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

Good morning, and welcome to the Trevi Therapeutics Phase IIb/III PRISM Top Line Data Conference Call. [Operator Instructions] Please note, this event may be recorded. I would now like to turn the conference over to Katie McManus, Communications Manager of Trevi Therapeutics. Please go ahead.

On behalf of Trevi Therapeutics, I want to thank you for joining us for the Trevi Therapeutics Phase IIb/III PRISM top line data conference call of Haduvio for the treatment of prurigo nodularis. Various remarks that management makes during this call about the company's future expectations, plans and prospects constitute forward-looking statements for the 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 form on Form 10-Q for the quarter ended March 31, 2022. In addition, any forward-looking statements represent the company's views only as of today and should 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 it sees change. I would now like to turn the conference call over to Jennifer Good, President and CEO of Trevi Therapeutics. Please go ahead.

Thank you, Katie. Good morning, and welcome to Trevi's call to review the top line data from our Phase IIb/III PRISM trial in prurigo nodularis or PN. Joining me today on this call from Trevi are Dr. Bill Forbes, our Chief Development Officer, who will review the data; and Farrell Simon, Head of Commercial and Strategy, who will provide some commercial thoughts on the disease and Haduvio's place in the treatment paradigm. We are also very pleased to be joined by Dr. Jennifer L. Parish, a dermatologist at Parish Dermatology, which is located in Philadelphia. Dr. Parish has lectured internationally and is on the faculty of Sidney Kimmel Medical College at Thomas Jefferson University and Tulane University School of Medicine. She is currently a principal investigator in several clinical trials, evaluating new treatments for psoriasis, acne, keloids and other skin conditions. Dr. Parish is an investigator in this trial, and she had the distinction of enrolling both the first patient and last patient in the PRISM trial. We are grateful she is able to join us today, and we have asked her to provide insight into the severity of PN, the impact pruritus has on these patients and her interest in taking part in the trial. We will go through our slides and prepared remarks, and we will be happy to answer any questions. I am pleased to report these positive results from the PRISM trial. For the primary end point, 25% of Haduvio subjects achieved a 4-point reduction in Worst Itch NRS, or WI-NRS, at week 14 versus their baseline compared to 14% of placebo subjects. This resulted in an overall p-value of 0.0157. Haduvio also showed statistical significance on the mean reduction in Worst Itch NRS with a p-value of 0.0056, and this itch reduction was sustained through week 14. In addition to the itch relief, we were pleased that patients also had a nice response in the ItchyQoL beginning at week 1 and demonstrated statistical significance at week 14 with a p-value of 0.0002 and importantly was statistically significant across all 3 domains of the instrument. Finally, we also used the Prurigo Activity Scale, or PAS, to measure skin healing as determined by the study investigator. Using the PAS, 55% of Haduvio patients saw at least a one category improvement at week 14 in a 5-point scale versus 38% on placebo, also resulting in a statistically significant change. Bill will give you more details on the data, but we were very pleased to achieve statistical significance on the primary end point of itch reduction and also to see the improved quality of life as assessed by the subject and skin healing as assessed by the physician. As many of you know, I am one of the cofounders of the company. We started Trevi to explore this drug and mechanism in both severe pruritus and cough conditions. There have been several companies over the past 10 years who have studied both cough and pruritus, and there have been many failures. These are serious conditions with their own challenges in drug development. So I was very happy to see the success in this trial, which we believe is validation of the overall hypothesis and mechanism of the drug. As a reminder, earlier this year, we also reported very strong interim results from our Phase II trial in cough in idiopathic pulmonary fibrosis, or IPF, which enabled us to end the trial early and accelerate development in that indication. Turning now to the market opportunity in prurigo nodularis. PN is a chronic dermatologic disease characterized by intense pruritus with raised nodular lesions, plaques and papules that are usually distributed symmetrically on the body. Pruritus is a cardinal symptom of PN and is among its most severe and treatment-resistant manifestations for which there are no approved therapies. This makes an effective and safe oral treatment option appealing as many PN patients remain uncontrolled after off-label therapies such as topicals and immunomodulators. We were interested in studying pruritus in PN because it is a chronic neuroinflammatory skin condition that we felt had a strong mechanistic link to Haduvio. As you can see on this slide, our drug targets the endogenous opioid system, which works broadly throughout the body both centrally and peripherally. Importantly, there are several opioid receptors in the brain, spinal cord, peripheral nerves and skin, which mediates itching. Because our drug is active at 2 of the 3 receptors, mu and kappa, we hypothesized that we could improve the neurological signaling going on during the itch-scratch cycle as the pruritus associated with PN can be self-perpetuating and neuronally driven by itch sensitization. We also believe that balancing these 2 receptors is important in the overall treatment of the disease. I also want to remind you that because nalbuphine antagonizes or blocks mu and agonizes or activates kappa, it is currently unscheduled by the U.S. DEA and WHO and does not seem to have the same addiction characteristics of new agonists. With that background, I will now turn it over to Bill to take you through the data.

Thank you, Jennifer, and good morning. Today, I will review Trevi's top line results for our PRISM trial studying nalbuphine ER in prurigo nodularis. Remember, this trial ran into the headwinds of COVID. We found ways to safely support subjects enrolling in this trial during a very difficult time in their lives. We thank these patients and our investigators and the research staff for their dedication and support. With that, I'm excited to share with you today these strong and clear results. Slide 9 provides some historical context. Prior to the initiation of PRISM, Trevi conducted 2 trials in 2 pruritic conditions to assess the effect of Haduvio on chronic itch. The first involved 373 subjects on hemodialysis with a chronic itch referred to as uremic pruritus. The second was a 63-subject trial in patients with prurigo nodularis, the predecessor of the PRISM trial. Importantly, both of these trials successfully demonstrated itch reduction with a clear dose response. Open-label experience out to 52 weeks also suggested that patients saw continued itch suppression, improved quality of life and a reduction in the number of skin lesions over time. All of this information led us to the design of the current PRISM trial. Slide 10 has a diagram of the study design. PRISM is a randomized, double-blind, placebo-controlled, 2-arm study with an open-label extension period following the double-blind treatment period to investigate the antipruritic efficacy and safety of oral Haduvio for the treatment of PN taking place in the United States and the EU. PRISM had a 2-week blinded titration period where subjects were titrated from 27 milligrams to 162 milligrams BID, followed by a 12-week fixed-dose period. After completion of the double-blind stage of the trial, patients were allowed to enter the 38-week open-label extension. Today, we are disclosing just the available top line data on the double-blind portion of PRISM. We do not yet have all of the tables and listings. But because of the importance of the data for Trevi, we wanted to share the top line in a timely fashion. The primary efficacy was acquired using the Worst Itch Numerical Rating Scale, or WI-NRS, at baseline and at the end of treatment. A responder is defined as a subject having a 4-point reduction from their baseline. Key secondary endpoints include the ItchyQoL, Prurigo Activity Scale and PROMIS. Slide 11 outlines the primary and 2 key secondary endpoints that I will present today. Currently, we are not in possession of the data on sleep disturbance as measured by the PROMIS questionnaire as it has not yet been analyzed. Primary endpoint is based on 11-point Worst Itch Numerical Rating Scale, where 0 equals none and 10 equals the worst imaginable itch. Subjects entering the study had to have a baseline itch of 7 or greater, which is a severe itch. This is recorded daily, and weekly averages were used to determine success or failure from baseline. To provide context, a WI-NRS of 1 to 3 is a mild itch; 4 to 6 is a moderate itch; and 7 to 10 is severe itch. The goal of therapy is to eventually get patients into at least the mild category, which is characterized by no longer needing to scratch. This reduction to mild is an important goal in this disease for skin healing and disease modification. Moving subjects' score by 4 points not only moves them a category overall, but also gets them either in or close to the mild itch category. The ItchyQoL was administered at baseline, week 6, 10 and 14 to assess the impact of Haduvio on itch-related quality of life over the past week. The ItchyQoL has 22 questions consisting of a total score as well as individual subscores across 3 domains consisting of symptoms, functional limitations and emotions. All questions are on a 5-point scale, as noted on this slide. The Prurigo Activity Scale, or PAS, consists of 5 quantitative and qualitative measurements related to the physician's examination of the subject skin. Of specific interest to us was question 5a of the PAS. This asked the physicians to categorize the number of pruriginous lesions and excoriations or crusts. Categories are in 25% increments. In PRISM, we considered it a success if the subject improved by one or more categories from baseline. Slide 12 shows the patient disposition. 353 patients were randomized, with 344 comprising the modified intent-to-treat population, which was defined as a subject randomized and receiving at least one dose of study medication. 168 were allocated to Haduvio and 176 to placebo. 62 subjects on Haduvio and 34 on placebo discontinued during the 14-week blinded portion of the study. This left 63% of Haduvio and 81% of the placebo-treated groups completing the full 14 weeks. Slide 13 provides important inclusion-exclusion criteria for PRISM. More information on inclusion-exclusion can be found on clinicaltrials.gov. Importantly, subjects had to be diagnosed with PN covering 2 separate body parts with 10 or more pruriginous nodules and have severe itch as a result of PN, which was classified again at 7 or greater on the WI-NRS. Slide 14 highlights some key baseline characteristics. Randomization across the 2 treatment groups demonstrate comparable baseline, and subjects entered with a mean WI-NRS of 8.6, approximately 89% had 20 or more pruriginous lesions with an average age of 58 years, and 60% were female. From a geographic location, 60% came from Europe and 40% were enrolled in sites in the United States. On Slide 15, you will note the statistically significant result on the primary endpoint. At week 14, Haduvio subjects had a 25% response compared to 14% for placebo-treated patients, corresponding to a p-value of 0.0157 with a corresponding odd ratio of 2.12. These results are supported by subgroup analysis involving age in patients greater than 39 years of age, gender and geographic location when broken down by the EU and the U.S. Haduvio is the first and only oral therapy to show a positive result in treating prurigo nodularis. Slide 16 depicts the proportion of responders at the end of titration, which is week 2, and at 1, 2 and 3 months of fixed dose. Statistical significance was reached at each month of fixed dosing. Today, we do not have the data comparing the treatment groups in between these time points but hope to have that in the future. Certainly, statistical significance was reached at 1 month of fixed dosing but may have happened earlier. Slide 17 has the WI-NRS as a mean change from baseline instead of by responder analysis. Similar to the responder analysis, looking at the mean change from baseline in WI-NRS showed separation at the end of the titration period, week 2, and this becomes statistically significant at 1, 2 and 3 months. We would expect pruritus reduction to continue to decline with extended treatment, which we will better understand in the open-label extension data when it becomes available to us. Slide 18 demonstrates significant improvement in Haduvio over placebo-treated patients on quality of life using the ItchyQoL. The diagram on the right shows the total score at month 1, 2 and 3 of fixed dosing. Each time point showed significant improvement in the Haduvio versus placebo-treated patients. The 3 subscales comprising the total score also showed significant improvement. These results corroborate the data from the patients on the WI-NRS and further help us to understand that reducing a patient's itch appears to also improve functional limitations and emotional response to prurigo nodularis. Turning our attention to the physician assessment of the skin. The PAS was assessed at 2 and 3 months of fixed-dose therapy. Both time points showed highly significant skin improvement in the Haduvio-treated patients when compared to the control group. Over 50% of the Haduvio-treated patients showed at least a one-category improvement in their lesions with excoriations at the end of the fixed-dose period. As you see here, a picture is worth a thousand words. These subjects in the PRISM trial -- these are subjects that are in the PRISM trial on Haduvio. These pictures allow you to understand the benefit the subjects and investigators we're seeing on skin clearing and healing. By treating the pruritus, Haduvio has the potential to break the itch-scratch cycle and treat PN, clearing lesions over time. Slide 21 presents the treatment-emergent adverse events during the 14-week PRISM trial. As Jennifer explained, we believe that nalbuphine rebalances the endogenous opioid system both centrally and peripherally by blocking mu and stimulating kappa. This produces a rapid and clear effect on pruritus as well as cough, which was previously disclosed by Trevi in February. It is also known that these actions on the endogenous opioid system can present with certain side effects. And like the efficacy, these side effects can appear early in dosing. We continue to learn new techniques to help manage these AEs, such as providing a 2-week dose titration. Over the first 2 weeks, subjects are titrated from 27 milligrams up to 162 milligrams BID. During this phase, 66% and 31% of subjects experienced treatment-emergent AEs in the Haduvio and placebo groups, respectively. Incidence -- the incidence of treatment-emergent adverse events during the 12-week fixed-dose period were 48% and 45% of subjects in the active and placebo groups, respectively. And 8 Haduvio subjects and 6 placebo subjects experienced serious adverse events during the course of the trial. None of these serious adverse events were considered treatment related by the investigators. Overall, treatment-emergent events resulting in discontinuation on Haduvio were 33.3% versus 6.8% on placebo. During the 2-week titration period, discontinuations due to treatment-emergent AEs were 19.6% and 2.8%, and during the 12-week fixed-dose period, was 13.7% and 4.0% for subjects on Haduvio and placebo. There were no deaths in the trial. This data reinforces our understanding of the tolerability of Haduvio. Specifically, once patients complete the 2-week titration, they appear to tolerate therapy more in line with the control group as reflected in the reported treatment-emergent AEs and the slowing of the rate of discontinuations over the 12 weeks of fixed dose as compared to the 2 weeks of dose titration. Slide 22 lists the most commonly reported treatment-emergent adverse events over the 14 weeks of double-blind therapy. Nausea, dizziness, headaches, constipation and somnolence were the top 5 events reported by subjects on Haduvio. With the open-label portion of the PRISM still ongoing and with more data still arriving on the double-blind portion of the study, Trevi is eager to continue the data analysis. In the near term, we plan to request in a Phase II meeting with the FDA, submit a briefing document and discuss next steps with them. With that, I wish to introduce Farrell Simon. Farrell is Trevi's Head of Commercial and Strategy. Farrell?

Thank you, Bill, and good morning. We are excited about the potential to help prurigo nodularis patients with a safe and effective oral treatment option. We feel there's an opportunity for Haduvio in prurigo nodularis. There are 4 pillars as to why we feel well positioned in this market. First, there is a large addressable global patient population. Second, these patients are in need of effective therapies to manage their pruritus and lesions, and there continues to be a demand for an oral option. Third, there is potential for Haduvio to be positioned early in the treatment ladder. And lastly, there are a number of pruritic conditions where itch is a cardinal symptom. I first want to touch upon the importance of continued research in the area of prurigo nodularis, which has an estimated global prevalence of 730,000 patients, 300,000 of which are in the U.S. and an equal amount in Europe. There are no approved treatment options available, and Haduvio is the lead oral in development. When you look at the available population for an oral therapy, approximately 50% of these patients are uncontrolled. This may be uncontrolled from topical corticosteroids or from other systemic off-label therapies such as immunomodulators. This leaves a significant patient population still requiring an effective and safe oral therapy. PN impacts multiple aspects of patients' lives, and the lack of effective treatment options can lead them feeling physically and psychologically drained. Physically, PN patients describe their itch as the most bothersome symptom as it is frequent and severe. However, the itch is not only debilitating aspect of their disease as the repetitive scratching is accompanied by the presence of lesions that can cover patients' bodies. The burden of disease is driven from their itch but is much more broad reaching as PN also impacts their psychological, emotional and sleep health. In a JAAD publication last year, when PN is compared to other disease states and impact on quality of life, PN is similar to emphysema and has a worse quality of life when compared to other chronic debilitating diseases, such as asthma, diabetes and stroke. Lastly, there is a broad range of emotional impact PN patients experience from their itch. This all-encompassing impact highlights the importance of developing an oral option to calm the pruritus, allowing patients to improve their overall quality of life. This slide reflects the U.S. perspective on PN treatment goals and the current treatment ladder for dermatologists to consider. The goals of therapy for PN are consistent with the international [ IPSI ] guidelines. As you can see, the treatment goals are focused on reducing pruritus and breaking the itch-scratch cycle, a response which is ingrained in these patients. There are currently no approved therapies for the treatment of PN. Within each tier, there are options, which act on the neuronal or immunologic aspects of PN. We feel Haduvio has a unique role to play in rebalancing the central and peripheral mu and kappa receptors to calm the itch, along with having the potential to break the itch-scratch cycle and modify the underlying disease. Haduvio could have the potential to be second-line therapy, concomitantly with topical if itch depression is not achieved, or after failure of topicals as monotherapy. Most diagnosed PN patients have already failed topical therapy and would be eligible for second-line oral therapy at the time of launch. The potential for an oral therapy to be positioned in earlier lines of treatment before moving on to advanced biologic therapies is further supported by a good analog in Otezla and how a safe and effective oral therapy can disrupt a biologic-led market. Now psoriasis is a much larger market than PN, but this demonstrates that with an effective access strategy, route of administration and management of titration, an oral in a biologic market can be advantageous. With Haduvio's shown efficacy in 2 of the most challenging conditions in uremic pruritus and prurigo nodularis, we believe we have the potential to tap into the global pruritus market, which is estimated at $20 billion. We will continually assess if there are other itch-dominant conditions that warrant further development. With that, I wish to introduce Dr. Jennifer Parish. Dr. Parish is a study investigator for PRISM, and whose insight and work on the study is invaluable. Dr. Parish?

Thank you very much. I think that was a wonderful introduction to prurigo nodularis, but I think what's missing is seeing the pictures and the patient in -- with prurigo nodularis says a thousand words. Prurigo nodularis was actually first reported in 1880, and they actually described it as a case of multiple tumors. So this is, as you described, something like emphysema or heart disease. You can hide that you have a condition like heart disease, but you can't hide prurigo nodularis. Someone -- we're in the middle of 90-degree weather in Philadelphia and someone with prurigo nodularis is humiliated with their condition, and they can't really walk outside wearing shorts and T-shirt. As a result, this condition really does cause a lot of emotional issues. There is not only the aesthetic issues. There is the intense itching, the -- and then there's the nodules that are -- you can see them as excoriated, and you can tell it's sort of a vicious cycle. They itch. They have more nodules. They itch. They have more nodules. And they can go from 2 to 200 lesions. So as a physician in dermatology, this has always been one of those diseases that you were never excited to see because we had no real treatment. And dermatologists like to give -- like to be the hero, give them a cream and say, "Hey, you're done. You'll get better. Come back later." But in prurigo nodularis, we really didn't have any treatment. And so as a result, the patients were dreaded patients. You could give them antihistamines. That might just make them sleepy. You could give them steroids, which may make them a little bit less itchy but not too much and then there's the side effects. Cryotherapy. In Philadelphia, we had a large African-American community, and that could lead to just toleration from the cryotherapy. So the numerous options were just not really viable options. So when we were asked to be part of this study 4 years ago, we were excited, but we were also a little nervous because it is an opioid. And my team said, let's go for it. Let's see how it works. And this study has been an extremely exciting study for us because we've seen amazing results. As a dermatologist, I assumed that you couldn't just give an oral agent, and that the nodules would resolve. So for us, it was exciting to see people taking the pills without any topical steroid and the nodule to actually resolve. It sort of goes against what I always thought in prurigo nodularis because I assumed if I gave a topical, that would block the itch or if I gave an antihistamine, I could also inject into the lesion. But really, just with a pill, many of these patients improved. So it actually has been a really fun study to be part of. And in terms of any of these side effects, at our site, we really haven't had as many problems with some of the nausea and issues such as dizziness and whatnot because in dermatology, we like -- we tend to like side effects. So we manage their expectations. We make sure that they know to take the pill with food. You saw that also in placebo, they have nausea. So really oftentimes, if a patient is really -- or a subject, if you explain to them how to take a medication and you manage their expectations, they tend to do much better, and they tend to accept any side effect. But really, oftentimes side effects can be your friend because you can use that as a proof that it's working or it's just really in managing their expectations. So for us, it's been a great experience, especially when we do many clinical trials, and some just don't have as many success. There isn't anyone on my team who doesn't get excited when we get to enroll in the studies. And we're all kind of sad that enrollment has stopped. And we even had subjects that came from out of state to get on this study, which shows you how much it affects patients if they're willing to travel. And the other thing that we often noticed is sometimes, there's a concern that opioids will cause sleep disturbance. In our population, from discussing and asking patients how are they doing, most of them reported they felt less anxious. They were not -- no problems with sleep disturbance. In addition, we didn't have any patients who were doing any type of addictive behavior, which was one of my original concerns with all the opioid epidemics, even though -- and it really did -- the study really proved to me that this is a great drug without the risk of being a opioid-addictive drug. Nobody was hoarding drug. Nobody had showed any signs of addictive behavior. So for us, we quickly got over that concern and didn't see any signs that there's any risk of opioid addiction, that really the antagonist aspect of the drug really does help any type of risk of addiction. And so for us, we are excited to see the final result, but we're not going to be surprised. A picture's worth a thousand words. Our patients, whether they told us they were still itching or not, their lesions, most of them had remarkable clearances. Does anyone have any questions?

I'll open it up. Thank you, Dr. Parish. It's always so interesting to hear your perspective on the ground with the patients even for all of us here. So thank you for sharing that. We are now happy to open up the call to your questions. Operator, go ahead, and I'll mediate the questions and sort of hand them around to our team.

[Operator Instructions] Our first question comes from Annabel Samimy from Stifel.

Congratulations on reaching this important milestone. I guess I'll ask several here. I guess the first one is specifically data-related. So clearly reached statistical significance. I guess, how should we think about the clinical meaningfulness of a difference of 9% over placebo -- about 9% over placebo? I guess realizing that the -- probably the endpoints that matter most to the patient are ItchyQoL and maybe the lesion scores, but how should we really think about that? And is that -- is it the responder WI-NRS of greater than 4 points something that means something to the patients and the difference? And then I want to also ask about the high discontinuation rate. I guess in the real world, how should we think about a discontinuation rate of that level? Are patients going to know how to take this drug, how to manage their side effects? And is that going to potentially, I guess, impact the real-world response to the drug? And then I guess, finally, a bigger picture. I have to think about Dupixent because obviously, they had a couple of positive PN trials, and I realize that Dupixent is immune-targeting drug in potentially later stages. But how does -- they had some pretty strong response rate. And obviously, they address inflammatory nature of the disease as well, not just the neuronal pathway. So how do you really see this -- and this is probably for Dr. Parish, how do you really see this fitting into the treatment paradigm? Do you think they -- would you expect them to step through this drug? Would you expect the population to never get to Dupixent? How do you really see this playing out?

In terms of comparing injection versus oral, I don't know -- most patients -- and this is even if you're not a physician, everybody knows people have needle phobia. Very few patients come in and say, "Please, can I have an injection instead of a pill?" So I think everything has its place. Typically, in dermatology, we often -- the -- you often start with a topical. That doesn't work, then you go to a pill. That -- if that doesn't work, you go to injection. Most people don't opt for an injection first. The only person, in my experience with this drug, I would say, I would -- I think most people are going to pick the oral first. You -- and also, this one will not -- one of the problem with Dupixent, and that is a wonderful drug for atopic derm, but one of the problems with that is you do have to have being followed by an ophthalmologist. So that has other issues. And also, there are other issues in terms of it does help in asthma, but you also have to worry about other issues in that sense. In terms of -- you mentioned question managing side effects in the population. I think that really goes to, in any drug, how good the physician relationship is with the patient. In terms of the -- I tend to be a physician who tends to really discuss side effects because if you plan for the worst, they tend to think, "Oh, wonderful. I didn't even get that." Or if it happened, "Oh, that was normal." So I think it's kind of like -- just forgive me. I got a lot of pregnant patients lately. It's kind of like when you tell a pregnant woman, "Oh, you're very nauseous? Wonderful. That means your pregnancy is going well." So it's all about managing expectation. So I don't think -- we really didn't have -- we look -- I was kind of surprised when I kept having discussions with people from different parts of the world about this drug in different meetings. And they had more issues with -- they talked about nausea, but our subjects really didn't complain about it. And if they did, it quickly resolved itself over time, kind of the same way Otezla does. So oftentimes, I think it's how well is the physician relationship with the patient. My hope also as a practicing physician and not as a PI is that because it is a pill, it will probably be easier to get -- to prescribe. I think sometimes -- and the biologics are wonderful, but they are oftentimes not prescribed by a majority of physicians and dermatologists because it is extremely aggravating to get them through insurance. So if it's drugs such as this, it probably would be easier to prescribe. Did I answer your question?

Thank you, Dr. Parish. Yes. There was one more here, which I'm going to divide up between you and Bill, which was noting the trial reached stat sig. But just sort of the clinical meaningfulness on the spread, which I think is 11 percentage points and the 4 points. And so I think there's sort of 2 answers to that. And Bill, I'll let you take the first answer, which is the FDA and sort of regulatory opinion. And then, Dr. Parish, maybe you can talk about these results and clinical meaningfulness to the patient and time and some of those things. So Bill, why don't you start off with the sort of FDA position and sort of drug developers' lens?

Okay. Well, thank you, Annabel, for the question. And I think you kind of started to answer one of them. I mean with a 4-point reduction, that is a very high hurdle for any therapeutic to hit. And as we pointed out in this presentation a couple of times, we're the first oral agent to be able to do this. So to have a 4-point reduction in and of itself, we believe, is clinically meaningful. And obviously, the FDA has kind of weighed in on all of this. So I think we have the consensus that certainly, 4-point reduction is clinically relevant. In the literature, it could be anywhere on the WI-NRS from 2 to 4. We'll take a look at 3-point reductions and 2-point reductions as well just to have a better understanding. When you look at the spread between the active and placebo, keep in mind, this is over 14 weeks, 2 of which were the dose titration. So this is 12 weeks. We've always had the belief that the longer we go, the bigger the spread will become on this. And so it's just a matter of trying to weigh the practicalities of running pivotal trials for certain durations of time. But as I also pointed out in my talk, one of the things that we're anxious to get to is the open-label experience to see how patients did longer term. But we're excited about these results. I mean if you look across, you can see multiple time points on each assessment always going in favor of drug over placebo. And so regardless of what domain you look at on the ItchyQoL, when you look at the skin, those kind of improvements and then, of course, with just the itch scale itself. So with that, I'll pass it over to Dr. Parish.

So I have the luxury, I have seen the patients over the 52-week period. And after 14 weeks, I'm blinded so I can only say, but it often almost seemed obvious to us over the long time who was getting the drug and who's not because you could see the differences on their skin if they didn't notice. And sometimes, I think it takes longer. If the itching has resolved, it takes longer than the 14 weeks to see that the lesions have completely healed. You've seen -- you ever have seen someone with a very big bump on their skin, that doesn't just completely flatten in a month or 2 months. It can take a time. And then the longer these subjects were in the study, it was actually quite impressive to us to see the skin become smooth. And then the longer they were on, then some of the discoloration resolving. So I think my hope would be that the statistics would show that we were kind of seeing that. That over the long term, I think the differences will become more obvious. Sometimes it's hard for a certain PIs to notice that the skin -- if you see even a tiny bump, you're still going to count it as a nodule, even though it reduced significantly from baseline.

Okay. Great. And I apologize. It wasn't 11% over placebo as being a little...

It's early still [ thereabouts ]. Thank you for the questions.

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

The first 2, I guess, are for Jennifer and Bill. I guess just your expectations on when Haduvio could reach its maximal effect. Would it make sense to extend the dosing or the treatment period from 12 weeks to 16 or even 24 weeks? And then just your thoughts on how the placebo group performed in the study, both on efficacy and in terms of the safety tolerability. Then I have a follow-up for Dr. Parish.

So Bill, why don't you go ahead? You've had a whole few days to think about this topic. So you're probably the best person to ask for both of those.

Yes. No. I mean -- thanks, Serge, for the question. Let me kind of tick them off here, and hopefully, I'll cover them. The placebo, I think you were asking about the response rate. We were very happy with the performance of the study overall. And I think when you listen to Dr. Parish and some of the [ CONMED ] exclusions, we really were coming at this as monotherapy versus placebo. And so the use of steroids and antihistamines and all of that was tightly controlled through this study. So we're happy to show that there is a very low placebo response. And as I often joke, placebo response occurs in the active group as well. So I mean I think this is a -- the way this study performed, it was a hard study to do because of some of those restrictions because patients could enter other trials that might allow for some of that and might make it more convenient for them. But at the same time, I think it makes for detecting a signal more of a challenge. So from that perspective, I think it performed extremely well. As far as maximal effect, I mean, I think we're still trying to understand that. We obviously have data that goes out a year, and we'll get the open-label data here, which will be a lot more patients than we've had before on prurigo nodularis going out that far. So I'll kind of reserve comment on that. The one thing we've had discussions on is how far out do we need to go to show efficacy. And as you can see, after 1 month of therapy, we can show a difference between placebo at that point in time, certainly, maybe sooner. But we certainly know at 1 month, it's starting to show. So we know the onset seems to be quick for an oral agent. And I think as far as maximal effect, I think the longer these patients go on, the more disrupted they're itch-scratch cycle, the better their skin heals, the better they'll do. I don't know where that effect -- the improvement in effect ends.

Okay. Curious before I go on to Dr. Parish's question. Since the study was conducted basically at the height of the COVID pandemic, curious if any -- there was any impact in terms of discontinuation that could be related to COVID here.

I would say that it's definitely a possibility in some other sites. We had very -- I never stopped looking. So every subject was -- in our site was able to get the -- to come in and see us. And a lot of things were done -- like travel was arranged so that they could come in. I think at many other sites, they were shut down, so that could have affected it. I think most subjects were excited to be -- once they started -- if they were already on it, they were excited because it was actually helping them. The one question I sort of wanted to add my $0.02 is if you -- from being an investigator and if you extend a placebo time, it gets harder to keep people from dropping out of the study because you have to understand these patients are despondent. You have to see them, oh, come on, keep staying on the study. We'll see how it does. So if you keep the placebo time longer, it's harder to keep the patient or the subject enthusiastic about being in the study.

And then my follow-up to Dr. Parish is we've seen this as an indication that affects a large number of patients and should be an attractive market opportunity for most companies in our industry. So just curious why we haven't seen a treatment for PN thus far. Is it because that -- very difficult to treat or it's been poorly diagnosed where the opportunity hasn't been there? But so far, in the last year, we've seen 3 positive Phase III trials from 3 different programs. So curious what has changed and why you think we haven't seen any approved treatment so far.

The answer would be yes. And then I'll explain is that it is a very difficult disease to treat. Number one, I don't -- I think these patients have largely been dismissed as nuisances, crazy, that it's all based on their anxiety. One of the other terminologies is neurotic excoriation. So you can tell that we -- in medicine, we often ignore these patients because they were just, unfortunately, just deemed nuisances and neurotic. And unfortunately, they got ignored, and things were just thrown at them, the idea that you just throw an antidepressant at them, you throw an antihistamine and make them tired. So -- and oftentimes, in medicine, if we don't have a good treatment, we just view the patient as a nuisance. That's not nice but unfortunately, that's what happens. I think you see it in other diseases like hidradenitis suppurativa has become the hot disease. It's sort of where all these people are just overweight. If they just lose weight, all their problems will go away. So -- but also, in terms of why have all these studies come about, I think that's more of the case that people decide or sometimes somebody decides what's going to be the new hot disease or what has been ignored for a while. I also think prurigo nodularis is just like hidradenitis suppurativa, which no one was diagnosing except the dermatologists. I think primary care doctors don't have a clue, and they misdiagnose it all the time. I have many, many patients who -- when you start doing advertisement for a drug on TV, they start coming in and saying, "Oh, I didn't realize I have that disease." So I think once you do one study, there becomes more of an awareness and show them -- more people start becoming interested and more diagnosis -- correct diagnosis to be made. I think there's much more than the number that Farrell Simon discussed. I think the numbers are probably much higher.

Thank you, Dr. Parish. Serge, are we good?

Thank you.

[Operator Instructions] The next question comes from Leland Gershell from Oppenheimer.

Congratulations on getting PRISM across the finish line and to a successful outcome. Just a couple of questions from me at this point. First, and this actually relates to some of the comments from Dr. Parish just a few moments ago. And I'm not sure if, Bill, you can discuss this or maybe too early, but PN comes in different forms. It can be an intrinsic disorder with respect to kind of the itch-scratch sort of neuropsychiatric versus maybe secondary to inflammatory conditions that affect the skin like atopic dermatitis. Wondering if there's any information you can share with respect to the types of patients who came into the study. Obviously, all of them had PN, but is there any differentiation in perhaps the clinical profile of those patients that you can share? Second, I wanted to ask just about when we might see the full data, if there might be a time frame for a medical presentation conference venue down the road this year, perhaps. And actually, a third question, if I may. Just as you continue to pursue the IPF chronic cough indication, and you will likely be having another trial to do in PN to secure approval, just wanted to ask kind of how you see the time lines there as those -- as the 2 programs march forward with respect to starting up next activities in prurigo? And any FDA discussions that might be required and if any meaningful changes to the study design like in your part?

Bill, why don't you take -- we can kind of share the last one, but why don't you take the first one about subgroup analyses and any info you have? I can talk about sort of time lines and sort of our path forward. We can share the last one a little bit.

Sure. Leland, we kind of exhaustively collected information on these patients at baseline. Unfortunately, right now, I don't have all of that information. So I have to kind of tell you we'll have to talk about this in the future once we get all of the data. And I think your question was when will the rest of it come through. And I think that hopefully will be over the next few months that we'll be able to wrap things up. I think a lot of us in the industry that use vendors know that there's -- that they're being crunched quite a bit as it comes to data analysis. There's a lot of data coming in from all over the place. And their resources, like everybody's resources, are getting stretched. But our partner on this did a great job of getting all of this information to us. It's just not all of it yet. So I'll have to get back to you at another call on how all that breaks down from a baseline characteristics perspective. I don't know if you want Dr. Parish to answer the question about the different types of PN that Leland's mentioning, Jennifer?

I think he was just looking for what we saw in our study. So I think we're good. We don't know it yet. I think, Leland, you were also asking where we might present. And so our current plan is to get into late-breaking data at EADV, to the European dermatology meeting. We're already working trying to get this published there. So that meeting is in early September, actually, September 7-ish, I believe. So that will be sort of the next publication we make. And I think as far as -- your question is a good one about IPF cough and PN. We're a small company with a high-class problem of having 2 indications that work in potentially big markets. And I had always said I could build a company around either of these indications. I think now Bill sort of called my bluff here and delivered up 2 trials. So we've got to step back, look at all the data, sort of figure out the path forward. I will say our IPF cough program, just because it had the benefit of reading out sooner, is sort of on its way. Bill has already requested the meeting, and we've got a protocol written, et cetera. We now have to get the rest of the PN data and sort of go through that same journey. So our plan is by the fall to do some kind of -- probably some kind of R&D Day and lay out the time lines and sort of the path forward. We just need a little bit of time to get all the data. Bill, anything you want to add to that?

No. I think that's -- yes. Like I said, we're moving towards pulling together a meeting request and moving forward on that front with the FDA on the derm side. But we're making progress on the IPF side.

The next question comes from Nathan Weinstein from Aegis Capital.

Congrats to you and the whole Trevi team for another outstanding and successful clinical trial, particularly in such a challenging indication. So a lot of great questions already asked. So I just wanted to ask a question on the commercial side. Based on the data that you presented today, both including the safety and efficacy, how would that compare maybe to the ideal target product profile you might have had in mind? And basically, the question is, does the data presented sort of confirm the potential commercial outlook as you've been considering it? And then the second question is on the combo potential. Just given the mechanism of Haduvio is different from some of the other things out there, could it be used in combination with them?

Yes. Farrell, why don't you go ahead and answer the question on commercial? I'll just take the combo one quickly because -- and Bill can chime in. We don't have current plans to do any kind of combo therapy. One, it's challenging from a drug development perspective and expensive. And we think our drug sort of does what it needs to do. So I think that's a quick answer. That's not a path we're looking at. Farrell, I'll let you take the commercial piece.

Yes. Thanks, Nathan, for the question. We do feel well positioned in PN with the data presented today. I think the promising thing is we expect over time for the percent of responders to continue to increase, so I think you heard that from Dr. Parish in her remarks. So the pictures that Bill showed, along with the PAS data, show the potential of the underlying disease. So I think we were actually pleasantly surprised and pleased with the lesional clearing that we saw and as early as that occurred within this study. So we hear from derms on the need for an oral therapy, and we think Otezla is a great analog on how an oral could provide value in this market. So we're still optimistic on the value, which we can provide. And I would say [indiscernible]. Yes. Nathan, thanks. And in terms of combination therapy, I think there's a lot of flexibility for Haduvio. So whether that's with topicals, monotherapy, with biologics, those are all things that would have to be assessed in terms of clinical practice.

I'm not showing any further questions. This concludes our question-and-answer session. I'd like to turn the conference back over to Jennifer Good for closing remarks.

Thank you for joining us this morning. As a reminder, we will be reporting our full trial results from the IPF cough trial in the third quarter of this year. So our busy data year continues. So Bill, no rest for you and your team. We would like to thank everybody for participating in today's call. I also want to thank the Trevi team, our study investigators and all the subjects who participated in the PRISM trial. We will be available after this call for any follow-up questions you may have. Thank you.

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