Good morning and welcome to the Trevi Therapeutics Webcast, presenting the top-line results from the phase II-A RIVER Trial of Haduvio in patients with refractory chronic cough. At this time, all participants are on listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then one on your phone. To withdraw your question, please press star, then two. Please note this event is being recorded. Various remarks that management make during this conference call about the company's future expectations, plans, and prospects constitute forward-looking statements for purposes of the Safe Harbor Provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated from these forward-looking statements as a result of various important factors, including those discussed in the risk factors section of the company's most recent quarterly report on Form 10-Q. In addition, any forward-looking statements represent the company's views only as of today and should not be relied upon as representing the company's views as of any subsequent date. While the company may elect to update these forward-looking statements at some point in the future, the company specifically disclaims any obligation to do so, even if its views change. I would now like to turn the webcast over to Jennifer Good, Trevi Therapeutics President and CEO. Please go ahead. Good morning, everyone, and thank you for joining us bright and early this morning for the top-line data presentation of our River phase II-A refractory chronic cough trial. We are excited to share the robust positive results from this study, and following the presentation, we will open it up for Q&A. Joining me today on this call are my Trevi colleagues, Dr. James Cassella, Trevi's Chief Development Officer, and Farrell Simon, Trevi's Chief Commercial Officer. We are also joined by Professor Jacky Smith. Professor Smith is a leading key opinion leader in the chronic cough space and a professor of respiratory medicine at the University of Manchester. She runs a multidisciplinary research team whose focus is on understanding mechanisms underlying pathological cough. I think she has touched every RCC study conducted to date. Thank you, Jacky, for joining us. I know everyone will appreciate your expert perspective. I will provide an overview of our results, the high unmet need of RCC patients, as well as our differentiated mechanism before James goes into the data in more depth. On this slide, I will summarize at a high level the key data from the RIVER study, which you will get more color on throughout the presentation. As you can see, Haduvio showed robust positive results in RCC patients, reducing 24-hour cough frequency in the overall population by 67%, representing a 57% placebo-adjusted change and a p-value of less than 0.0001. This strong effect was seen across a range of cough counts, including both exploratory arms in moderate and severe. You will also see in the responder analysis that this effect was not driven by only a few patients, but rather 84% of patients treated with Haduvio saw at least a 30% reduction in their cough frequency versus baseline. The effect with Haduvio was rapid, highly statistically significant as early as day seven at the 27 mg dose, and it was supported by the patient-reported outcomes, or PROs, that were included in the top-line data received to date. AE profile remained consistent with prior studies, with no new safety signal. I do want to remind everyone that we have only received top-line data to date, and there will be a lot more information to come over the next month as we get the full data set. With this data, Haduvio is the only therapy to show a significant reduction in chronic cough across both idiopathic pulmonary fibrosis, or IPF, and refractory chronic cough, or RCC patients. The results encourage us to continue development as we believe Haduvio may provide the best cough therapy for these severe cough conditions that are so disruptive to the quality of patients' lives. I want to take a minute to talk about the unmet need in RCC patients, which includes patients with unexplained chronic cough. This disease has a significant impact on patients' lives, who often suffer for eight years before being diagnosed. Even upon diagnosis, there is no approved treatment in the U.S., and patients have a high rate of anxiety and depression, a reduction in functional capacity in and out of work, and impairments to their physical and psychological health. When we look at rates of cough frequency in RCC patients, as shown on the right-hand side of this slide, they have similar cough frequency to IPF patients. RCC is a category of patients with a high unmet need and a large burden of disease. I want to close my introductory remarks reminding everyone of Haduvio's mechanism of action, which is different than other peripheral-only agents studied in RCC. Haduvio works differently by targeting the cough reflex arc, both centrally and peripherally, as a kappa agonist and mu antagonist, or KAMA, which are opioid receptors that play a key role in controlling cough hypersensitivity. By working centrally, we believe Haduvio is inhibiting the cough reflex in both the cortical and brainstem centers independent of the peripheral stimuli. By pairing that with Haduvio's peripheral activity in the lungs, Haduvio blocks afferent signaling independent of the initial trigger, which can be caused by multiple receptors, whereas other therapies only target one single peripheral receptor. We believe it is the link of the mechanism to the full cough arc from the lung to the spinal cord up to the brain that provides the robust response you will see in these results. I will now turn it over to James to go over the study design and the trial results. Thanks, Jennifer. I'm very happy to share with you today the positive top-line results of the RIVER Trial and the potential of Haduvio for patients with refractory chronic cough. Let me review the study design and objectives with you, and then I will go into more detail on the endpoints. This was a randomized, placebo-controlled, two-treatment period crossover study in patients with refractory chronic cough, which includes patients with unexplained chronic cough. The primary endpoint of the study was a relative change from baseline in 24-hour cough frequency reported as coughs per hour at day 21 for Haduvio compared with placebo. Also included was a planned analysis assessing the change in 24-hour cough count for patients with a baseline objective cough frequency of 20 or more coughs per hour and those with baseline cough counts of 10 to 19 coughs per hour. This was a two-period crossover design with a three-week washout period between. Each treatment period was 21 days in length, and for the Nal ER treatment period, the dose was titrated from 27 milligrams to 108 milligrams twice daily. Dose titration was approximately every seven days, and objective cough count and secondary endpoints were assessed on day seven while on the 27-milligram b.i.d. dose, day 14 while on 54 milligrams b.i.d., and day 21 at the 108-milligram b.i.d. dose. Cough was measured by objective cough count monitoring using the VitaloJAK device. Patients' reported outcomes were captured as secondary endpoints. We will share with you today the patient-reported outcomes and secondary endpoints provided for the top-line analysis. There were a total of 66 patients randomized into the trial, and the baseline characteristics of these patients are in line with other RCC trials. The study population was approximately two-thirds female and one-third male, with an average age around 60 and a mean 24-hour cough frequency of 35 coughs per hour. Of the 66 patients randomized into the trial, 59 were included in the full analysis set for evaluation of the primary efficacy endpoint. The full analysis set includes all patients who received at least one dose of study drug and have objective cough count data on both baseline and day 21 in at least one treatment period. The primary efficacy endpoint of relative change in 24-hour cough frequency assessed by objective cough monitoring on day 21, corresponding to the 108 mg b.i.d. dose, was analyzed by a mixed effects repeated model, otherwise known as MMRM. We are very excited that the trial achieved its primary efficacy endpoint. Haduvio showed a 67% reduction from baseline compared to a 10% reduction from baseline for placebo. This difference was highly statistically significant with a p-value of less than 0.0001. There was no apparent treatment effect on the primary efficacy outcome. The previous slide showed the cough count reduction effects of Nal ER at the 108 mg b.i.d. dose on day 21. This slide shows the relative change from baseline in 24-hour cough frequency across the earlier time points and at the lower doses. A large and statistically significant reduction in 24-hour cough frequency was found on day seven with dosing at 27 mg b.i.d. Increasing the dose to 54 mg b.i.d. and testing on day 14 also showed a similarly large and statistically significant cough reduction. The magnitude of effect for the 27 mg b.i.d. and 54 mg b.i.d. doses was similar to that found with the primary efficacy endpoint at day 21 at the 108 mg b.i.d. dose, highlighting the broad and significant reduction in cough frequency across our entire dose range. This slide shows the effects of Haduvio on two different cough frequency populations. As previously shown, the 108 mg dose produced a statistically significant and large reduction in 24-hour cough count. Importantly, this slide shows that Haduvio reduced 24-hour cough frequency in a very consistent way for patients with counts of 20 or greater coughs per hour and those with 10-19 coughs per hour, with placebo-adjusted changes of 51% and 57%, respectively. This large effect of Haduvio in the 10-19 cough group per hour is especially remarkable. Slide 14 displays the placebo-adjusted relative change from baseline for 24-hour cough frequency for the two different cough frequency populations described in the previous slide. There was a similar reduction in cough frequency starting at 27 mg b.i.d. up to and through the 108 mg b.i.d. dose for patients with 10-19 coughs per hour and greater than 20 coughs per hour. This again shows the consistency of the performance of NALIR across these two groups and gives us confidence of being able to reduce cough and offer potential benefit across a broad range of cough counts as we move forward in development. Lastly, we compare NALIR and placebo using a responder analysis assessing response rates at different targeted levels of cough reduction. It is widely believed that a 30% reduction in cough frequency from baseline represents a clinically meaningful improvement. As you can see, 84% of the 108-milligram b.i.d. dose patients achieved this clinically meaningful level of cough reduction. As you look at a more stringent threshold of 50% change from baseline, there still are 77% of the patients responding to therapy. Importantly, more than half of the patients at this dose achieved this 75% reduction in 24-hour cough frequency, highlighting the strength and magnitude of effect of Haduvio on cough. We are able to share with you two of the patient-reported outcome measures that were assessed in the trial and made available for this top-line readout. The PRO for cough severity was assessed using a visual analog scale. The CSVAS is a 0-100 scale, where 0 is no cough and 100 is worst cough. There is a clear improvement in patients' perception of severity of their cough starting at the 27 mg b.i.d. dose, with growing improvement evident with dose escalation. These cough severity PRO data provided an important patient perspective on the dramatic cough frequency reduction found with our primary analysis. The patient-reported cough frequency question asked patients, "Over the past 24 hours, how often did you cough?" This is a question to patients that parallels the measurement of objective cough frequency assessment. As you can see, there is a statistically significant and meaningful improvement on the CSVAS. Collectively, these PRO data show robust patient perceptions of reduced cough severity and cough frequency, which corroborate and complement the reductions observed with objective cough monitoring. Turning to the safety analysis to date for the trial, we see a profile that is consistent with the safety data collected in the NALIR program to date. The overall patient discontinuation rate in the trial was 22.7%, with the majority of the discontinuations being attributed to AEs. The discontinuation due to adverse events represents about 15% of the trial population. Importantly, there were no serious adverse events reported in the trial. The common adverse events reported in the trial include nausea, fatigue, constipation, somnolence, dizziness, and headache. The majority of the AEs reported were mild to moderate in severity. Six patients experienced grade 3 AEs with four in the Haduvio arm and two in the placebo arm. Overall, the adverse events reported in the trial are typical for this class of drug and are consistent with those in other trials with Haduvio. In summary, Haduvio achieved the primary endpoint in this phase II-A trial with highly statistically significant reduction in 24-hour cough frequency. Patient-reported outcomes and other secondary endpoints assessed in this top-line readout showed significant results across all the doses and support the broad efficacy of Haduvio. There were consistent effects across all doses, and significant effects on cough frequency and other endpoints occurred as early as seven days with the 27-milligram b.i.d. dose. Consequently, we are very happy with the strong results of Haduvio in this study and look forward to discussions with the FDA in further exploring the potential of Haduvio to help patients with refractory chronic cough. With that, I'll turn it back to Jennifer. Thanks, James. We are very excited by these results and look forward to getting the full analysis of all the data and talking with the FDA and other regulatory authorities about our next study. As we prepared for this RIVER data readout, many of you asked me what it would take to move forward in RCC with the significant opportunity we have in IPF. I want to spend a couple of slides talking about that and our commercial strategy. When we look at the current development landscape in RCC, the main mechanisms in development have been P2X3 inhibitors, where there have been mixed results. While there have been a number of discontinued or failed programs, those that have been successful trials have shown a moderate effect. You can see on this slide the results from the various phase II and III trials summarized and show a range in the reduction of placebo-adjusted cough frequency between 12%-37% overall. I recognize that these are different trials with different designs and different patient populations and that you can't make direct comparisons. However, the results James just shared with you achieved a 57% placebo-adjusted change with a robust response across a broad number of patients. We feel this kind of response could be very meaningful to patients suffering from RCC. The second important point is that the competitive landscape in the last couple of years has thinned out due to multiple failures. Recently, Merck just announced that they withdrew their FDA application for Gefapixant and will not refile, leaving Camlipixant as the lone product in phase III. With the strength of the RIVER data and the sparse competitive landscape, we believe Haduvio has the potential to be best in class in patients with RCC, filling an important gap in a category with significant patient need. In RCC, we are planning for a targeted and focused approach to commercialization to follow our lead program in IPF cough. Although RCC is a very large patient population, we are looking to focus on the most refractory patients which have failed the standard of care. By taking this approach, we will target up to 1 million RCC patients who have the highest unmet need in the category. This also allows us to maintain specialty pricing from our IPF population, which is our lead indication and will be first to market. The commercial footprint also would follow this approach and only look to add on high decile prescribers in a single additional specialty other than pulmonologists. We'll already be calling on pulmonologists with our IPF sales plan, and this would maintain a small commercial footprint. We have tested the transition of pricing from IPF to RCC with payers and have seen a number of analogs take the same approach of going from a small orphan population to a larger population and maintain or even increase price. With this data, it provides strong evidence to support this commercial strategy. This RIVER trial is the first of two main data readouts from Trevi in the upcoming months. We expect to have the top-line results from our phase II-B CORAL trial in IPF patients with chronic cough in the second quarter. It has been very energizing for our team reading out three positive data events over the past few months. I thank all of them for executing good trials. This is an exciting time for Trevi and the patients we look to serve. In closing, we have a strong balance sheet with approximately $108 million in cash and cash runway in the second half of 2026. We are in a position where we can progress the next study in RCC without needing to raise capital. Thank you to patients, caregivers, investigators, and clinical trial teams who made this study possible. We will now open it up to Q&A, and as the operator queues up the Q&A, I'd like to bring Jacky Smith into this conversation, and Jacky, I'll offer you a moment to make a few comments on your thoughts on the data. Thanks, Jennifer. I guess the main thing I would say is how excited I am about this data. There's no question in my mind, and I think you showed evidence on it on one of your later slides there, that this is one of the most positive studies we have seen in a long time. For me, it's the most promising data I've seen since that very first P2X3 antagonist study with Gefapixant, so I'm exceedingly excited about this and think it's a great thing for the field of cough that we've got another mechanism of action that seems to be tractable here. Great. Thank you, Jacky. Operator, I'll let you go ahead and cue the questions. We will now begin the question and answer session. To ask a question, you may press star, then one on your touch-tone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then two. Due to the number of participants on the call today, questions will be limited to one per caller and any relevant follow-up to your question. If you have other questions, you may get back in the queue. At this time, we will pause momentarily to assemble our roster. The first question today comes from Annabel Samimy with Stifel. Please go ahead. Hi. Congratulations, everyone, on some great data, and thanks for taking my questions. I guess one two-part for me, actually. Are you surprised by the greater effect in the moderate population given how hard to treat that population has been? Now that you potentially have access to this larger RCC population, including both moderate and severe, what do you think the study requirements are moving forward? Obviously, I think larger populations require larger studies. Would you be able to pursue this development yourself, or do you absolutely need a partner to keep this going? Thanks. I'll get back in the queue. James, why don't you give your answer around the first part about were you surprised? Jackie, I'd also like you to weigh in as you've seen sort of all the data about a little larger effect in moderates. James, go ahead and give your perspective. Yeah. Hi, Annabelle. Thanks. I think we go back to the mechanism of action for our drug and the fact that we are treating a hypersensitivity type of cough reaction here. I think the fact that we see a very strong and robust effect with this 10-19 or moderate cough group, I think reinforces the fact that we have a broader effect on cough by our mechanism of action. I think that really, when you look at the effects in RCC and the effects in IPF that we reported previously, I think it really just reinforces that we have a unique mechanism of action here with essential activity that really does hopefully knock down this hypersensitivity response causing the cough. I think that's probably the best answer I can give, but Jackie, love your opinion. Thanks. No, I would agree with that completely. I am not surprised. I was hopeful that we would see an effect in this moderate population simply because the central mechanism of action, in my mind at least, suggests that the effect should be way more agnostic to the baseline cough frequency. It is quite a different mechanism from the P2X3 antagonist where we are very much talking about blocking P2X3 receptors we believe in the periphery that are responding to ATP being released. That is very much dependent on those mechanisms being heightened to block that effect, and I suspect that ties in quite directly to the baseline cough frequency. I would also say it is great news for our patients because we need drugs that are going to be effective for patients with more moderate cough frequencies, not just that very severe group. The second part of your question, Annabelle, I'll sort of start with it from a business perspective and James certainly chime in, which is since we work in this broader population, can we run larger trials? I think the advantage we have, Annabelle, I'm not sure that they are larger trials. We have a bigger effect size that we can power around. I think we know a lot about the dose, which is helpful, and we can run going forward more of an all-comers trial. We'll, of course, have a floor around minimum cough levels that makes sense, but we don't have to try to only recruit from that small severe group. I would hope that means we can recruit a trial that's much more representative of the population, can go quicker, and get done. We have been planning for this next study. Obviously, we have some work to do now with the data in hand. It's a trial that's very executable by us. We have the money to do it, and so we definitely are planning to move ahead with the next study. James, any color you'd like to add from a development? Just to reinforce that it's a strategy question. It's not a logistical or tactical question that we have the capabilities, and I have the confidence that we can run any size trial globally that we need to run. I think we need to just take that piece of it off the table. It's really what's best for us and what's best for the patients. Great. Thank you. That's helpful. Thank you, Annabelle. The next question comes from Serge Belanger with Needham & Company. Please go ahead. Hi. Good morning. I also like to offer my congrats on these nice results. I guess one question maybe for Farrell regarding the market opportunity for RCC. I think on slide 24, it was highlighted that there's 2-3 million patients that represent the market opportunity here. Just curious if you can provide more color on these patients. There's no treatments approved for this, so how many of these are diagnosed and treated and would require a second or third-line treatment? Thanks. Yep. Thanks, Serge. When we look at the market opportunity, as you note, this is a fairly large market, 2-3 million addressable patient population. When you start looking at the treatment failures, and I'll just break down the market at a high level, about a quarter of the market are those severe patients. Less than 50% of that market are those moderate patients where nothing is really proven to work. That is what opens up the addressable patient population. Those who are diagnosed today and are currently uncontrolled on off-label treatments represents about around 70% of the market today. The nice thing is these patients will not only be available to us in terms of us getting to market, they've already stepped through other therapies, so there's not additional steps that they would have to take to be a candidate for Haduvio. Thank you, Serge. The next question comes from Ryan Deschner with Raymond James. Please go ahead. Hi. Thank you very much, and congratulations on the data set here. Given the strong placebo-adjusted signal in this dataset, does this change how you're looking at indications you might potentially launch into next, like COPD cough, other non-IPF ILDs, and post-viral cough? Ryan, thanks for that. Congrats, and thanks for the question. We have looked at other things. As we sort of signaled to investors, obviously, IPF is our lead. This RCC data is very supportive of us moving ahead here. We are also doing some work. Farrell and James teams are looking at the opportunity in other interstitial lung diseases, which are closely related to IPF, just a big portion of the ILDs. I think beyond that, as a company our size, those are all three enormous opportunities, and we will stay focused. We're not going to keep broadening out. I do think we probably have a mechanism that works broadly in a lot of different cough conditions, but I think at this point, I've been at Trevi a long time, and I think it's time to circle the wagons and put together a business that's got a big opportunity that we can move forward with. We will stay focused in those three indications and think they're doable for us from a development perspective. I also think we have a commercial plan on the table that's executable in a specialty model. Thanks, Jennifer. The next question comes from Leland Gershell with Oppenheimer. Please go ahead. Good morning. Clearly, terrific data here. Thanks for taking our questions. One from us, although probably could benefit from both management and Dr. Smith. I want to ask, thinking longer term, clearly, Haduvio is a drug with broad potential beyond IPF cough. Here we have RCC, but RCC is defined as chronic cough that's due to, I think, any underlying condition. I guess, Jennifer, do you see a need to do formal studies? If things play out according to aspirations, you'll have an approval for IPF cough followed by a label expansion to RCC. Would you think you would need to do additional studies and/or get any type of label expansion for ILDs? I guess related to that, Dr. Smith, would you be willing to try Haduvio, presuming it's approved, in any variety of coughs that may be due to some of those other rare conditions in the absence of either some sort of label or data supporting? Thank you. Yeah. Thanks, Leland, for the question. I'm going to let James answer the regulatory side here. I know where he's going to come out, but I'll let you answer it and then let Jackie answer your second half. I think it's a two-part answer. One is the regulatory side where I think the FDA clearly is going to look for studies that support indications, and that's clear across all divisions of the FDA. I think it's especially clear in the pulmonary division. I think the other question is probably more related to the question you're asking, Jackie, and it's going to be for physicians, is doctors can prescribe drugs off-label. They need guidance. They need support. They need to have some knowledge that's going to work in that space. I think it's a physician-patient decision to use a drug that is not currently on label. I think as far as the regulatory authorities go, I think we have a clear path with regulators on, and we know what we need to do in order to sort of expand our label with certain populations. I think the rest of it is more in the rest of your question is more in regards to practice. Jackie, you want to take that? Yeah. Absolutely. In terms of what we do right now in treating refractory chronic cough patients, we are certainly in quite a habit of prescribing off-label treatments because we simply do not have anything else. However, I would say that I think the minute you start to get licensed therapies available, I think that does change things. Whilst I guess I might be tempted to try drugs like Haduvio in patients who have got very severe coughing but an underlying condition that is causing it that maybe the existing treatments are not working so well, I think I would be uneasy unless they really had that sort of hypersensitive phenotype. Unless they had things in common with the kind of patients that we have been putting into the RIVER trial. You see those features very much as well in a lot of the patients with pulmonary fibrosis too. My personal view is that I think if you really want to reach out into a broader market, you would have to do those studies in those different conditions. You'd have to start thinking about with conditions like COPD, there are so many different phenotypes of COPD in there. You'd want to be careful about people with productive coughs, for example. Yes, I think there'll be some off-label use, but I'm not so sure that you could get away with not doing studies in other conditions. You'd want to really pick the right phenotypes that are going to respond. Jackie, maybe you could just comment a minute. I'm sorry, Leland, just about the hypersensitivity because I think that's the important thread that ties all this together or at least is hypothesized by the experts. I think just maybe if you could just expand on that a little bit and how you think maybe IPF, ILD, RCC could connect. Yeah. Absolutely. The interesting connection here is the kind of ways that patients describe their symptoms. Our refractory chronic cough patients will say they've got tickling, itching, irritation, and dryness in their throat all the time that's making them want to cough. They will describe thermal and environmental irritant triggers. They'll say that anything that moves their larynx around is likely to make them cough, so talking, laughing, singing, eating. You don't see the precise same triggers in patients with IPF, but there are a lot of similarities in there. This sort of combination of coughing to relatively innocuous triggers and having lots of throat sensations is the sort of clinical picture we recognize as being a sort of hypersensitive state in terms of the neuronal pathways that control cough. I think that's the group of patients that we have confidence that these sorts of treatments are effective in. All right. Thanks for the additional perspective. Again, my congratulations. Thanks, Leland. The next question comes from Faisal Khurshid with Leerink Partners. Please go ahead. Hey. Good morning. Thank you for the presentation, Jennifer and James. I want to talk about the tolerability profile a little bit and would also love Dr. Smith's opinion here. First, just more of a technical question. Do you have the data split by treatment period? Is there a chance the distinct tolerability profile of the drug might have unblinded the study to some extent, or how do you think about the risk of that? I have a follow-up as well. Thank you. We do not have all the data in yet for the full analysis set, but we do not have it broken down by treatment period at this point in time. In regards to your question about unblinding, I think that a crossover design with a drug that is essentially active, of course, there are possibilities of unblinding, especially if you are using totally subjective endpoints. I think in this case, the crossover design was an incredibly powerful design that has been used before that really is informative to us. When you look at our primary efficacy endpoint, it is objective cough count through a monitor. I think if a patient was willing to have a placebo effect that has really effectively reduced their cough count, they would not need medication, right? I think the objective cough count here is our anchor that controls for any type of crossover effect that you might see in this trial. Jackie, I would love your perspective on that. Yeah. Yeah. Sure. Happy to chip in. As with any trial design, there's a bunch of different ways you can do this. The crossover designs, we find they're very powerful for these initial studies to really prove the concept that a drug is effective for cough. In terms of unblinding due to adverse effects, I mean, it's something we've been thinking about and looking at for a long time because, of course, the P2X3 antagonists and particularly Gefapixant cause lots of taste AEs. I guess what I would say is despite our best efforts to sort of link taste AEs to treatment effect, you really don't see much difference between those patients with and without the AEs in those studies. I would be very surprised if all we're seeing here is an effect based on a degree of blinding. The last point I'd make is that my experience is that if you've got an effective therapy, it's very hard, even without AEs, to keep the study blinded because patients notice they're feeling a lot better. There's not a lot we can do about that. Maybe just one final comment. I'm sorry, Fes. One final comment that might be useful for you is that, again, we haven't dug into all this yet, and we don't have all the final datasets. In our very first look at the potential differences that could exist between objective cough count reduction by treatment period, we're not seeing anything that would suggest that we have a period treatment effect here. At the 108 dose, the effects in period one and period two look pretty comparable. I'm not sure that we're seeing, from that perspective, any kind of a carryover or loss of effect in one treatment period or another. I think it's another thing where crossover designs are incredibly useful, but when you start looking at whether or not there's a treatment imbalance in the treatment period imbalance in the overall effects, I don't think we're seeing that. Got it. Thank you, James. Thank you, Dr. Smith. That was super helpful. Just a quick follow-up. Can we talk a little bit about the tolerability profile, sorry, more generally? Dr. Smith, I'd love to hear if you think this drug is easy to use or not in this patient population. Thank you. I think this drug is easy to use in this population. I haven't seen all the detailed data yet, as you might imagine. My understanding from my involvement in the first IPF study is that a lot of these side effects tend to come as patients first start the dose and settle with time. Chronic cough patients are very tolerant of things like that if they know what to expect. As I've already mentioned, I've done a lot of studies with Gefapixant where there were very significant taste AEs in the first studies where we were at very higher doses. In terms of patients being willing to put up with side effects, and particularly side effects that will perhaps settle down if you can just get through them, chronic cough patients are very willing to do that for a good antitussive effect. Thank you, Faisal, for the questions. The next question comes from Deb Chatterjee with Jones Trading. Please go ahead. Hi. Thanks for taking my question and congrats on the data. Just to follow up actually on Faisal's question, how do you think the AE profile will evolve if you test lower doses in a potential phase II-B or phase III trial? In CANAL, you saw the most AEs were showing up in the week one and kind of decreasing as patients are longer in their treatment, I mean, in their treatment period. How do you think it will be in RCC? I think this is a mixed agonist-antagonist opiate-class drug. I think that initial exposure to the drug might cause some of the adverse events. I think that we can get around some of those things at the lower dose and dose escalation periods using a little bit of titration, nighttime dosing, and get people used to the product. I think that there are ways that we can mitigate some of those effects going forward with what has been decades and decades of knowledge about inducing tolerability with titration-type periods for drugs like opiates. I think we could definitely capitalize on that to reduce that early impact. I think one of the clear things coming out of our dataset here is that the effects that we have are broad across our dose range, starting with the 27-milligram b.i.d. dose. There clearly is a great finding here in that we see very dramatic and very large effects with these lower doses. I think as we could take all the data in perspective, look at all the PRO data, all the secondary endpoints, we're seeing a consistent pattern across doses right now. As we put all the data together, we'll evaluate what the most effective part of our dose range is. Obviously, going lower is better. I think that can also have an overall effect on the tolerability going forward. I think your question is really about how do we help patients sort of get on drug and tolerate it better. I think that there are well-known and characterized ways we can do that through titration, starting off with nighttime dosing, etc. Thanks for that. I have a quick follow-up. This is probably better for Professor Smith. While unlikely, if Haduvio does receive a schedule 4 or 5 scheduling, to what extent is that a roadblock for using this drug in RCC patients? Can somebody explain to me what a schedule 4 or schedule 5 is because I'm not familiar? Key practices in the U.K., Debanjana. What it means here, so morphine is schedule 2. Jackie, schedule 4 and 5 are things like tramadol or sleep aids, low likelihood of abuse, low likelihood of addiction. I guess the question is, if you were practicing and there was some level of scheduling, would that deter you with these type of RCC patients? It wouldn't deter me, no. As I think I've hinted at already, in the U.K., we are using low doses of morphine already in our severe patients, which is an unlicensed drug and that does have significant abuse potential. What we do is we have to follow the patients up carefully and keep a close eye on them. No, if it were scheduled in a lower category, I would probably find that easier than what I almost certainly find that easier than what I'm managing at the moment with these most severe patients. That's very helpful. Thanks. Thank you, Debanja na. The next question comes from Mayank Mamtani with Leerink Partners. Please go ahead. Good morning, team. Congrats on the results, and thanks for taking our questions. Maybe first one for Dr. Smith. Could you maybe touch upon why the moderate cough subgroup ended with maybe a slightly lower sample size? I believe there was an expectation of having balanced recruitment across moderate and severe subgroups. I was also thinking, given the execution here, specifically in the severe cohort, what would you think is the expectation on IPF chronic cough study that's ongoing? I'm thinking, in particular, the placebo response where you saw a decrease. It was 10% relative to, I think, 25% that was seen in CANAL. If you could comment on any execution-related pieces, implementation of the lead-in period that was helpful and also relevant to CANAL. I have a quick follow-up. Jackie, I'm laughing because I remember asking you this very question a few months ago. If there's so many moderates, why can't we find them? You can tell everybody what you told me at the time. Yeah. I am very keen on the moderate patients simply because there are an awful lot of those patients in our clinic, and I think they need some treatment. It can be slightly trickier finding people who just fall between two specific cough counts. I guess the other thing I would say is that when you are recruiting for clinical trials of novel therapies, and for certainly a first trial like this where there's no track record, you don't know whether it's going to work or not, there's always a tendency for your most severe patients to put their hands up to be in these studies. That is not to say that the patients with the more moderate cough frequencies don't deserve treatment and would not benefit a great deal as well. Jackie, any comment on the 10% placebo-adjusted rate? I know crossovers tend to be lower, but where does that stack up in sort of the trials you've seen? I mean, I do think part of the trick here is picking the right sites and getting the right patients, which clearly you helped guide us towards. Maybe you can comment on that as well. Yeah. No, we typically see much less in the way of placebo effects in these crossover trials. I would say it's something that, again, has evolved over time. With the very first studies we did, we practically saw zero. It's more typical now to get small placebo effects like this, and the sort of 2%-10% is not unusual at all. It's the kind of order of magnitude of change in cough frequency that patients don't really notice, in my experience. The changes of plus or minus 10% are not, and it's not really a noticeable effect in terms of people thinking that they've improved, if that helps to put it in context a little. Thank you. It's. Keep it short, Mayank. This is your third question. I'm counting, buddy. Yeah. I'll keep it very short. What additional PROs are of significance? We hear regulators caring about a bunch. What additional ones would you report at future medical meetings, and which ones should we be on the lookout for, the conferences in spring or summer? Thanks for taking our questions. We got some areas. Yeah. You wrote the protocol, so you're a good one to answer this. I absolutely hear what you're saying about the PROs. The FDA have not been terribly keen on the PROs we've been using. I think it's important not to just drop them, though, because they do help us benchmark against the studies that have been done previously. The other thing I would say is the particular position that we found ourselves in with Gefapixant and the FDA was leaning heavily on the PROs because their question was very much for what was a big reduction in cough from baseline, but a small reduction over placebo was, was that a meaningful effect? That's where you have to start to lean on your patient-reported outcomes to say whether this was meaningful or not. Some of the PROs were developed a long time ago prior to FDA guidance, and things like the VAS have never been perhaps fully validated to FDA standards. I would not chuck them out. I think that if you were to get a much bigger difference over and above a placebo effect, then I think you are relying less heavily on the PROs. If you want to ask me what to look out for, I am slightly biased because I have been involved in the development of this, and it is Imran Satya who has led the development of it, who was my previous PhD fellow. They have developed something called the McMaster Cough Severity Questionnaire, which they have developed to FDA standards and are starting to validate now. I like the look of the items in that one. I think the sort of severity measures, as opposed to, say, the Leicester Cough Questionnaire that leans to more quality of life, I think severity measures are more acceptable to the FDA. They don't have these downstream effects that the FDA is less keen on. They're much closer to actually capturing the severity as perceived by the patients. Hopefully, that helps. Yes, it does. Thank you. Thank you, Jackie. Imran was our lead enroller in this study, so very involved. We have three more people in the queue. If you guys could get your questions in, keep them to one each, then we'll get everyone off by 9:25. The next question comes from Brandon Folkes with Rodman & Renshaw. Please go ahead. Hi. Thanks for taking my question. I'll keep it to one. Congratulations on the really good data. Thank you very much. Maybe just from me, just given the strong data in the lower doses, how should we think about the potential widening of the population regarding inclusion/exclusion criteria in the go forward studies? In particular, with regard to sleep apnea patients in later stage trials? Without asking a second part, if Farrell has anything to add in terms of how he's thought of this patient population in this commercial assessment, feel free as well. Thank you. I'll comment quickly on the low dose and how it relates to inclusion/exclusion criteria. I don't think that those are actually related. I think the low dose results in this trial really are encouraging us for thinking about our dose range, commercial doses, clinical doses, etc., going forward. I think the key to running effective trials and successful trials in this space is really controlling the patient population and the inclusion/exclusion criteria. I think those are kind of separate items in my mind. I think the real key here is that we have a very strong trial. This is a crossover design. We need to convert this into a parallel group design to do more formal dose ranging. It's all about the patients, and it's all about the centers, and it's about making sure that we have the right patient involved in the trial. I think inclusion/exclusion is really not influenced by the dose here. It's influenced by what we see in the total dataset and talking with experts like Jackie to make sure that we still have the right patients in these trials. Yeah. Brandon, just a quick comment commercially. I think it's more about the rapid and broad effect that we saw within this data point and what that does in terms of a payer and prescriber environment. It changes the benefit risk for them because they will know if a patient is successful on therapy in a very short period of time and don't have to take that additional length of time in order to make that assessment. Thank you. Brandon, thanks for the question. The next question comes from Oren Livnat with H.C. Wainwright & Co. Please go ahead. Thanks for taking the question. I guess James just did touch on wanting to do more formal parallel arm dose ranging trials. If I may ask, if the phase II-B for trial study shows similar efficacy in the lowest dose range, which I believe is the same as the range you tested here and saw early efficacy, is there any possibility that you could say, "Hey, we've already got formal dose ranging and a good view on efficacy there. Why don't we, as we move forward in pivotals, potentially with IPF, also go right into phase III with RCC?" Is that potentially on the table? Can you just remind us what's going on with the IPF phase I physiology study? Any progress there and what dose range you're doing? I know that's two questions. I apologize. It's okay, Oren. Let me take the first question. These are two very different populations, IPF and RCC. From a strictly regulatory requirement, we are obligated to do a definitive dose ranging study that will be a parallel group design like we're doing with Coral right now. I do think that we need to do that with RCC population. This crossover design is very, very useful but does not really answer the question about what our effective doses are in a longer-term study and a study where we're not confounding dose and time together. I think we do need to do that study. It is a regulatory requirement to do a definitive dose ranging study of a parallel design. Thanks. The second part of your question, Oren, I'm sorry, was what? Oh, just any progress, yeah, on IPF phase I and what dose range you're studying there. Oh, yeah. Right. Yeah. We are moving along with that trial's in progress. We are using the same dose range that we've used in this trial. Thank you. Great. The final question? The final question today comes from Kaveri Pohlman with Cowen Street. Please go ahead. Yeah. Good morning. Congrats on the results, and thanks for taking my question. Can you provide any insight into what kind of treatment duration patients will have? If there's any way to determine that through clinical trials, are there any plans for open-label extension of this trial afterwards or any subsequent trials with longer follow-up to establish duration of treatment and response? Would love any perspective from Dr. Smith as well. Thanks. Yeah. I will just mention, moving forward, we need to start doing open-label extension trials. We'll need one year of safety, and that's our intention. Jackie, I'll let you comment on I presume you view this as chronic therapy, but I'll let you answer sort of the thought around that. Yeah. I would. I mean, there's always the possibility that treating people for long periods with medications that are addressing hypersensitivity might have some effect in terms of inducing neuroplastic change and that maybe you can stop treatments in future. We haven't seen any evidence of that so far. Yeah, I'd very much view this as a long-term therapy. I would certainly expect this to be efficacious as a long-term therapy as well based on our experiences with the P2X3 antagonist and with low-dose morphine clinically. Thank you. With that, I think we'll wrap up Q&A. I've got just a couple of closing remarks. I want to thank everyone for joining the call. I especially want to thank four or five of our investigators who I can see have joined the call. Thank you for your excellent execution and guidance during this. We look forward to working with you going forward. This was an important trial for us. We are really happy to report out these results. We are equally looking forward to the IPF results coming in just the next few months. We're available after this call for any follow-ups you may have. Just send Lisa or me an email, and we'll get you scheduled and talk with you. Thank you, everyone, for your time. The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.