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

Good morning, and welcome to the Trevi Therapeutics webinar on Understanding the Seriousness of the Chronic Cough in IPF Patients and Trevi's latest data. [Operator Instructions]. As a reminder, this call is being recorded, and a replay will be made available on the Trevi website following the conclusion of the event. Various remarks that management makes during this 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 annual report on Form 10-K, which the company filed with the SEC on March 17, 2022. 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'd now like to turn the call over to your host, Jennifer Good, Co-Founder, President and Chief Executive Officer of Trevi Therapeutics. Please go ahead, Jennifer.

Good morning, and thank you for joining us. The purpose of today's call is to better understand the disease of idiopathic pulmonary fibrosis, or IPF, and the seriousness of the related cough in these patients as well as to review our recently reported positive interim data for chronic cough in this patient population. Joining me today for this discussion are my colleagues Dr. Bill Forbes, Trevi's Chief Development Officer; and Danine Summers, Trevi's Head of Medical Affairs. We are also very happy to be joined by Lisa Lancaster, who is a Professor of Medicine at Vanderbilt University. Dr. Lancaster is also the Medical Director of the Interstitial Lung Disease Program at Vanderbilt University Medical Center and a medical adviser for the pulmonary rehab program at Vanderbilt. She has deep experience treating patients with interstitial lung disease, including idiopathic pulmonary fibrosis. Dr. Lancaster's hands-on experience will provide deeper insight into cough associated with IPF and the impact on these patients and their caregivers. To briefly review the agenda, I will provide some introductory comments and hand it over to Bill, who will review our positive interim data for chronic cough and IPF, which includes some new insights into the data. And then Dr. Lancaster, the star of the show, will share her clinical views on both the disease and treating these patients. At the end, we will open it up for a Q&A session, which will be moderated by Danine. As a reminder, we have 2 lead programs at Trevi. Today, we will be discussing our cough and nalbuphine study or, as we call it, CANAL, being conducted in patients with chronic cough and IPF. We recently announced the exciting interim analysis results, which were highly statistically significant. Bill will be reviewing those results in a minute. Based on the magnitude of effect and consistency of the interim data of Haduvio, we wrapped up enrollment for this study early in March, and we expect to report top line data from the full set of subjects in the third quarter of this year. The full data set will include approximately 40 subjects. We are also in the final stages of our PRISM trial, which is being conducted in patients with severe pruritus and prurigo nodularis. This is a Phase IIb/III trial, which completed enrollment at the end of January. The double-blind dosing period is 14 weeks, and we expect to report top line data for that trial in the second quarter. I want to quickly touch on the differentiated mechanism of action of our investigational therapy, Haduvio, nalbuphine ER, which is the cornerstone that Trevi was built upon. Haduvio targets the endogenous opioid system, which works broadly throughout the body. We believe that both cough and pruritus share a common pathophysiology that are mediated through opioid receptors in the central and peripheral nervous system. Importantly, as it relates to cough, there are several receptors in the lungs, the spinal cord and the brain stem, which mediates coughing and breathing. Because Haduvio is active at 2 of the 3 receptors, mu and kappa, we hypothesized that we could rebalance the neurological signaling between the lungs and the brainstem that were resulting in cough, dyspnea, breathlessness and, ultimately, fatigue. These are considered the most bothersome symptoms to patients. Also as a reminder, because nalbuphine ER antagonizes or blocks mu and agonizes or activates kappa, the parenteral form is currently unscheduled both in the U.S. and EU and does not have the same addiction characteristics of pure mu agonist. We look forward to releasing top line data on PRISM later this quarter and top line data from all subjects in CANAL in Q3 of this year. In parallel, we are actively preparing for the next stage of development for both of these indications as well as evaluating opportunities for indication expansion. I will now turn it over to Bill to take you through the interim data. Bill?

Thank you, Jennifer. Good morning. I'm excited to share with you the positive data from the interim analysis from our CANAL trial, studying nalbuphine ER and chronic cough in IPF. And later, you'll hear from Dr. Lisa Lancaster on her clinical experience in managing chronic cough and IPF. We're lucky to have her joining us today. Before I get into results, I want to thank the patients and investigators for their continued support in conducting the CANAL trial. I will take you through the interim analysis results and later provide new additional analyses since our data call previously held. This interim analysis was conducted only on efficacy data, and we are very pleased with the strong and clear results. Nalbuphine ER reduced daytime cough frequency by 77%, resulting in a 52% difference from placebo and a p-value of less than 0.0001. We analyzed this data in multiple ways, and we're impressed with the magnitude and consistency of the efficacy of nalbuphine ER. Patient-reported outcomes follow the same trends as the primary endpoint, and the safety profile remains consistent with prior nalbuphine ER studies, where nalbuphine ER has been studied in over 1,000 subjects. Slide 11 has a diagram of the study design. CANAL is a proof-of-concept trial that is designed as a double-blind, randomized placebo-controlled 2-treatment, 2-period crossover trial, assessing the efficacy and safety of nalbuphine ER for the treatment of chronic cough in patients with IPF and is taking place in the United Kingdom. Each treatment period is 3 weeks, with a 2-week washout period after each treatment. In the nalbuphine treatment period, subjects titrate to a final dose of 162 milligrams administered twice a day in the form of an oral tablet. The primary efficacy is acquired by the use of VitaloJAK digital cough monitor at baseline in the end of each treatment. For purposes of the primary endpoint, the study baseline was used. The study baseline is the very first VitaloJAK recording prior to subjects receiving any study medication. Trevi is aware that there are other companies in the cough field that have used the same study design and have reported results using the treatment period baseline. During the conduct of CANAL, we acquired data on both of these baselines and have included supplemental analyses that show changes by each treatment baseline in today's presentation. The exact patient reported outcome data was used as a secondary measurement tool to assess cough, breathlessness and other chest symptoms. Slide 12 provides baseline characteristics of the patients included in the analysis. Approximately 80% were male, with a mean age of 72 and an average awake cough frequency of 31 coughs per hour. We had 38% of the subjects in the full analysis data set on an antifibrotic, and the awake cough frequency ranged from 3 coughs per hour to 92 coughs per hour. On Slide 13, you will note the primary endpoint for the 26 subjects, who completed at least 1 treatment period. Subjects on nalbuphine ER saw a 77% reduction in the geometric mean percent change in daytime cough compared to a 26% reduction in the placebo arm. This results in a 52% placebo-adjusted change and, again, a p-value of 0.0001. We are impressed with the magnitude of the efficacy of nalbuphine ER and the level of significance seen. This is a picture of the digital cough monitor used, the VitaloJAK. It is a 510(k)-approved device that has been widely used in clinical trials, including the pivotal trials of refractory chronic cough conducted by other sponsors. Slide 14 has a lot of information, but I'm showing you this to demonstrate the robustness of the data. The magnitude of effect of nalbuphine ER remains consistent across all of these analyses, demonstrating an approximate 70% reduction of cough from baseline. Consistently, nalbuphine ER shows a 50% improvement over placebo when compared to study baseline, and upwards of a 90% improvement over placebo when compared to treatment baseline. What is striking in this data is that the results remain consistent across all baseline cough counts, whether you look at this against study baseline or treatment baseline, whether you look at the full analysis set or completers or if patients are on or off antifibrotics. On Slide 15, we looked at our data using a responder analysis. I'd like to say that we flip the axis on this particular presentation. Subjects that demonstrate a 30%, 50% and 75% reduction in their daytime coughs were analyzed and the results reflect that at every cut, the nalbuphine arm outperformed the placebo-treated arm. Interestingly, 42% of the subjects treated with nalbuphine ER achieved a 75% reduction in daytime cough, where 0 patients treated with placebo achieved such a reduction. Slide 16 shows new information on the patient reported outcome most closely related to our primary efficacy analysis. We used the exact tool, and this shows that the exact 2 questions asked patients and I quote, "How often did you cough today?" We feel this most closely correlates to the objective cough monitor measuring cough frequency. The response on nalbuphine ER began to -- begins to separate from placebo at day 1, showing the speed of response and was numerically better at every time point. This information will help us in the design of our next trial, where we expect to run a parallel design study with 2 active arms in a placebo arm. One of the active arms will include 162 milligrams BID and the other will be a lower dose, which is still being determined. Slide 17 covers what we know about safety. Trevi has treated over 1,000 subjects, ranging from healthy volunteers to end-stage liver and kidney disease, to patients with prurigo nodularis. The safety of -- safety profile of nalbuphine is well characterized in a broad range of populations. This interim analysis was undertaken to specifically assess efficacy. We did not assess safety. And at this time, the company remains blinded as to the allocation of the specific adverse events. Our Data and Safety Monitoring Board continues to oversee the safety of the study, and we have -- and have met routinely and received frequent updates. To date, they have not indicated any safety concerns to us. From a blinded perspective, we do know this about this trial in IPF patients. There have been no reported deaths and 1 reported serious adverse event, which was a pneumonia, and this was not considered treatment-related. There have been 5 patients discontinued due to adverse events. I cannot say whether or not these 5 patients that discontinued due to adverse events were on active or placebo in the trial. But what I can tell you is that there was 1 for anorexia, 1 for depression, 1 for nausea, vomiting, 1 for insomnia, fatigue, and 1 for agitation, anxiety, dyspnea. Slide 18 highlights a couple of key next steps. I'm impressed with the magnitude and consistency of these results and look forward to accelerating development with nalbuphine ER in the treatment of chronic cough in IPF. We've already completed trial enrollment and look forward to beginning discussions with relevant health authorities to review the next protocol design in parallel to receiving the top line data in the third quarter. And we expect to initiate the next trial in the first half of 2023. With that, I wish to introduce Dr. Lisa Lancaster. Dr. Lancaster is a Professor of Medicine at Vanderbilt University Medical Center. Dr. Lancaster also serves as a member of the steering committee for the Pulmonary Fibrosis Foundation in Interstitial and Diffuse Lung Disease Network Steering Committee for the American College of Chest Physicians. Dr. Lancaster?

Thanks so much. Good morning, everyone. We'll go to our next slide. So let's talk a little bit about idiopathic pulmonary fibrosis and chronic cough and really how that affects those patients. So what is idiopathic pulmonary fibrosis? Well, interestingly enough, it's a very common, yet uncommon disease. We've all heard or have some awareness of cystic fibrosis, and this is actually a disease that affects many more people than those with cystic fibrosis. It's a chronic fibrosing lung disease that affects the space between the air sac and the blood vessels that surround the air sac, creating a meshwork of fibrosis that blocks oxygenation and gas exchange, contributes to shortness of breath, progressive hypoxia and cough over time. It's a progressive disease once it's diagnosed. And after diagnosis, the average survival -- median survival, that is, is only about 3 to 5 years. We have current therapies, antifibrotics, that were first approved in 2015 that slow disease progression and do help some with survival in these patients, but we still don't have anything to fully abrogate the disease. And the disease process has only slowed by 50% with both of these antifibrotic therapies. Along with antifibrotic therapies, we have comorbidities or common diseases that are associated with idiopathic pulmonary fibrosis. These common diseases associated with idiopathic pulmonary fibrosis can also contribute to cough, like, reflux, sleep apnea and lung cancer as well as emphysema. So we have the intrinsic disease that can be a part of the cough-causing mechanism and then their comorbidities as a part of the cough-causing mechanism. This is a cough that's chronic, one that lasts greater than 8 weeks or more, essentially from the point of diagnosis. That's where they're first manifesting symptom complaints, cough and shortness of breath, usually starting out with exertion and then continuing into rest. It occurs in up to 85% of IPF patients. And clinically, I think you'll find most providers saying they experience that at an even higher amount as we assess patients in clinic. It's mainly a nonproductive dry, hacking cough, and the median coughs that occur per day are 226 to 520. That's an enormous amount. And that's greater than somebody, for example, in coughs related to asthma. Cough can also be a marker of disease progression and it can lead to oxygen desaturation, as people are having trouble catching their breath as they're coughing and it affects their gas exchange with ventilation perfusion mismatch, fatigue, exhaustion, air hunger and anxiety. Next slide. So what do we think is actually going on with cough in the IPF patient? Well, we already talked that their intrinsic mechanisms probably related to the disease and the comorbidities. Also know that cough receptors are really throughout the [ thorax ]. You name the organ, it's -- cough receptors are going to be present. They're also present in esophagus and in the stomach. Now there are several mechanisms that can, we think, potentially be responsible for cough in patients with IPF. And that includes upregulation of the [ sensory ] fibers in the lungs. And that increases the cough sensitivity in patients with IPF. Stimulation of cough receptors, and that can be related to inflammation, chemo [indiscernible], cytokines, chemicals in the lung or from just having stiff lungs. Fibrosis are spurring in the lungs, makes the lung stiff and increases mechanical forces of stretch with inspiration and expiration, and that can contribute to cough. There are higher levels of chemicals called neurotrophin that can contribute to cough and increase cough sensitivity. Cough in and of itself is irritating to the airway, and airway irritation can ultimately result in cough, begetting cough. So what happens? Well, there's some stimulation of one of these forces to the cough receptors that are out peripherally in our chest, that results in sending neurologic impulses up through the vagus nerve to the brainstem and the medulla, and then ultimately out through efferent impulses, signaling contraction of muscles in the diaphragm and prompting cough. Next slide. So let's talk about the psychological impact of chronic cough in patients with IPF. And what I want you to do is picture yourself in this situation. You're at a work meeting, you're at church, you're trying to give a talk and you have the problem of chronic cough and that tickle. How are you going to get through that cough -- that talking during the meeting? How are you going to get to speak? How are you going to get through just breathing without coughing in a situation where you need to be silent? Well, it's embarrassing. People now, we're in the middle of a pandemic. So somebody is coughing, well, what happens? People look at you as if you have an infection, like coronavirus, and are worried about you passing an infection to them. It makes people feel very uncomfortable and insecure in being in a public environment. And as a result, they [indiscernible], they isolate themselves and feel anxious. So they start not going to their usual activities, not going in public or social situations with their friends or with groups of patients because they're embarrassed about their cough, embarrassed about what people will say and concerned if they have a speaking responsibility that they will start coughing and it will be intractable. And these cough episodes can go on for several minutes or longer. Next slide. So physiologically, it has an impact to patients. Well, that -- those coughing episodes that can last several minutes or longer can create fatigue, exhaustion, shortness of breath, oxygen levels can plummet and take a nose dive and it takes a while to recover after that. Patients get hungry for air, it creates anxiety and they're wondering if this is going to be it. Some of these coughing spells can be that severe. For women, especially those who have children, coughing can beget urinary continence, which can result in even more embarrassing social situations. Next slide. So what do things look like from the physician perspective? Well, cough certainly is a worrisome symptom. It impacts patients physically, it impacts patients emotionally and socially and psychologically as well, but it has no clear therapy for patients. So that is problematic. We tried various things, and at the same time, we know that these things we're going to try are not going to abrogate the cough, not even scratch at the surface of taking care of the cough. So it becomes a very frustrating dance for patients and for the physician. Next slide. Presently, there are currently no approved therapies for IPF patients, who are suffering from chronic cough. And that's really true for any interstitial lung disease patient or fibrotic patients. So there's a large collections of patients out there suffering from this condition. What do we try? Well, we try our typical over-the-counter antitussive cough medicines, like dextromethorphan. We -- like the Robitussin type medicines out there, they generally have minimal-to-no impact on cough. Low-dose steroids have been tried in the past, but there's really no substantial data that supports using that. And chronic steroids are fraught with problems. And then certainly, in IPF, we know that immunosuppressive therapy is not helpful. And we know that from the PANTHER study, it was published in 2011, that immunosuppressives actually may be harmful. And patients who are taking immunosuppressants had a higher mortality than those who are on placebo. Neuromodulators have been tried in small studies, but definitely don't fully abrogate the cough. And many of them also have side effects of sleepiness, of confusion, that could affect quality of life. Speech therapy is able to teach techniques to help minimize cough, but it is minimally effective, yet we try it in everyone. So we try a whole collection of therapies in patients, yet we don't have anything to fully abrogate the cough, even slightly take the edge off of it. So the need is incredibly high for physicians and for their patients suffering from this condition of chronic cough with IPF. Next slide. And I think we're all happy to take questions. And at this point, I'll turn it back over to Tara.

Great. Thank you, Dr. Lancaster. At this time, we will be conducting our question-and-answer session with our speakers. [Operator Instructions]. I'll now turn the call over to Danine Summers, Vice President of Medical Affairs at Trevi Therapeutics. Please go ahead, Danine.

Thank you, Tara. Our first question is for Dr. Lancaster. In your clinical experience, what impact have antifibrotics had on IPF patients? And how do you see a potential cough therapy being used in this patient population?

Well, definitely, it's been a huge advance from something to nothing. We've gone from identifying the disease and really defining it through our consensus statement definitions in 1999 and 2000, with modifications along the way and, ultimately, 15 years later, having 2 antifibrotic therapies. And hopefully, that will blossom even more therapies as we learn more about different pathways. But these therapies only slow the disease progression by about 50%. They do not fully stop there or abrogate it and they do nothing for symptoms. So this is like treating high blood pressure. We have medicines that treat the high blood pressure and ultimately slow disease progression for consequences of hypertension, but we don't have anything necessarily for symptoms. And symptoms play such a huge role with especially cough, even greater than shortness of breath, because that emotional embarrassment that goes along with that, having a loud cough in public in the middle of a pandemic with concerns over infection. So I think of all the symptoms, this is probably one that's of paramount importance.

Thank you. The next question is from Nathan Weinstein of Aegis Capital. Good morning, great question -- good morning. Great presentation. Two questions. This is directed to Dr. Lancaster. Although many of the off-label drugs used clinically in cough have proven ineffective, if there are -- is there a scenario where we could see Haduvio used in a combo strategy with existing agents? And second question, can you talk about patient education as an important component of staunching discontinuation rates?

Yes. I think absolutely. So first and foremost, we're probably going to see our most effective antifibrotics. We may see other antifibrotics layered on that, and we'll probably see symptomatic therapies or treatments as they're showing -- when they show efficacy layered on top of that. So I think we'll have approaches for the fibrosis, and I think we'll have approaches for symptom management as well. And perhaps even down the road, therapies that address both. Second question, can you repeat that one again?

It's been removed from the -- let me go back to it here, hang on a second. The second question is, can you talk about patient education as an important component of staunching discontinuation rates?

So I'm guessing you mean discontinue rates -- discontinuation rates of antifibrotics. So I think it's a double-edged sword that requires education at the provider level and education at the patient level. We can titrate both medications. We can even take little dosing holidays and come back on board because a lot of the GI symptoms that are part of the side effects of both medications can be abrogated with dose modulation, holidays, titration, and many other things, concomitant medications, illness, gastroenteritis, whatnot, can also cause similar symptoms. So I think there is education on the patients end of things that's important, but also on the provider end of things so that there's an understanding that you do have strategies and you do have things to do to work with patients to encourage them to continue the medication. And I think that's part of our success in having patients continue the medication in our ILD, IPF center is because of that educational component to it.

The next question is from Serge Belanger of Needham, and this is for Bill. Can you go over the current preliminary Phase IIb trial plans? Are you planning to meet with FDA prior to initiating? Would this be the only trial required for FDA approval?

Yes. Thanks, Serge, for your questions. So let me try to handle some of these. Our current thinking, I mean, I kind of alluded to this a little bit in the presentation. I mean, we're really looking at a parallel group, double-blind, placebo-controlled trial. So probably 3 doses, 1 being placebo and 162-milligram BID and then we have to choose a lower dose. So that's kind of our vision for it, probably a 3- to 6-month study. We're having discussions about that internally of how long the study should be. Obviously, we'll open up an open-label extension study separate from the Phase IIb/III study that we're going to go into next. The question about whether or not this is -- this could be a one and done, I think, is an interesting one. And we've been pretty vocal that we think this is an unmet need in this patient population. We believe this first study will certainly serve as providing evidence that there's efficacy here. We know mechanistically that makes sense. So usually, it's mechanistically does it make sense? Is there some data that says that, in fact, you're one-and-done study, if you do 1 Phase III study, is there other data that you can bring to bear? This study shows that there is. And now you have to do a definitive third study or a second study, which would be the one pivotal study. So then I'm kind of talking around because we have to be a little bit cautious. The ability to go with one study and say that it obviously depends upon the results, but a lot of that is hedged by what we see in this current data set. And when we get the full data set together, we'll show you that. We'll have additional data looks, not only we'll have daytime cough, but we'll have 24-hour cough and nighttime cough. We don't expect there to be any differences in any of that. This drug is dosed twice a day. So we believe we have full coverage on it. And then as far as like when we're going to be doing some of this? I think in the second half or early on, hopefully, we'll be talking to the FDA. When we do this next study, we anticipate at least 2 countries, probably about 50 centers, somewhere in that range. So it will be kind of a 2-country -- 3 countries involved in the recruitment of the study. And I think for the most part, we hope we get started in the early part of next year with patients being enrolled. So I think I answered all your questions. If I missed something, Serge, let me know.

The next question is for Dr. Lancaster. Are you aware of other promising treatments in development for cough in IPF?

If you look at clinicaltrials.gov, you'll be able to find studies on IPF cough, related cough. I am presently involved in some of those studies, so I can't comment on that.

Okay. And the next question is also for you, Dr. Lancaster. How many patients per year suffer from IPF in the U.S. and worldwide? And where there are no FDA-approved therapies?

Yes. So the incidence and prevalence of IPF is rising, probably about 40,000 plus per year maybe in the U.S. But it is a number that's continuing to rise over time as we look at not just Medicare databases, but other databases and registries. And we don't really know why that is, but it may be in part is that we're discovering patients earlier in the process. We are obtaining more imaging, more CT scans for various other reasons, pulmonary embolism, cardiac disease, lung cancer screening that perhaps are identifying interstitial lung disease and progresses at an earlier point in time.

Okay. We have a couple of questions about sodium cromoglycate in chronic cough. The questions are, and this is for Dr. Lancaster. How do you -- how would you expect these compared to nalbuphine? And what are your overall thoughts on that agent?

Yes. I think no one's going to be able necessarily to answer that question without any comparative studies, without head-to-head studies. So I'm just going to have to refer you back to the published literature, and I can't really comment on cromolyn sodium because we were involved in the past clinical trial with that particular study.

The next question is for Bill, and it's from Leland Gershell of Oppenheimer. Bill, how should we think about the relative timing of potential approvals in the 2 indications? Should we contemplate a PN approval first, followed by an eventual sNDA?

Leland, thank you for your question. It's a tough one right now. We obviously have data coming out at the end of this quarter, the coming quarter on the PN indication. So we'll see what that data looks like. We may have to do another study. And I think, in general, you're probably looking at, if we have to do another study, in prurigo nodularis, you're probably talking about getting that study done in about 18 months and then going to NDA for that indication. So we'll be able to speak more intelligently once we get the data set. In a similar situation that Serge asked about before, we'll take a look at it. If the data is extremely strong, we'll weigh our options at that point in time with the PRISM study in the prurigo nodularis. With CANAL and now doing another study, I think it's similar kind of metrics. You're probably talking about -- about a year for enrollment, about 6 months if you figure you could do a 6-month study. And then if the data supports, completing the program at that point in time, you're talking about a couple of years to NDA. And so those are probably good placeholders for right now. We can talk about it as a 2, 2.5 years. But for right now, given kind of the optics that we have on everything, we'll have to wait and see. Plus, we're having discussions with health authorities, particularly the FDA, on the next steps for both of these programs. So with all of those caveats, Leland, that's the best I can give you.

We have a couple more questions in the queue. I just want to remind you if you would like to ask a question, you can do that by using the box at the bottom of your screen. The next question is from Serge Belanger of Needham, and this is for Bill again. Any plans at this time to elevate Haduvio -- evaluate Haduvio in cough indications beyond IPF cough?

No. Thanks, Serge. I'm going to actually defer that to my boss. Jennifer?

Yes. No, happy to answer it. I think Lisa touched on this. There is a lot of other cough that probably make some sense to think about. 2 specific patient populations we have had discussions around is cough and other interstitial lung diseases, as Lisa mentioned, that it goes beyond just idiopathic pulmonary fibrosis. We are also looking at the refractory chronic cough market. As you all probably know, it's a big opportunity or a big unmet need. There are other therapies being looked out there. I think we would bring a different mechanism to that patient group. So those are 2 indications we'll be talking about as a team and deciding where we go next.

Thank you, Jennifer. Next question is from Leland Gershell of Oppenheimer. Bill, are you able to give a rough estimate of the cost of the next IPF cough study?

I'm going to ask Lisa Delfini. Can you...

No, I can jump in here, Bill. I think we're still working that out. I mean Bill laid out sort of what he thinks the study design looks like, but we've still got to get to the agency. I think as sort of initial guidance, based on what we've run in the past, sort of assuming a roughly 300-person study, I would say probably about $25 million. But again, we've got to go get bids on that and sort of dial that number in a little better.

Jennifer, the next question is for you. What is the company's strategy for partnering for one or both indications?

Yes, it's a good question. We've been out actively in discussions, really with a focus on territory discussions. So we've talked to partners in China and broader Asia, Europe. I would say we're sort of deep in discussions around both indications. We intend to keep the rights in the U.S. ourselves. So hopefully, with the data from both of these trials, we can sort out the best partnering strategy to be able to access the rest of the world.

Thank you. Again, if you have questions, please use the box at the bottom of your screen. We have one more to go, otherwise. Bill, the next question is for you. As you progress development, what thoughts do you have on the size of the next trial?

So right now, at least in my mind, to do what would be an adequate and well-controlled study, we're probably talking about 75 to 100 patients per treatment group. And those are discussions that we'll have as we bring in this full data set from CANAL and we take a look at how to power the next study. I think it's pretty clear from the data that we've received that this is really -- I mean, it doesn't take that many patients to drive a p value, when you have these kind of reductions in cough versus placebo. So obviously, there will be some variance that increases when you start to add centers, add countries and things like that. But -- but for the most part, I think, to be an adequate and well-controlled trial, you're probably talking about something like that. So probably around 300 patients total is a good way to look at the next study for right now, 3-treatment arms, 100 each.

Thank you, Bill. I don't see any further questions in the queue. So at this time, I will turn the call back over to Jennifer for closing remarks. Oh, wait a minute, hold on, we had one slip in here. A couple of them. Hold the phone. I'm not sure who best to put this to. Maybe I'll start with Dr. Lancaster. What is the annual price of antifibrotic meds for IPF?

Well, it depends on your insurance coverage. So most patients will need insurance coverage for their medications. About 80% of the cost is covered. About the other 20% can be $2,000 to $3,000 a month out of pocket for some patients at the max. And there are foundations for support that can help patients based on income, cover those out-of-pocket costs.

Danine, I would just add there, too. I know the gross price is roughly $140,000. Clearly, there's going to be a net price out of that. There was just, I think [indiscernible] just lost in sort of a patent challenge, so you'll probably see that go generic here at some point. So there's some changing dynamics in that space.

And Jennifer, there was a second part to this question that I think is best posed to you. Would you expect similar pricing for Haduvio in chronic cough and have harmonized pricing across indications, for example, PN versus chronic cough?

Yes, it's a good question. I think, first of all, we're going to need to see all the data and think about the value proposition to patients. It is an orphan-ish-looking population. It's about 130,000 patients in the U.S. I just don't know. I don't think it will be as high as the antifibrotics, but I do think there's good pricing leverage in this space. I think we will have to harmonize across our indications generally, although I think, sorting out if the dosing here will be at a little lower dose. But I think we will have to harmonize the pricing. The PN markets, as you probably know, are really driven by biologics-type pricing. So also good pricing there. I think Dupixent is priced at about $40,000 a year. So we have good leverage here. We want to make it accessible to patients. We wanted to reflect the value proposition for patients. And we just don't have a good enough eye on that yet to know what that will be.

Okay. We have another question from Serge Belanger at Needham. It's addressed to Bill, but I'm thinking, Dr. Lancaster, perhaps you can address this first and Bill can add to it. What are your thoughts on Haduvio having an impact on fibrosis and IPF disease progression?

So I think that's a question that I'm going to pass this one to Bill because I think it takes data to sort that one out. But certainly, I think if a drug were found that were to impact both fibrosis and cough, we have a little bit of data with pirfenidone and cough just by improvement in cough questionnaires. But if we were to truly define effective data for an impact, that would be something substantial in this space.

Yes. So I guess, in a way, this is kind of the big question, right? If you can achieve these kind of reductions in cough on an hourly basis in this patient population, what effect will that have longer term in outcome and allowing patients to condition their lungs a little bit better because now they can actually move about a little bit better. I think this is all part of -- when we talk about 3 months versus 6 months and when you look at the antifibrotics, where they went some of them a year or even longer in some of their clinical trials. I mean to get to some of these questions, we have to follow patients a little bit longer is my intuition on this. And so when we -- as I said before, to show a change in cough counts, I only need a couple of days because the drug acts fast and so we don't need a lot of time to show efficacy and reduction in cough counts. The desire inside the company when we talk about this to go longer is to try to see if we have some sort of an effect on hospitalization, on something like a 6-minute walk test, spirometry, do these patients decline slower over time relative to placebo, if that's what they're on. And we anticipate that a lot of these patients will be on antifibrotics, too, by the way. One of the things that I pointed out in my talk and we didn't actually show the data for, but when you look at the patients in CANAL that were on antifibrotics at baseline and during the course of the study, they performed very well on nalbuphine for reduction of cough. So we know that we will do well on top of that. And in the United States, a lot of these patients will be on antifibrotic. So I think in a way, I don't mean to talk around your question, but those are some of the things that we're wrestling with right now.

Thank you, Bill. And there are two questions from the audience, one from Leland Gershell at Oppenheimer. Can you please remind us what percentage of the patients from CANAL were on antifibrotic therapy?

Yes, 38%.

Thank you. And the final question, unless there's any more to kind of slip in here, is when in Q2 should we expect PN data, Bill?

At the very end of Q2. So we're cleaning now and wrapping things up.

Okay. I do not see any other questions in the queue at this time. So Jennifer, I will pass the call back over to you.

Thank you, Danine. Lisa, thanks so much. We really appreciate your time, and it's really valuable, I think, for us as a company and for investors to understand sort of this patient and their journey and what needs are. So thank you very much for your time. We know how busy you are. And I just want to thank everybody for joining us this morning. We are around this afternoon if anybody has follow-up questions, happy to be available for that. So thank you for your time. Have a good day.