we've seen in animals strongly suggests for ADX-248 a once-daily oral administration, which, as you know, Yao, is the holy grail in pharma. If we could just have a pill that we took once a day, I think biotech and many of its large pharma partners would be very happy. Okay. Great. Maybe the last question here really is that for the 248, that you have a broad spectrum of sort of disease area you can tackle. And you mentioned CNS today specifically as new expanded directions. So how would you prioritize these different indications, atopic dermatitis and others, over the next several quarters to see where you eventually place the bet in a more promising wise? And thanks. Yeah. That's a good question, Yao. One, we've thought a good bit about ADX-248, as I said in my preliminary comments, highlights the concrete advantage of immune-modulating drugs in that the breadth of clinical indications that could be exploited is quite large. If you look at companies like AbbVie or other companies that are in the immune-mediated disease space, there are many indications for each drug. I think that's a worthy goal for us here at Aldeyra. If ADX-248 is a once-daily pill that is able to modulate inflammation, then it should apply to many different diseases. That's why we have in our pipeline metabolic inflammation and now, as of today, CNS disease and atopic dermatitis. In terms of priority, I would say atopic dermatitis is the furthest along. As we know from reproxalap, RASP are intimately related to itching. Eczema or atopic dermatitis is characterized in large part by itching. We are quite interested in a placebo-controlled phase two trial for ADX-248 once we have narrowed down dose ranges to test the ability of ADX-248 to modulate itching in atopic dermatitis patients. I would say that is number one. Neck and neck behind are metabolic inflammation. By that, I mean hypertriglyceridemia, some of the other markers I have discussed today, including CRP, possibly weight loss since RASP are precursors to lipids, and the CNS conditions. I think for CNS, as Dr. Lazorchak mentioned, we are actively in discussions with key opinion leaders. We are deciding what indications are best for our drug candidates. We look forward to updating the street in the near future as to how we plan to proceed. Great. Thanks. Congrats on the progress. Thanks, Yao. Thank you. This concludes our Q&A session. I'll hand back over to Dr. Todd Brady for closing remarks. Thank you, operator. Thank you all for joining us this morning. As I've said previously, we do appreciate your time and interest in Aldeyra Therapeutics. As always, we look forward to updating you on future developments. This concludes today's call. Thank you for joining us. You may now disconnect your lines.