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

Good morning, and welcome to the Trevi Therapeutics webcast presenting the topline results from the Phase IIb CORAL trial of Haduvio for the treatment of chronic cough in patients with idiopathic pulmonary fibrosis. [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 by 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. Thank you for joining us to review these exciting positive topline results from our CORAL Phase IIb trial of Haduvio in patients with IPF chronic cough. I feel like we are reporting the final piece of the data trifecta that has occurred at Trevi over the past 6 months with positive results in 3 studies, human abuse potential, refractory chronic cough and now in our lead program, treating chronic cough and IPF. Times like these make a fun to work in biotech. We are excited to share the robust 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 Phil Molyneaux. Professor Molyneaux is a leading key opinion leader in the IPF ILD and chronic cough space and a Professor of Respiratory Medicine at the Royal Brompton Hospital in London. He runs a multidisciplinary research team focusing on interstitial lung disease and pulmonary fibrosis. He was a principal investigator for our CORAL trial and the U.K. trial lead investigator and has continued to provide his deep expertise to Trevi's development program in IPF chronic cough. Thank you, Phil, for joining us. Before diving into the results shown in graphs and P values, I wanted to take a step back and bring the voice of the patient to the forefront. When we talk to patients about the management of their IPF, we continually hear the challenges these patients face in controlling their cough. IPF is a terminal disease and chronic cough can impact nearly every aspect of these patients' daily life. You can see on this slide some of their direct quotes. The challenge for these patients is there is -- there are no approved therapy for the cough and the available antifibrotics do not improve their cough or quality of life. Even in the recent data presented on the new antifibrotic by BI put out ATS, we once again saw that patients with IPF and PPF saw no benefit in their cough, consistent with the 2 antifibrotics on the market. These quotes remind us of the high remaining unmet need that patients with IPF face when experiencing chronic cough, and how we must do better to innovate to improve on this key comorbidity that is debilitating and disruptive to patients' day-to-day lives. A quick snapshot of the disease of IPF and the role chronic cough plays. We estimate there are currently about 140,000 patients with IPF in the U.S. and the number continues to grow due to increased incidence of IPF earlier diagnosis and increased use of antifibrotics extending the lives of these patients. Up to 80% of IPF patients have reported a chronic cough and have an average life expectancy of 3 to 5 years from diagnosis. There are no FDA-approved therapies for the treatment of chronic cough in patients with IPF. On the right-hand side of this slide, you can see in a large U.S. patient registry study that better cough quality of life of patients is correlated with better outcomes in respiratory hospitalizations and death, and there is some evidence that cough may be profibrotic in these patients. Okay. Now for the -- slide. I will review at a high level the trial results before Jim provides more detail and color. I want to remind everyone that these are the first positive results in a Phase IIb parallel group trial for the treatment of chronic cough in patients with IPF. No other program has made it this far. The results are clear in this trial with a dose-related response on the primary endpoint and the secondary endpoint aligning. First, as you can see with our primary endpoint, we saw a dose-related effect on the relative change at 6 weeks from baseline in 24-hour cough frequency ranging from 60% at the high dose group to 48% at the low dose group. All 3 doses were statistically significant and the highest dose group of 100 milligrams BID translated into a 43% placebo-adjusted difference. The objective cough data were supported by the patient reported outcomes, including topline data, which related to both the patient's perception of cough frequency and severity. In the CORAL trial, we consistently saw the rapid onset and broad effect of Haduvio. Based on the objective 24-hour cough monitor, cough frequency was reduced as early as week 2, which was the first time point measured. We also saw a majority of patients on Haduvio achieve a 50% or greater reduction in their cough frequency. This is consistent with what we have seen in our previous trials across chronic cough indications and confirms the strength of the data in this parallel arm design. I was also very pleased to see that overall discontinuations were low and were pretty evenly split between placebo and drug with placebo being 5% and the Haduvio dose group in total being 5.6%. As the drug advances in development, we have been able to optimize the titration schedule and educate the patient to better move through the early tolerability AEs, which are primarily grade 1 and 2 events. It also helps when the cough response is so dramatic early on. Jim will review the top treatment-emergent AEs, but the adverse event profile in this study was consistent with other studies we've conducted with Haduvio. I'll close my upfront comments reminding everyone of our unique mechanism of action for Haduvio. Haduvio targets a cough reflex arc both centrally and peripherally as a kappa agonist and mu antagonist, which are opioid receptors that play a key role in controlling chronic off. We believe it is engagement of the mechanism along the full cough reflex arc from the lung to the spinal cord up to the brain that provides the robust response you see in these results. I'll now turn it over to Jim.

Thanks, Jennifer. Good morning. I am very happy to share with you today the findings from CORAL, our Phase IIb trial investigating the effect of NAL ER Haduvio in patients with IPF who are experiencing chronic cough. The results show significant improvement in both objective and subjective measurements of cough frequency and cough severity in these patients following treatment with NAL ER. The parallel group design trial replicates and expands on the findings from CANAL, our previously reported Phase IIa crossover design study, which showed the potential benefit of NAL ER on cough in patients with IPF. Since the Phase III trials will utilize the parallel group design, the results from CORAL will directly guide power and considerations and design efficiency for the Phase III program. 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 double blind parallel group dose-ranging study assessing 3 doses of NAL ER and placebo on cough in patients with IPF. The 3 doses of NAL ER were 27 milligrams twice daily, 54 milligrams twice daily and 108 milligrams twice daily. Going forward, twice daily dosing will be referred to as BID. For entry into the study, patients were required to have a diagnosis of IPF and a history of chronic cough that lasted at least 8 weeks prior to screening. Also, in order to ensure a meaningful level of cough severity for entry into the trial, patients had to have a score of at least 4 on a scale of 0 to 10 and on a cough severity patient-reported outcome scale at both screening and baseline time points. Since these are patients with significant lung disease, background antifibrotic therapy was allowed in the trial. The primary endpoint of the study was the relative change from baseline in 24-hour cough frequency reported as cough per hour for NAL ER compared with placebo at week 6. Secondary endpoints available for the topline data analysis included 24-hour cough frequency responder analysis as well as patient-reported outcomes for cough severity and cough frequency. The study design included an initial 2-week dose titration period followed by a 4-week fixed-dose treatment period. All patients initiated dosing at 27 milligrams. Titration to 54 milligrams BID occurred at day 7 for the 54-milligram BID and the 108-milligram BID dose groups and the final titration for the 108-milligram BID dose group occurred on day 14. Dosing was fixed for all dose groups starting on day 14. Cough was measured by the injective cough monitor using the VitaloJAK device at baseline, week 0 and at weeks 2, 4 and 6. The primary efficacy endpoint was the relative change from baseline and the 24-hour frequency compared to placebo at week 6. Patient reported outcomes were captured as secondary end points. There was a total of 165 patients randomized into the trial and the baseline characteristics of the patients are in line with our previous IPF cough trial and what we would expect from patients with IPF. The study population was approximately 3/4 male with an average age of around 70 and a mean 24-hour cough frequency between 24 and 31 cough per hour ranging across the dose groups. This translates to approximately 600 to 750 coughs per day. Patients had reported that, on average, they experienced chronic cough for a little over 4 years. About 80% of the patients were taking an antifibrotic drug for the treatment of their IPF. The primary efficacy endpoint of relative change in 24-hour cough frequency assessed by objective cough monitoring at week 6 was analyzed by a mixed-effects repeated model, MMRM. The primary analysis was conducted on a modified intent-to-treat population, MITP, which consisted of all subjects who were randomized and received at least 1 dose of study drug or placebo. One patient from the placebo group was an extreme outlier for their effective cough data at week 6 and was excluded from the primary efficacy analysis. Inclusion in this patient would have resulted in an increased cough frequency from baseline in the placebo group, which would result in a much greater placebo-adjusted difference for NAL ER. So we determined with our statisticians that it was most appropriate to exclude this patient from the analysis for the 24-hour cough frequency. NAL ER showed a dose-related reduction from baseline cough frequency compared with placebo with approximately 48% reduction for 27 milligrams BID, 53% reduction at the 54-milligram BID and 60% reduction at the 108-milligram BID compared to a 17% reduction for placebo. The 108-milligram BID dose represents a 43% placebo-adjusted difference. All the NAL ER differences and 24-hour cough frequency from placebo were statistically significant with P values ranging from less than 0.01 for the 270-milligram BID dose group in less than 0.0001 for the 54-milligram and 108-milligram BID dose groups. This slide shows the reduction in cough frequency by week and shows a rapid reduction in cough frequency for NAL ER across all doses, starting with the first post baseline objective office spend at week 2 of dosing. The magnitude of the reduction from week 2 through the end of the study is steady and persistent, indicating a near maximum once the cough response in NAL ER is evident. Note that statistical analysis depending on these data and is not currently available for these topline results. The next slide shows the comparison of NAL ER with placebo using a responder analysis assessing response rates at different levels of cough reductions. It is widely believed that a 30% reduction from baseline and cough frequency represents a clinically meaningful improvement. As you can see, at least 75% of the patients treated with NAL ER achieved this clinically meaningful level of cough reduction, which was statistically significant from placebo for all dose groups. As we assess a more stringent threshold of 50% change from baseline, approximately 60% to 65% of the patients on NAL ER achieved this response level. All the NAL ER dose groups at this threshold were statistically different from placebo as well. And for the very high bar of 75% reduction in 24-hour cough frequency, we see a dose-related response with the 54-milligram BID and 108-milligram BID dose groups being significantly different from the 5% placebo response rate. 37% and 43% of the patients in the 54-milligram BID and 108-milligram BID dose groups, respectively, achieved this meaningful 75% reduction of cough frequency. We are also able to share with you today 2 of the patient-reported outcome measures that were assessed in the trial and plan for this topline data readout. Other patient-reported measures will be available when full data analysis completed in the near future. The patient reported cough frequency question asked patients over the past 24 hours, how often did you cough. This scale is scored with the patient choosing responses on a 5-point scale ranging from 0 equals not at all to a 4 equals almost constantly. The right panel of this slide shows the separation of responses over time for all the NAL ER dose groups compared with placebo. Statistical analyses across all the time points for these cough frequency values are pending and not yet available. However, we do know that at week 6, the 54-milligram BID and the 108-milligram BID dose groups were significantly different from placebo, but the 27-milligram dose group were not. The left panel shows the relative change from baseline at week 6 for the same patient reported cough frequency scale. The 54-milligram BID and the 108-milligram BID dose groups differed significantly from placebo with approximately 40% relative change from baseline compared to 23% for placebo. For the patient-reported cough severity question, Patients were asked to indicate the severity of cough they experienced over the last 24 hours on an 11-point scale with 0 equals no cough and 10 equals worst possible cough. Patients had an average score of approximately 6 at baseline. The 54-milligram BID and the 108-milligram BID dose group showed a 3-point or greater improvement at week 6 with a statistically significant difference from the placebo group. The 27-milligram dose group showed numerical differences from placebo that were not statistically significant. So for the PROs assessed to date, we find consistent and robust patient perceptions of reduced cough severity and cough frequency, which corroborate and complement the reductions observed with objective cough monitoring. Let's turn our attention to the safety data from the trial. There were no deaths reported in the trial and the serious adverse events that occurred were at a higher rate in the placebo group than in the combined NAL ER dose groups. Discontinuation due to adverse events were similarly distributed in the placebo and active dose groups, which we were very pleased to see. This slide shows the overview of the state data, and as previously mentioned, there were 4 SAEs in the placebo group and 2 across NAL groups. 5% of the patients on placebo discontinued due to adverse events and 5.6% of the patients of any dose group of NAL ER discontinued due to adverse events. The most common adverse events leading to discontinuation were headache, nausea and vomiting. These findings are consistent with our experience with NAL ER in our previous cough trials. This slide displays the common adverse events, defined as greater than or equal 10% in the total active group reported in the trial and include nausea, vomiting, constipation, dizziness, headache, fatigue, somnolence and dry mouth. The majority of the AEs reported were mild to moderate in severity. There appears to be some dose-related increase in some CNS and GI adverse events. But for the most part, the adverse events reported in the trial are typical for this class of drug and are consistent with those found in other trials conducted with NAL ER. In summary, NAL ER achieved the primary endpoint in this Phase IIb study with statistically significant and dose-related reduction and 24-hour cough frequency. This is the first parallel group study to demonstrate a significant reduction in cough frequency in patients with IPF. Patient-reported outcomes and other secondary endpoints assessed in this topline data analysis showed significant results consistently across the 54-milligram and 108-milligram doses and support our belief in the broad effect of NAL ER on cough. Overall safety and the NAL ER dose groups is consistent with our previous cough studies and are consistent with this class of drug. We are very pleased with the outcomes of this trial and look forward to discussions with the FDA in further exploring the potential of NAL ER to help patients with IPF, who are experiencing chronic cough. I will now turn it back over to Jennifer.

Thanks, Jim. As we've looked at the competitive landscape in IPF chronic cough, we continue to believe that we have the potential to be best-in-class and first-in-class. With these parallel arm results supporting the efficacy and safety profile of Haduvio in patients with IPF chronic cough, we move a step closer to making this therapy available to patients. We are planning for this indication to lead our commercial strategy with high unmet need in these patients and no approved therapies, it sets up very favorable specialty commercial dynamics in terms of pricing and field force footprint due to a focused call point in pulmonologists and ILD care centers. From our research, we would expect a rapid uptake in physician prescribing as they don't have any safe and effective therapies that work across patient types for IPF chronic cough. You can see in the middle of this slide the various off-label treatments that are being tried now, none of which work that well. So we believe this is a strong commercial opportunity that can be executed in a highly efficient manner. We have also been thinking about the equally high unmet need among patients with non-IPF ILD chronic cough. IPF sits in the broader category of interstitial lung diseases and represents the largest individual indication. The remaining non-IPF ILD category encompasses over 200 indications and shares a common lung fibrosis with IPS. And because of that fibrosis, these patients have a difficult-to-treat by dry chronic cough. With the positive CORAL results announced today, we are finalizing a protocol to stay Haduvio for the treatment of chronic cough in patients with non-IPF ILD in a basket study and expect to move forward and initiate a study by the end of this year. Our current timelines project these data in late 2026. We will provide more formal guidance around this trial when it is initiated, but we are excited to move into this patient group and potentially double the market size of this opportunity broadly in interstitial lung diseases. So in closing, chronic cough represents a high unmet disease burden in both IPF and other interstitial lung diseases as well as refractory chronic cough and Haduvio is the only investigational therapy to have been shown to work both IPF patients with chronic cough and RCC patients. There are no approved therapies for these indications in the U.S. and a limited development pipeline. This CORAL Phase IIb trial confirms the strong results we previously saw in the crossover designs. We conducted in both chronic cough IPF and RCC, setting us up nicely to design and execute our Phase III program. Finally, our team has been preparing in the background for positive results, and we are ready to move quickly into the next phases of development for each of our programs. Here is a quick list of the catalyst pathway over the next 18 months at Trevi. In the second half of this year, we plan to request an end of Phase II meeting with the FDA to align on the Phase III program in IPF chronic cough. Also in the second half of this year, we plan to initiate a trial in patients with non-IPF ILD chronic cough. In the first half of 2026, we are preparing to initiate the chronic cough Phase III program as well as initiate the Phase IIb RCC trial. In the second half of next year, our timelines project topline data for the non-IPF ILD chronic cough trial. It Is an aggressive but focused plan. We know how to run these trials. They are not large and mostly replicate what we have done to date. We feel confident in our ability to execute, and believe, we have an opportunity to develop a therapy that is very meaningful to patients that are suffering from the disease of chronic cough. With that, Jim and I are finished with our prepared remarks, and now we'll open it up for questions for our broader team. Operator, please go ahead and queue the questions. While the operator is queuing the questions, I would like to ask Dr. Molyneaux to make a few comments about the unmet need of cough he sees in his patients as well as any thoughts on the data. And Drew, I realized I cut off your instruction. So give your instructions and then Phil, maybe you could make a few comments.

[Operator Instructions] And again, back to you, Mr. Molyneaux for your comments, sir.

Thank you very much. And firstly, congratulations, Jennifer to you and the whole team at Trevi. You really outdriven it forward from the first phase, standing into this. What is the first positive Phase IIb study. We can't really overlook that. There have been a number of compounds that have tried to get to this stage and all failed, and this is a really remarkable achievement. I mean if someone who looks after patients and these patients every day, cough is a massive problem, is what the majority of our patients talk about. We historically think about breathlessness, but when you actually speak with patients, they can slow down, they can stop, they can pause none of that helps them with our cough. And cough is a significant problem. Probably 80% to 85% of our patients will report cough, and we know that if you have cough at the time of diagnosis, that's going to plague you for the rest of your disease trajectory. It gives people a worse quality of life. It causes them to stop exercising. It causes them to stop going out. It becomes socially isolating. Post-COVID, cough has a stigma like nothing else. And the patients will often tell me that they can't go out to the house. They can't do the activities they once did, going to the cinema, going to the theater. It's just -- it just ruins everything for them. So with no effective treatments, they are really, really limited. So I really can't underplay the significance to the patients that cough brings. I think when we look at these data, they really are fantastic. We see over 40% overall reduction against placebo. And that number is striking. But when you dive down Jim into the numbers of patients, who've got a 50% reduction and the 75% reduction. We're talking about 65% of patients getting an over 50% reduction in their cough count. That's a massive reduction. And 1/3 are getting over a 75% reduction in their cough counts. I mean these are numbers that are going to translate really well to patients, 50%, 75% reduction in cough counts. Not only that, these are reductions that are coming on in the first 2 weeks of therapy, patients are going to be able to see immediately the benefits of this drug. And we talk about the benefits we have to talk about the potential side effects. I mean we've really well tolerated large numbers of patients here very few discontinuations. So even though we see the expected side effect profile that we know comes with nalbuphine ER, very few numbers of patients discontinued. And for me, that really speaks volumes to, one, how significant the problem is, two, how motivated the patients are, and three, how much they're willing to tolerate to get on to an effective therapy, which they just don't have at this moment in time. So please, cough is a significant problem for our patients. It's a massive unmet need. And these are fantastic data, the first IIb -- positive IIb we've had. So I'm happy to help answer any questions at this point.

Thank you, Phil. That was helpful. We can go ahead and take questions now, Drew.

The first question comes from Faisal Khurshid with Leerink Partners.

So could you provide any initial thoughts on what the Phase III program could look like, including things like what doses are you thinking about moving forward? And also, do you think a 12-week end point would be possible for 1 of the Phase IIIs?

Faisel, Jim here. Thanks for the question. So these data really start our -- the firming of our plans now to the Phase III program. So thanks for raising that. I think the doses -- these are 3 effective doses. We clearly have some dose response here, especially when we look at the secondary end points I think we're going to make some decisions based on the full data set that we're going to see. The question of doses will really be on risk benefit at each of the doses, and we still have more data to come. So if we can stay tuned for that, we'll be able to give more guidance on that once we see the full complete data set over the next few weeks. In terms of the trial duration, we've had a lot of discussions. We believe that something like a 12-week primary endpoint will be a reasonable one and probably one that will sit well with the regulators. But obviously, we need to have that meeting with the FDA, have that discussion on study design, duration, et cetera. So I think you're in the right ballpark when we think about 12 weeks. And once we get all the data in, assess the safety side and assess the efficacy side, we'll be able to make a good plan for the doses we want to bring in. I think it's fair to say we were thinking about 2 doses in the Phase III and a placebo.

The next question comes from Annabel Samimy with Stifel.

Congratulations on the data. So I know you're contemplating the go-forward dose for Phase III, and you talked about the risk-benefit factors. But what are those factors exactly to determine the go forward dose? It does look like there are more As for the 108-milligram versus the 54%, but you've mentioned in the past that more side effects are on initiation of treatment, and I can't help notice the lower-than-expected discontinuation rate. So what else should we be thinking about? And maybe for Dr. Molyneaux, you can describe the experiences in patients who were at the higher dose and whether you see any problem with.

Thanks, Annabel, I'll take the first part of that, and then I'll let Phil respond. So Annabel, I think you're right. I mean, we see things at the 108, we -- maybe we see a little flattening between 54 and 108. We clearly see less adverse events at the 27%. These are things that we need to put in the context of when did they occur? We don't have all the data yet to dig into time course of the adverse events. We know that traditionally, what we've seen here is that with the class of drug that we're talking about, things do usually come in earlier. I think we will be able to look at that. That's going to be a critical factor in weighing in. But I think it is a matter of is there additional benefit of going to the higher dose? Are there advantages going to the lower dose. I'm sorry to put you off, but I do want to see all the data, and I think it's going to be really important. This is probably the most critical question we have going into the Phase III. I think we know how to run the study we'll do a lot of diligence on dose selection. Phil, I'll let you comment on the rest.

Thanks, Jim. And obviously, this is only the topline data, and we haven't been unblinded to individual patient level data to know exactly who is on what drug -- what dose, sorry. Our experience has been that this has been well tolerated as you can see by the topline data doing a number of ways to mitigate the potential side effects, which the study sites will have adopted. That can be translated into clinical practice. And I think the number of sites, the distribution of sites worldwide. This is not just a concentrated effort on 1 or 2 sites with a lot of extra support to get patients through things. This is a package that was put together that has been well executed and has meant that the dropout rates have been low. I think it speaks to the -- perhaps the differences between patients who is refractory chronic cough, and I the different patient demographics, patient population and also the life expectancy and the significant impact that it has on these patients. I think you can look at the distribution of the side effects across the different doses. We can't really interpret anything as Jim says, until we know when it happens. But when patients are getting clear benefit within a 2-week period, I think that's speaking to them that they are then able to see that something is working. And if you know that something is working at that point in time, and you've got a 75% reduction in your cough. And you're more likely to carry on taking the drug, especially if you've got a shortened life expectancy. So I think we have to look at the data that we have in front of us. It's a large patient population. It's geographically diverse across a multitude of sites. So we have to hope that that's the dropout rates we're going to see in this patient population going forward.

The next question comes from Leland Gershell with Oppenheimer.

Good to see the solid data set. A question for Dr. Molyneaux. I appreciate your reflections on the data and your commentary about the unmet need. Just wanted to hear your thoughts with respect to when in the IPF disease continuing this cough really become a problem do the baseline criteria accounts in patients in the oral trial do those represent the types of patients that you'd be using Haduvio, or would you actually look to use it perhaps in those who have milder cough, perhaps with an eye on the potential to improve disease progression.

Yes. So great question. There's probably 2 parts to that. So we know that patients that present with significant cough at the time of diagnosis continued to have significant cough. And that is a problem for them throughout the course of their disease. So we can identify these patients at the time of diagnosis. And if your patient has a significant cough, then you have a period of time to intervene on that. And there's no real reason to wait. These are patients with a life -- average life expectancy at 3.5 years to 5 years. So if you wait 12 to 18 months to start instigating therapy, you've already taken away 1/3 of that patient's remaining life and when you could have improved their quality of life. So I see absolutely no point in delaying intervention. And certainly, our current practice with all of the non-approved and non-licensed therapies start as soon as we see a patient with significant cough. So I see no problem with this being instigated as soon as the patients see and cough is recognized as a significant problem. With respect to the alter disease trajectory, that is something that we simply don't know. The hypothesis being that cough induces stretch, induces TGF beta to release -- could drive the fibrotic process. That is borne out in a number of mouse model, animal models, that paradigm of stretch TGF beta. We don't know what that means for lung function trajectory. And I think as we find effective therapies for patients then following them long term is going to be the only way of knowing that. So I personally look forward to getting an approved therapy that we can give patients in the long term and lock at the outcome because that is a potential that not only could it improve their quality of life, it could be disease modifying as well.

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

I'd also like to offer my congratulations on the data. A couple of questions for Dr. Molyneaux. First, can you talk about the nature of the cough in IPF patients and how it differs from cough you may have seen in patients with COPD and other lung diseases. And then the follow-up to that is, do the antifibrotic treatments have any impact on cough? And if they don't, how do you address the cough issue in IPF patients?

So great questions. IPF cough is more frequent than patients with COPD. So when we look at 24-hour cough count, we see an increase in COPD. We'll see a further step up in cough frequency in patients with IPF. So it's more -- the higher cough rates, not as high as in patients with refractory chronic cough, but certainly in IPF, it's higher than we see in COPD. The cough is slightly different as well, being that it's predominantly daytime, and there's hardly any nighttime cough events in patients with pulmonary fibrosis, which make it slightly different than other cough diseases or diseases where cough is a significant problem. So there are some differences. Antifibrotic agents have not been shown robustly to have any effect on cough frequency. There have been a number of post-hoc exploratory projects and certainly, registry projects come with all the caveats that these pieces of work in tail where there's been a suggestion therapy with some of the antifibrotic agents have approved patient-reported outcomes. But the problem with some of the patient-reported outcomes is the symptom intertwined with things like impact on breathless and other aspects of quality of life that is hard to actually determine whether they've had a significant effect. But there's certainly been no randomized controlled trials that have demonstrated any benefit of cough with the current antifibrotic therapists. So we're present, we're left with no recognized standard of care for cough in pulmonary fibrosis, which means that physician management is very varied from country to country. Some will use antidepressants, or someone who abitriptilib, gabapentin, others will use various opioids, but there is no real guideline or all standard dose for any of these things. It's often a trial and error process, which will take some months. And the normal patient will see a number of escalations or attempted therapies over 18 to 24 months to try and find something that may help them. So as I've dialed -- rewind back to the average life expectancy of 3.5 to 4.5 years, you spent 2 years trying to find something that has a slight impact upon cough, then you've really wasted half of the patient's disease course when you could have had an effective therapy from day 1.

[Operator Instructions] The next question comes from Deb Chatterji with Jones.

Congress on data. So I know there this is 2-week follow-up after you stopped losing in the study. I know that's mainly for safety, but would you be looking at cough as a safety endpoint in those 2 weeks?

We are not looking at cough in that time period. This is mostly a diligence follow-up just to make sure that there's no residual effects. So mostly, we're capturing adverse event data during that time.

Jim, as we go forward in our studies, we intend to measure coughs sort of over the safety time period of the year.

We will. So in an extension trial, we would clearly look at cough and other endpoints as well as safety once we go beyond our primary endpoint, if it is 12 weeks, and we have to go longer, we'll be looking at both safety and efficacy in that extension type trial.

The next question comes from Ryan Deschner with Raymond James.

Congrats on the data, and thanks for the question. Just curious on how you'd be looking at titration strategy in Phase III based on what you've learned so far in Phase IIb. And was the placebo that we're seeing here on the primary end point lower than you expected.

Thanks, Ryan. It's a really interesting question on the lead-in. I think based on our previous experience, and I expect that once we get into the the time course data for the adverse events, et cetera, here, we will probably have greater color on what we need to do to maybe increase some of our titration. We know that based on our previous experience that some of these adverse events that we see and even some of the early discontinuations may be to that initial exposure to the drug as opposed to even being dose dependent. So there are some strategies. I think we have a lower than what we expected discontinuation rate here. We did have some strategies in the trial that -- in the CORAL trial right now, including the potential for going from twice a day to once a day, some mitigation strategies with other therapies to to fight the nausea or the vomiting. I think we're definitely going to take a very, very close look at if we need to maybe enhance our dosing strategy coming in the titration period. So those are all things on the table that we'll definitely take a look at.

And then he asked about placebo rate?

I -- we -- it was a big debate. I mean this is the first parallel group study. Let's just say that I think we all were very curious as to see how that placebo response. We've got to look in a parallel group study. We know in the RCC world, that was a little bit of land mine. We're very happy to see the response rate, the placebo response rate that we have. But I think it does it's credit to our investigators, the investigator site team the trial management that we were able to hold that kind of response rate down. I think maybe Phil has a comment on what he was thinking about for a placebo response rate, but I think we're very happy in the long run.

Thanks, Jim. I mean, I think the true answer is no one really knew what we were going to expect because only the data we have to base on the crossover studies, I think, and other Phase II studies, which have different delivery modalities so therefore, probably suffered from a higher placebo effect. So I think this is higher than some of the crossover studies we've seen lower than the other Phase II studies. And again, hopefully, given the size of the patient cohort, the geographical variability of the sites and a number of sites. This is probably a true reflection of what we're going to see in the Phase III study.

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

Congrats on the spectacular data. Could you touch on the importance of your lower dose clearing statsig at a 30% placebo-adjusted treatment effect, if this was a function of lower discontinuation rate higher sample size than you assumed? And if you're able to comment also on the sort of TRO information we may get, including at maybe some of the upcoming conferences. Then I have a quick follow-up.

So I mean, powering works on a number of assumptions coming in primarily your best estimates of effect size and standard deviation. And with that, you come up with an end for the trial. I think the lower discontinuation rate in the trial means that we had more in each of the doses than we had originally powered for. We did power for a 30% discontinuation rate. So obviously -- and that's overall rate. So when we look at our 10% rate, we still have more power there. So I think the effects that we see at the lower dose, the significance of that, even though it came in technically less than what we had power for, the assumptions of variability, this study was probably tighter in terms of variability than what we had expected. So that allows for more cushion on the effect size. Also, we had more sub dose arm because of the lower discontinuation rate. So technically, we were overpowering our initial assumptions during the conditional powering calculations. So I think all those things together led us to the significant findings with a slightly lower-than-expected effect size for the lowest dose. In terms of the additional information that will be coming in, we will have more patient-reported outcome measures, the LCQ patient reported, patient global impression scores, et cetera. And as we continue to improve the cough count data, there might be some additional ad hocs that we might be able to put in there as well. So I think stay tuned for those, we will be looking at the meetings where we can meet deadlines for submitting our abstract. So we'll take those available once we were going to have.

Brief clarification of a prior question. Any chance you looked at FVC measure as part of the safety analysis or maybe in the ongoing respiratory physiology study, recognize you look at short-term effect, but obviously, wonder if antifibrotic information could come through, that could inform the scale scope of next Phase III program, particularly since the drug is being used in the context of background antifibrotic.

We do have FVC data at baseline at the end of the study. So we'll be able to report that out once we get all the data.

We haven't seen that yet.

We haven't seen that yet.

The next question comes from Brandon Folkes with H.C. Wainwright.

Maybe a sort of follow-up on an earlier question for Dr. Molyneaux. I know we've talked about the dosing a little bit, well I love to call you. And sort of how we're going to assess it on a risk reward and full data set. But I'd love to lean Dr. Molyneaux on the efficacy differences he's seen in the 50-milligram dose and the 106, how do you view those as potential real-world patient experience differences. Are you seeing what you think you need to see in the 54-milligram dose alone here and sort of just any insight into what you think the potential real-world benefit would be for these patients taking a 108 dose forward versus the 54, which seems very effective itself.

I'm happy to talk through that and probably Jim will come in and come halfway through. When you're looking at the -- as you look at the data as it evolves and the story evolves that Jim went through. And obviously, this is all caveat by saying this is just the topline data. We see a rapid improvement in cough counts in both the 54 and 108 and the 27 dose at 2 weeks, and we see these significant changes at 53% to 60% in the 54-milligram and 108-milligram. So at that point, it's going to come down to what we perceive is going to be the best dose with the best side effect profile. I think we're in a position here where we've got 3 doses that were effective on cough counting. We see some differences and disconnect between that when we look at the patient reported outcomes, but we've only got some of the headline data in. I think once we get the rest of the PRO data, and we're able to deep down into some of the AE profiles to exactly when these events happened. We're going to be able to pick a clear dose strategy for the next Phase III going forward. I think, Jim, do you want to comment at any point on that?

Phil, you hit it on nose, no cut offs, no hook.

I think it's just good news that essentially, there are multiple doses here that are having an effect on cough. So that gives the company option to pick, and it's going to give the patient option to pick as well.

And the last question will come from Kaveri Pohlman with Clear Street.

Congrats on the results. My question is mostly related to Slide 14. So if we look at the 2 doses 27 and 54, I believe, the effect kind of like goes up from week 4 to week 6, slightly. I believe similar pattern was seen in RCC data. Could you comment on that? And the placebo continues to go down. And -- so going forward for the Phase III trial, when you plan to do a longer follow-up, can you maybe tell us how you plan to control this placebo effect in those certain trials? And what issues you have addressed in the Phase II studies that give you confidence? And what other challenges do you expect from the Phase III studies?

Yes. It's a great question and good observation. I think we do see this rapid decrease at week 2. We probably -- these are -- remember, these are no longer with the subject types of variability here. I think we're going to expect to see some balance around these endpoints. I mean nothing bounces up above for the active dose group, nothing really bounces up above what we see in that first 2 weeks. So I don't really worry about loss of effect with the drug. But obviously, we'll see that when we go out longer. Again, on the placebo response, we do see some decline over time. But it would be hard to imagine that, that's going to continue to drop down because it is a placebo group. And these patients -- this might be reflecting some so maybe some instability in the cough. We can try to control that a little bit better as we plan for the Phase III. So I think I'm not worried about these data. These are very strong effect, and I think that we will do our best to really keep placebo under control in the Phase III program. And at this point, we'll just take all the data into account and just plan for the price controls that we can.

Okay, thank you. In closing, I want to thank Jim and his team for the excellent trial of conduct. Of course, we also want to thank the trial sites and the patients for helping to move the research along in this important aspect of the disease. Thank you also to our shareholders for your financial support. Without that, these trials wouldn't be possible. You play an important role in advancing innovation and therapies to the patient. And for that, we are all grateful. With that, we'll end the call, and the management team will be available throughout the day for any follow-up. Thank you.

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