Ladies and gentlemen, thank you for standing by, and welcome to the Aldeyra Therapeutics Conference Call to present the positive phase two results of ADX-629 in chronic cough. I would now like to turn the call over to David Burke, Head of Investor Relations. Please go ahead. Thank you, Mandeep. Good morning, everyone. With me today is Dr. Todd Brady, President and Chief Executive Officer of Aldeyra. This morning, we issued a press release reporting top-line results for the phase II clinical trial of ADX-629 in chronic cough. 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, excuse me, in conjunction with the slides presented and the prepared remarks made on today's call. Please note that we will not discuss nor answer any questions regarding the clinical or regulatory status of ADX-2191, including the phase II clinical trial top-line results in retinitis pigmentosa, expected to be released later this week. Turning to slide two. This presentation and various remarks, which may be made during this presentation, contain forward-looking statements regarding Aldeyra, its investigational drug, candidate, including ADX-629, and its plans and expectations. 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, are based on assumptions and subject to risks and uncertainties, including the development of clinical and regulatory plans or expectations for Aldeyra's investigational drugs, including ADX-629. There are risks that result from earlier clinical trials or portions of clinical trials may not accurately predict the results of future trials or the remainder of a clinical trial, and Aldeyra's continuing or post-hoc review and quality analysis of clinical data, including p-value estimates. Aldeyra assumes no obligation to update these statements as circumstances change. Future events and actual results could differ materially from those projected in the company's forward-looking statements, including the results of operations and financial position. Additional information concerning factors that could cause results to differ materially from our forward-looking statements are described in greater detail in the 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, David. Today, we have the pleasure of announcing the results of yet another positive clinical trial supportive of the potentially broad-based immune-modulating activity of ADX-629, the lead drug product candidate in our orally administered RASP modulator platform, this time in a phase II clinical trial of patients with chronic cough, a disease that currently has no approved therapy and is thought to be mediated, at least in part, by recurrent inflammation. Achievement of all continuous cough reduction endpoints highlights the potential of RASP modulation as a new approach for the treatment of systemic immune-mediated diseases comorbid with coughing. The primary endpoint of safety was met. ADX-629 was well-tolerated, and no safety concerns were identified. The key secondary endpoint of awake cough frequency was met. The secondary endpoint of 24-hour cough frequency was met, and related post-hoc assessments of awake and 24-hour cough counts were met. At a high level, the results provide for novel evidence in support of anti-inflammatory approaches, distinct from neuromodulatory approaches for the treatment of persistent coughing. The results of the phase II trial in chronic cough were consistent with previously disclosed evidence of activity of ADX-629 in other inflammatory conditions, including psoriasis, asthma, and COVID-19, as depicted on slide four, all of which were presented in detail at our Research and Development Day last year. Slide five describes the protocol of the trial, a multicenter, randomized, sequenced, two-period, double-blind, crossover design, comparing 300 milligrams twice daily of ADX-629 to matching placebo. The design was comprised of two weeks of treatment in the first period, followed by two weeks of washout, followed by two weeks of treatment in the second period with whatever test article was not received in the first period. Among other enrollment criteria, patients must have had refractory or otherwise unexplained cough for more than one year, as well as at least 10 coughs per hour at baseline. The primary endpoint was safety, as assessed by adverse events. The key secondary endpoint was awake cough frequency, which is total coughs while awake, divided by hours awake. Secondary endpoints included 24-hour cough frequency, quality of life, and clinical impression scales. As indicated on slide six, baseline characteristics were generally balanced across both sequences. Mean baseline cough frequency was similar, although a wide range of baseline cough frequencies were enrolled in each sequence. Patients in the ADX-629 to placebo sequence had a longer history of chronic cough. Slide seven summarizes the safety results of treatment with ADX-629 and placebo. The primary endpoint of the trial was achieved. ADX-629 was well tolerated and no safety concerns were identified. No serious adverse events were reported. Adverse event frequencies were similar across treatment groups. No patients discontinued due to adverse events. Importantly, no patients reported taste disturbance. On slide eight, achievements of the key secondary endpoint of awake cough frequency with a p-value of 0.01 is presented on the left side of the slide, while the corresponding cough count across treatment groups is presented on the right side of the slide with a p-value of 0.001. Unlike other trials in chronic cough count increased during treatment with placebo and may have been due to a modestly different enrolled population or the presence of viral diseases, pollen, or other uncontrolled factors that have not been identified. A carryover effect was observed, such that activity in the second period depended in part on the treatment of the first period. For example, placebo response in patients previously treated with ADX-629 was higher than patients treated with placebo in period one, and as has been reported in other chronic cough trials, the baseline of period two was statistically lower than that of period one. To control for the influence of baseline and the carryover effect, statistical models were adjusted for baseline and previous treatment. Although not presented here, the superiority of ADX-629 versus placebo in the first period alone for awake cough frequency was highly statistically significant, with a p-value of 0.004 in favor of ADX-629. Importantly, the so-called placebo-adjusted drug effect, which is the change from baseline of ADX-629 minus the change from baseline of placebo, represents an approximate reduction of 14 to 15 coughs per hour. Divided by the baseline values reported today, the percentage reduction in awake cough frequency is in the range of 30%-35%, which is remarkably consistent with the reported reductions in phase IIB clinical trials of other chronic cough drugs in development, including the neuromodulatory P2X3 receptor antagonist class of compounds. Consistent with the awake cough frequency and cough count results, slide nine presents achievement of the secondary endpoint of the 24-hour cough frequency with a p-value of 0.001 on the left side of the slide, and the corresponding 24-hour cough count with a p-value of 0.001 on the right side of the slide. Other secondary endpoints of quality and life and clinical impression scales were inconsistent across groups over the two-week period, perhaps reflecting the immunomodulatory rather than the neuromodulatory mechanism of ADX-629. Separate from cough, slide 10 presents a statistically significant reduction of LDL to HDL ratio in ADX-629 treated patients relative to placebo-treated patients. The finding is surprising, given that enrolled patients, though on average overweight, were generally eulipidemic. The lipid results are, however, consistent with the phase I clinical trial and phase II clinical trial of ADX-629 in psoriasis, presented on slide 11. Reduction in inflammation, including inflammatory, lipophilic, and pro-lipidemic RASP, may explain the normalization of lipid levels in certain clinical settings and may have applicability in the treatment of diseases comorbid with dyslipidemia and obesity. As illustrated on slide 12, we believe our list of upcoming planned milestones remains robust and with regard to ADX-629, is highlighted by the announcement of part one results of phase II clinical trials in atopic dermatitis and nephrotic syndrome, and initial results from a phase II clinical trial in Sjögren-Larsson syndrome in the second half of this year. Separately, this week, we expect to announce phase II results of ADX-2191 in retinitis pigmentosa, a sight-threatening orphan retinal disease for which there is no currently approved therapy. Operator, I would now like to open the call for questions. The floor is now open for your questions. To ask a question at this time, please press star one on your telephone keypad. We'll now take a moment to compile our roster. Our first question comes from the line of Yigal Nochomovitz from Citi. Please go ahead. Hi, this is Carly on for Yigal. Thanks so much for taking our questions, two from our end. First, we were just hoping you could maybe elaborate a little bit more on your thoughts on the worsening you saw in the placebo arm, given typically we've seen a placebo response in other trials in chronic cough. I know you touched on it a bit in your prepared remarks, but maybe if you could just go into a little bit more detail on why placebo may have worsened in this study. The second question is, if you can speak to how you're thinking about next steps for chronic cough with 629, as well as potentially with the next gen program 246. Thank you. Well, good morning, Carly, and thanks for the excellent questions. Firstly, I'd like to say we're absolutely thrilled with these results. As I mentioned in my prepared comments, I think this is some of the first evidence that a non-neuromodulatory activity in chronic cough may have some applicability in treating these patients with such a persistently disturbing condition. I guess the reason we run placebo-controlled trials is to compare placebo to drug. That comparison here was quite successful. Why placebo elevated in this trial versus other trials? As I mentioned in my prepared comments, may have to do with a slightly different population. Most of our clinical sites were spread across the southern half of the United States. Most of the patients were enrolled in the winter season. There are a variety of uncontrollable factors, as we happen to know here at Aldeyra Therapeutics, having to do with seasonality, the pollen counts, comorbid viral diseases, and other factors that are really difficult to account for in this setting. I think what really matters, though, and what has been reported in the chronic cough literature, is the so-called placebo-adjusted difference relative to drug. Placebo minus drug here results in about 15 coughs per hour, and that, in turn, translates to changes from baseline that have been reported for other chronic cough drugs in the literature. To that end, the change relative to placebo is quite consistent. In terms of next steps, as I mentioned in the press release this morning, we're thrilled to speak with the regulatory authorities about next steps in chronic cough. I think unlike other drugs in the chronic cough arena at the moment, we have the opportunity to discuss inclusion of patients with inflammation. Today's chronic cough is treated not with anti-inflammatory medications primarily, but with neuromodulatory medications, opioids, anesthetics, drugs, for neuropathic disease, and so forth. Here we have, I think, some of the first evidence that immune-modulating activity could be important in this disease, and that allows us to treat a different class of patients where, as I mentioned in my prepared comments, inflammation may be comorbid, with coughing. It also includes shorter versions of chronic cough, subacute cough, post-infectious cough, so-called intermediate, coughing, and so forth, and we look forward to, discussing that range of options, with the regulatory authorities. Great. Thanks. Our next question comes from the line of Kelly Shi from Jefferies LLC. Please go ahead. Hi, this is Sean Pan on for Kelly. Congrats on the data talk. We have a question about the AE. Can you maybe give us more color on the AE profile? Also, our second question is, given the non-overlap mechanism with neuromodulators, how do you think about the possibility of combination therapy? Thank you. Good morning, Sean. I'm happy to talk about the adverse event profile, which, as I mentioned in my prepared comments, were balanced, it was balanced across treatment groups. The AEs were inconsistent and sporadic and generally mild, as you can see from the slides presented today. As I mentioned in response to Carly's question, the current treatment of chronic cough generally involves neuromodulatory agents, which are effectively anesthetics. What you typically see with those drugs are changes in sensation. I don't just mean opioid-like side effects, but in other cases, such as the P2X3 antagonist, changes in taste. We saw nothing of that sort with ADX-629. That is because the mechanism of ADX-629 is related to anti-inflammatory activity or immune-modulating activity. Thus, we would not expect to see any sort of neurosensory changes like you might see with other drugs in development or that are currently used to treat chronic cough. Because of the different mechanism here, that is an immune-modulating mechanism with ADX-629, relative to the standard of care in chronic cough today, I'm very bullish on polypharmacy. That is the ability to treat this disease, which is difficult to treat, with two different mechanisms. As a medical community, we need more drugs in this class. The chronic cough is a persistently disturbing condition. It is often refractory to therapy, and as far as I'm concerned, and I think as far as most physicians that deal with this condition on a daily basis concerned, we need more different kinds of therapies. I think today's data provides hope that yet another mechanism may have applicability for the treatment of chronic cough. Our next question comes from the line of Yale Jen from Laidlaw & Company. Please go ahead. Good morning, and congrats on the outcomes. It's very impressive. Just two quick questions. First, here is why the quality of life readouts did not change much compared to the two groups. Any theory? Do you have any theories behind that? Then I have a follow-up. I'm sorry, Yale, could you restate the question? The quality of life, of the two groups has not been changed. Yeah -much. I think the answer is the same answer that I gave to Sean's question, which is the ability to affect cough frequency relative to the ability to affect quality of life and symptoms, really relates to the mechanism of the drug. Today's chronic cough agents are neuromodulatory. They affect sensation. They affect perception of sensation, and that is not consistent with the mechanism of ADX-629. In general, with drugs that modulate inflammation, typically over a short period of time, such as the two-week treatment period featured in the present trial, you wouldn't expect to see changes in quality of life, or clinical impression scales, unless you had some sort of neuromodulatory therapy. Okay, maybe one follow-up question here is, given the landscape of the chronic cough, at this moment, what would be your overall sort of comment and the thought and the positioning of 629 at this point? Thanks. Well, I think it's good to see that the reduction in cough relative to baseline is certainly consistent with what's been reported in phase two trials, at least with the P2X3 antagonists. Greater than that, which has been reported in phase three trials, of chronic cough medications in the P2X3 class. I would say that in general, patients with concomitant inflammation, which is common in chronic cough, the patients with underlying pulmonary issues such as interstitial lung disease, asthma, and so forth, would more likely benefit from an immune modulating approach to treat cough than a neurosensory or neuromodulatory approach, which would not address underlying inflammation. The data today really open up a whole new market for the treatment of cough, and that market has to do with the comorbidity of inflammation and coughing. I would think that, sure, as Sean pointed out, we could administer these drugs together. At the same time, to the extent we're interested in treating underlying causes where there is inflammation, I would expect immune modulating approaches, such as the one featured by ADX-629, would be far more relevant. Okay, great. again, congrats. Thank you, Yale. Our next question comes from the line of Catherine Novack from Jones Research. Please go ahead. Hi, good morning. Congrats on the data. I had a question, you know, a little bit about the trial design. Is 14 days enough to see a therapeutic effect? You know, albeit different mechanism of action, but in P2X3 antagonists, we've seen the placebo-adjusted reduction definitely attenuates over time. You know, how comfortable are physicians with just two weeks of data, and are you intending to look at longer time points in the future? Catherine, good day to you. As usual, you raise an excellent point. Most of our trials going forward with ADX-629, and I hope soon ADX-246, which is another orally administered RASP modulator, will feature 90-day trials, which has typically been the phase IIB endpoint in chronic cough. Three months of treatment or 12 weeks of treatment are far more relevant clinically, as you point out, than two weeks of treatment. I think in trials like these, where patients are treated acutely, for a chronic disease, what we're really looking for are signals. I think we have identified those signals today that warrant future study, and as you correctly point out, future study will feature, longer trials, including, 90-day trials, which I think will be our, next stop in clinical development. Got it. That's very helpful. Congrats again on the data. Thank you, Catherine. Our final question comes from Tom Shrader from BTIG. Please go ahead. Hello, Todd, this is Tom on for Tom. Thanks for taking our question. I have two questions. One is, could you probably just shed color on where you're with dosing and whether a dose-ranging study makes sense moving forward? The second question is, in a more, in a broader context, is it known whether the RASP species involved in these indications are the same or different? If a specific type is identified, could they generate new IP for the class? Thanks. Hi, Tom, good morning. I don't expect we'll be doing too much dose ranging going forward. The reason I say that has to do with the second part of your question, which is RASP and RASP levels. Generally, in inflammatory diseases, the levels of RASP, at least in plasma, are single-digit micromolar, which is the PK we attempt to match with our orally administered platform, including ADX-629. we know that 250 milligrams to 350, 300 milligrams administered twice daily, approaches single-digit micromolar. There's a one-to-one stoichiometry between drug and RASP target, and thus, I think the therapeutic levels, at least as theoretically as they relate to levels of RASP, have been achieved. I think it would be hard to argue that ADX-629 has no activity at these levels based on the data we presented at the R&D day last year in psoriasis and asthma and COVID, plus the data announced today. I think going forward, we typically run 90-day trials at the 250 mg BID level, and I would expect the same here, following our discussion with the agency. In terms of the kinds of RASPs that are involved in inflammation, the two main culprits are malondialdehyde and hydroxynonenal. An interesting exercise is to go to PubMed and type in malondialdehyde or hydroxynonenal and pick your favorite inflammatory disease, and you'll often see levels elevated in those patients relative to healthy volunteers. Typically, as I mentioned, those levels are in the single-digit micromolar range, at least in plasma. There are probably other RASPs that are elevated that are less well described, but in general, those are the two targets that we believe are the main culprits in inducing inflammation. Great. Thanks for taking our questions. Thanks, Tom. I would now like to turn the call over to Todd Brady for closing remarks. Well, thank you as always for joining us this morning. We do appreciate your time and interest in Aldeyra. As always, we look forward to updating you on future developments. Thank you, ladies and gentlemen. This does conclude today's call. Thank you for your participation. You may now disconnect.