Trevi Therapeutics, Inc. (TRVI) Earnings Call Transcript & Summary

Good morning, and welcome to the Trevi Therapeutics webcast presenting the top-line results from the Phase 2a RIVER Trial of Haduvio in patients with refractory chronic cough. [Operator Instructions] Please note, this event is being recorded. Various remarks that management makes 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's 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 2a 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. Jim 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 coughs. 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 Jim 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 7 at the 27-milligram dose, and it was supported by the patient reported outcomes or PROs that were included in the top line data received to date. Our 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 copper 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 coughs. This disease has a significant impact on patients' lives, who often suffer for 8 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 capaagonist and new antagonist or CAMA, 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 afference signaling independent of the initial trigger, which can be caused by multiple receptors, whereas other therapies only target 1 single peripheral receptor. We believe it is the link of the mechanism to the full cohort 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 Jim 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 NAL ER for patients with refractory chronic coughs. Let me review the study design and objectives with you, and then I will go into more detail on the end points. This was a randomized, placebo-controlled, 2 treatment period crossover study in patients with refractory chronic cough, which includes patients with unexplained chronic cough. The primary endpoint of the study was the relative change from baseline and 24-hour cough frequency reported as coughs per hour at day 21 for NAL ER 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 cough per hour and those with baseline cough counts of 10 to 19 coughs per hour. This was a 2-period crossover design with a 3-week washout period between them. This 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 7 days and objective cough count and secondary endpoints were assessed on day 7, while on the 27-milligram BID dose, day 14, while on 54 milligrams BID and day 21 at the 108-milligram BID dose. Cough was measured by objective cough count monitoring using the VitaloJAK device, patients reported outcomes were captured as secondary end points. 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 2/3 female and 1/3 male with an average age of 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 1 dose of study drug and have objective cough count data on both baseline and day 21 and in at least 1 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-milligram BID dose was analyzed by a mixed-effects repeated model, otherwise known as MMRM. We are very excited that the trial achieved this primary efficacy endpoint. NAL ER 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 on NAL ER at the 108-milligram BID 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 7 with dosing at 27 milligrams BID. Increasing the dose to 54-milligram BID and testing on day 14 also showed a similarly large and statistically significant cough reduction. The magnitude of effect for the 27-milligram BID and 54-milligram BID doses was similar to that on with the primary efficacy endpoint at day 21 at the 108-milligram BID dose highlighting the broad and significant reduction in cough frequency across our entire dose range. This slide shows the effects of NAL ER on 2 different cough frequency populations. As previously shown, the 108-milligram dose produced a statistically significant and large reduction in 24-hour cough count. Importantly, this slide shows that NAL ER 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 to 19 coughs per hour with placebo-adjusted changes of 51% and 57%, respectively. This large effect of NAL ER in the 10 to 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 2 different cough frequency populations described in the previous slide. There was a similar reduction in cough frequency starting at 27 milligrams BID up to and through the 108-milligram BID dose for patients with 10 to 19 coughs per hour and greater than 20 coughs per hour. This again shows the consistency of the performance of NAL ER across these 2 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 NAL ER 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 BID dose patients achieved this clinically meaningful level of cough reduction. As you look at a more stringent threshold, a 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 a 75% reduction in 24-hour cough frequency highlighting the strength and magnitude of the effect of NAL ER on cough. We are able to share with you 2 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 CS VAS is a 0 to 100 scale, where 0 is no cough, and 100 is worse cough. There is a clear improvement in patients' perception of severity of their cough, starting at the 27-milligram BID 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 CS VAS Selectively, 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 NAL ER 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 represent 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, some less dizziness and headache. The majority of the AEs reported were mild to moderate in severity. 6 patients experienced Grade 3 AEs with 4 nalbuphine arm, the NAL ER arm and 2 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 NAL ER. In summary, NAL ER achieved the primary endpoint in this Phase 2a 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 NAL ER. There were consistent effects across all doses and significant effects on cough frequency and other end points occurred as early as 7 days with the 270-milligram BID dose. Consequently, we are very happy with the strong results of NAL ER in this study and look forward to discussions with the FDA in further exploring the potential of NAL ER to help patients with refractory chronic cough. With that, I'll turn it back to Jennifer.

Thanks, Jim. 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 prepare 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 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% to 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 Jim 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 loan 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 coughs. 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 IPS 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 a strong evidence to support this commercial strategy. This RIVER trial is the first of 2 main data readouts from Trevi in the upcoming months. We expect to have the top line results from our Phase IIb CORAL trial in IPF patients with chronic cough in the second quarter. It has been very energizing for our team, reading out 3 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 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, 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 coughs 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 queue the questions.

[Operator Instructions] The first question today comes from Annabel Samimy with Stifel.

Congratulations, everyone, on some great data. I guess 1, 2-part for me, actually. Are you surprised by the greater effect in the moderate population given how hard to treat that population has been? And 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 the...

So Jim, why don't you give your answer around the first part about were you surprised? And Jacky, I'd also like you to weigh in as you've seen sort of all the data about a little larger effect in moderates. So Jim, go ahead and give your perspective.

Thanks. I think, if 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 to 19 or moderate cough group, I think, reinforces the fact that we have a broader effect on clock by our mechanism of action. So 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 Jacky love your opinion.

Thanks. No, I would agree with that completely. I think -- so I'm 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's quite a different mechanism from the P2X3 antagonist, where we're very much talking about locking P2X3 receptors. We believe in the periphery that are responding to ATP being released. And so 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. So I would also say it's great news for our patients because we need drugs that are going to be effective for patients with more moderate cough frequencies, not just a very severe group.

And the second part of your question, Annabel, I'll sort of start with it from a business perspective, and Jim certainly chime in, which is since we work in this broader population, can we run larger trials. I think the advantage we have, Annabel, 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 [ Alzheimer ] trial. We'll, of course, have a floor around minimum cough levels that make sense. But we don't have to try to only recruit from that small severe group. So I would hope that means we can recruit a trial that's much more representative of the population can go quicker and get done. So 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. Jim, anything -- any color you'd like to add that may develop?

Just a 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. So 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.

The next question comes from Serge Belanger with Needham & Company.

I'd also like to offer my congrats on these nice results. I guess 1 question maybe for Farrell. Regarding the market opportunity for RCC, I think, on Slide 24, it was highlighted that there's 2 million to 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 treatments?

Yes. Thanks, Serge. When we look at our market opportunity, as you know, this is a fairly large market, a 2 million to 3 million addressable patient population. But when you start looking at the treatment failures, and I'll just break down the market at a high level, about 1/4 of the market are those severe patients, about 50% -- less than 50% of that market are those moderate patients, where nothing has really proven to work. So that's what opens up the addressable patient population. Those who are diagnosed today and are currently uncontrolled on these off-label treatments represents about 70 -- call it around 70% of the market today. So the nice thing is that these patients will not only be available to us, right, 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.

The next question comes from Ryan Deschner with Raymond James.

Congratulations on the data set here. Given the strong placebo deducted signal in the state that does this change how you're looking at indications you might potentially launch into next like [ COPD ] cough other on-IPF ILDs and post-viral cough?

Congrats, and thanks for the question. We have looked at other things as we sort of signal to investors, obviously, IPF is our lead. This RCC data is very supportive of us moving ahead here. We are also doing some work, Carol and Jim's teams are looking at the opportunity in other interstitial lung diseases, which are closely related to IPF is just a big portion of the ILD. I think beyond that, as a company our size, those are all 3 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. So we will stay focused in those 3 indications and think they're doable for us from a development perspective. And I also think we have a commercial plan on the table that's executable by -- in a specialty model.

The next question comes from Leland Gershell with Oppenheimer.

Clearly terrific data here. One from us, although probably could benefit from both management and Dr. Smith. I wanted 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 conditions. So I guess, Jennifer, would 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 that you would need to do additional studies and/or get any type of label expansion for ILDs? And then, I guess, related to that, Dr. Smith, would you be willing to try Haduvio presenting it's approved in any variety of costs that may be due to some of those other rare conditions in the absence of either some sort of label or data supporting?

Yes. Thanks, Leland, for the question. I'm going to let Jim answer the regulatory side here. I know where he's going to come out, but I'll let you answer it and then let Jacky, I'm sorry, your second half.

I think it's a 2-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, Jacky, 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 it's going to work in that space. So I think it's a physician, patient decision to use a drug that is not currently on label. But I think 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. But I think the rest of it is more -- and the rest of your question is more in regards to practice.

Jacky, do you want to take that?

Yes, absolutely. So 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 don't 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. And 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's causing it that maybe the existing treatments are not working so well. I think that'd be uneasy unless they really have that sort of hypersensitive phenotype. So unless they had things in common with the kind of patients that we've been putting into the RIVER trial. And when you see those features very much occur in a lot of the patients with pulmonary fibrosis too. So 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. So 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. And you'd want to really pick the rack phenotypes that are going to respond.

And Jacky, maybe you could just comment a minute, I'm sorry. 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. And so think just maybe, if you could just expand on that a little bit and how you think maybe IPF, ILD, RCC could connect.

Yes, absolutely. So the interesting connection here is the kind of ways that patients describe their symptoms. So 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 trigger, they'll say that anything that moves the larynx around is likely to make them cough so talking, laughing, singing, eating. You don't see the precise pain triggers in patients with IPF, but there are a lot of similarities in there. So this sort of combination of coughing to relatively innocuous triggers and having lots of threat sensations is the sort of clinical picture we recognize as being a sort of hypersensitive date in terms of the neuronal pathways that control cough. And I think that the group of patients that we would have -- we have confidence that these sorts of treatments are effective in.

The next question comes from Faisal Khurshid with Leerink Partners.

I want to talk about the tolerability profile a little bit and would also love Dr. Smith's opinion here. So first one, just more of a technical question. Do you have the data split by treatment period? And is there a chance the distinct tolerability profile of the drug that might have unblinded the study to some extent? Or how do you think about the risk of that? And then I have a follow-up as well.

Thank you. So we don't have all the data in yet for the full analysis set. But we don't have it broken down by treatment period at this point in time. In regards to your question about unblinding, I think that crossover design with a drug that is essentially active, of course, there's possibilities of unblinding, especially for using totally subjective endpoints. I think it's -- in this case, the crossover design was an incredibly powerful design that has been used before that really is informative to us. But when you look at our primary efficacy endpoint, it's objective cough count through a monitor I think if the patient was willing to have a placebo effect to really effectively reduce their cough count, they wouldn't need medication, right? So 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. But Jacky, yes, I would love your perspective on that.

Yes, sure, happy to chip in. So as with any trial design, there's a bunch of different ways do this. But 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 antagonist and particularly gefapixant caused lots of tastes. And I guess what I would say is despite our best efforts to sort of link taste to treatment effect, you really don't see much difference between those patients with and without the AEs in those studies. So I would be very surprised, if all we're seeing here is an effect based on a degree of blinding. And then 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 unblinded because patients notice -- keep the study blinded rather because patients noticed they're feeling a lot better. And there's not a lot we can do about that.

And maybe just one final one, I'm sorry, is 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 data sets. But 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. The -- at the 108 dose, the effects in period 1 and period 2 look pretty comparable. So I'm not sure that we're seeing from that perspective, any kind of a carryover or loss of effect in 1 treatment period or another. So 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 and the overall effects, I don't think we're seeing that.

Got it. That's super helpful. Just a quick follow-up. Can we talk a little bit about the tolerability profile, sorry, more generally, and Dr. Smith, I'd love here, if you think this drug is easy to use or not in this patient population?

So I think this drug is easy to use in this population. I haven't seen all the detailed data yet as you might imagine. But my understanding from my involvement in the first IPF study is that a lot of these side effects tend to come as patients that start the dose and settle with time. And chronic cough patients are very tolerant of things like that, if they know what to expect. And 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 high doses. But 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, then chronic cough patients are very willing to do that for a good antitussive effect.

The next question comes from Deb Chatterjee with Jones Trading.

So just a follow-up actually on Faisal's question. How do you think the AE profile will evolve, if you test lower notice in a potential Phase IIb or Phase III trial. In Canal, you saw like the most AEs were like showing up in the week 1 and kind of decreasing as patients are longer in the treatment -- I mean, in the treatment period. How do you think it will be in RCC?

So I think the -- this is a mixed agonist antagonist, opioid class drug. And I think that initial exposure to the drug might cause some of the adverse events. And 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. So I think that there's 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 opioids. So I think we could definitely capitalize on that to reduce that early impact. I think one of the clear things coming out of our data set here is that the effects that we have are broad across our dose range starting with the 27-milligram BID dose. They're clearly is a great finding here in that we see very dramatic and very large effects with these lower doses. So I think as we could take all the data in perspective, look at all the PRO data, all the secondary end points, we're seeing a consistent pattern across doses right now. But as we put all the data together, we'll evaluate what the most effective part of our dose range is and obviously going lower is better. And I think that can also have an overall effect on the tolerability going forward. But I think your question is really about how do we help patients sort of get on drug and tolerate it better. And I think that they are well known and characterized ways we can do that through titration starting off with nighttime dosing, et cetera.

I have a quick follow-up. This is probably better for Prof. Smith. So while unlikely if Haduvio does receive a Schedule IV or V like scheduling, to what extent is that a roadblock for using this drug in RCC patients?

Can somebody explain to me what Schedule IV or Schedule V is because I'm not familiar.

A key practices in the U.K., Debanjana. It's -- what it means here, so morphine is Schedule II, Jacky, Schedule IV and V are things like Tramadol or sleep aids, low likelihood of abuse, low likelihood of addiction. So 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 that already in the U.K., we are using low doses of morphine already in our severe patients, which is an unlicensed drug and that have significant abuse potential. What we do is we have to follow the patients up carefully and keep a close eye on them. So now that if it were scheduled in a lower category, that would probably find that easier than what almost certainly find that easier than what I'm managing at the moment with these most of their patients.

The next question comes from Mayank Mamtani with B. Riley.

Congrats on the results. Maybe first one for Dr. Smith. Could you maybe touch upon why the moderate curve subgroup? And maybe a slightly lower sample size. I believe there was an expectation of having balanced recruitment across moderate and severe subgroups. And then I was also thinking, given the execution here, specifically in the severe cohort, what would you think is the expectation on IPF chronic study that's ongoing. And 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. And then I have a quick follow-up.

Jacky, I'm laughing because I remember asking you this very question a few months ago, if there are so many moderates, why can't we find them? So you can remember what you told me at the time.

Yes. So I'm 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, but it can be slightly trickier finding people who just fall between 2 specific cough counts. And I guess the other thing I would say is that when you are recruiting for clinical trials of novel therapies and -- 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. But that is not to say that the patients with a more moderate cough frequencies don't deserve treatment and would not benefit a great deal as well.

Jacky, 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 -- the trick here is picking the right sites and getting the right patients, which clearly you help to guide us towards. But maybe you can comment on that as well.

Yes. 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. It's very first studies we did, we practically saw it was 0. It's more typical now to get small placebo effects like this and the sort of 10% is not unusual at all. And it's the kind of order of magnitude of change in consequence that patients don't really notice in my experience. The changes of plus or minus 10%. And it is not really a noticeable effect in terms of people thinking that they've improved, if that helps to put it in context a little.

Keep it short, Mayank we're getting. This is your third question, I'm counting buddy.

Yes, I'll keep it very short. What additional PROs are of significance, we hear regulators carrying about a bunch. So what additional ones you would report at future medical meetings and which ones should we be on the lookout the conferences in stream or summer?

You wrote the protocol, so you're a good one to answer this.

So I absolutely hear what you're saying about the PROs. So the FDA has 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 PRO, because their question was very much for what was a big reduction in customer baseline, but a small reduction over placebo which was a meaningful effect, and that's where you have to start to lean on your patient-reported outcomes to say whether this was meaningful or not. And some of the PROs were developed a long time ago prior to FDA guidance and things like the VA have never been perhaps fully validated to FDA standards. So I wouldn't took them out. I think that if you were to get a much bigger difference over and above a placebo effect, then I think you're relying less heavily on the PROs. If you want to ask me 1 to look out for, I'm slightly biased because I've been involved in the development of this then it's Imran Satia,who's led the development of it, who was my previous PhD fellow. But they've developed something called the master cost severity questionnaire, which they have developed to FDA standards and are starting to validate now. And I like the look of the items in that one. I think there's sort of severity measures as opposed to, say, the lesser cough question as that leads to more quality of life. I think severity measures are more acceptable to the FDA that they don't have these downstream effects that FDA less keen on them or they're much closer to actually capturing the severity as perceived by the patients. Hopefully, that helps.

Thank you, Jacky. And Imran was our lead enroller in this study, so very involved. We have 3 more people in the queue. So 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.

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 study? And in particular with regard to sleep apnea patients in later-stage trials? And then without asking a second part, if Farrell has anything to add in terms of how he thought of this patient population and this commercial assessment, feel free as well.

I'll comment quickly on the low dose and how it relates to inclusion/excluding 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 dose, et cetera, 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. So 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, but 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. So I think inclusion/exclusion is really not influenced by the dose here. It's influenced by what we see in the total data set and talking with experts like Jacky to make sure that we still have the right patients in these trials.

Yes. And 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 the 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.

The next question comes from Oren Livnat with H.C. Wainright.

I guess, Jim, just did touch on -- wanting to do more formal parallel arm dose-ranging trials. But if I may ask, if the Phase IIb floral study shows similar efficacy in the lowest dose range, which I believe is the same as the range you tested here and to our 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 Pivotal potentially with IPF also go right into Phase III with RCC? Is that potentially on the table? And 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? And I know that's 2 questions, I apologize.

Let me take the first question. These are 2 very different populations, IPF and RCC. From a particularly a 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 doesn't really answer the question about what our effective doses are in a longer-term study and a study where we're not confounding dosing time together. So I think we do need to do that study, and it is a regulatory requirement to do a definitive dose-ranging study over a parallel design.

And the second part of your question, Oren, I'm sorry, was what?

It was just any progress, yes, on IPF Phase I and what dose ranges are studying there?

Yes. So we are moving along with that trials in progress. We are using the same dose range that we've used in this trial.

The final question today comes from Kaveri Pohlman with Clear Street.

Congrats on the results. Can you provide any insight into what kind of treatment duration patients will have? And if there is 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?

Yes. I will just mention, moving forward, we need to start doing open-label extension trials. We'll need 1 year of safety, and that's our intention. But Jacky, 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.

Yes, I would. 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 the future. But we haven't seen any evidence of that so far. So yes, I'd very much view this as a long-term therapy. And 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.

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. And I especially want to thank 4 or 5 of our investigators, who I can see have joined the call. Thank you for your excellent execution and guidance during this, and we look forward to working with you going forward. So it's 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. And we're available after this call for any follow-ups you may have. Just suddenly serve me an e-mail and we'll get you scheduled and talk with you. So thank you, everyone, for your time.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.