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spk06: Good afternoon and welcome to the Trevi Therapeutics first quarter 2024 earnings conference call. At this time, all participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your phone. To withdraw your question, please press star then two. Please note this event is being recorded. Various remarks that management 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 factor section of the company's most recent quarterly report on Form 10-Q, which the company filed with the SEC this afternoon. 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 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 conference over to Jennifer Goode, Trevi's President and CEO. Please go ahead.
spk07: Good afternoon, and thank you for joining us for our first quarter 2024 earnings call and business update. Joining me today on this call are my colleagues, Lisa Delfini, Trevi's Chief Financial Officer, and Dr. David Clark, Trevi's Chief Medical Officer. We reported Q4 earnings just six weeks ago, so Lisa and I will give a brief update, then the three of us are happy to answer any questions. This is a busy time at Trevi, advancing our clinical development plans for both refractory chronic cough, or RCC, as well as cough and idiopathic pulmonary fibrosis, or IPF. Let me provide a brief update on our various trials, beginning with our Phase IIa trial in RCC, which is expected to read out later this year. Refractory chronic cough, or RCC, is a debilitating disease that affects up to 10% of the adult population and is defined as a persistent cough lasting greater than eight weeks, despite treatment for the underlying condition. With a lack of any approved therapies for RCC in the U.S., there continues to be a significant unmet and urgent need for new potential therapies. The key point of differentiation for Heduvia in refractory chronic cough is the mechanism of action. which works synergistically both centrally in the brain and peripherally in the lungs. We believe Heduvia's mechanism has the potential to work in more patients and potentially have a stronger effect across a broader range of baseline cough counts than peripheral-only mechanisms like the P2X3 inhibitors. Our RCC trial, RIVER, is a Phase IIa double-blind randomized placebo-controlled two-period crossover study evaluating the reduction of cough in approximately 60 patients. This design is similar to other Phase 2A cough trials run to date, but does incorporate a meaningful difference. These patients will be randomized with a one-to-one stratification between those with 10 to 19 coughs per hour and those with greater than 20 coughs per hour. Each treatment period will last three weeks, separated by a three-week washout period. Patients on Heduvia will have the dose titrated weekly from 27 milligrams up to 108 milligrams twice daily across the dosing period. The primary efficacy endpoint is the relative change in the 24-hour cough frequency as measured by an objective cough monitor. The study will also explore secondary endpoints, including patient-reported outcome measures for cough and quality of life. We now have all 14 sites activated for this trial and see almost an even split in the enrolled subjects between each arm, the 10 to 19 and greater than 20 cough counts in the study. Enrollment is progressing and we continue to expect top-line data from this study in the second half of this year. Next, an update on our lead program in IPF chronic cough. IPF is a serious end-of-life disease. Chronic cough is reported by approximately 85% of patients suffering from IPF and has similar significant physical, psychological, and social impacts to that of RCC, but may also be a risk factor that plays a role in the progression of the underlying disease of IPF. The constant lung injury, micro tears, and potential inflammation caused by persistent coughing may lead to worse health outcomes for patients, such as increased respiratory hospitalizations, mortality, or need for transplant. With no currently approved treatment options for chronic cough and IPF, patients and providers have an urgent need for new therapies. While there are a lot of ongoing development programs in IPF, current and in-development therapies have not shown an impact on chronic cough, which is one of the most difficult aspects of IPF, elevating the unmet need. Our trial, CORAL, is a Phase IIb parallel-arm dose-ranging study that will study three active doses of Heduvia and placebo. The study is a six-week trial in approximately 160 patients. We are conducting this study in multiple countries and sites to be able to complete enrollment in a timely manner. We expect to have the majority of our planned 60 sites activated by the end of June. Enrollment is progressing and we are working with our sites to ensure our study is top of mind. We reaffirm our guidance for this study in which we expect to read out the results from our sample size re-estimation analysis in the second half of this year and we continue to expect top line data for the full study in the first half of 2025. As a reminder, the SSRE is conducted when 50% of the subjects complete the study. We intend to share the SSRE results once it is complete, which will either confirm our current study sizing assumptions recommend upsizing within a pre-specified range, or indicate futility. We have also made good enrollment progress on our human abuse potential study, or HAP, this year. This study is now approximately 75% enrolled, and we expect to complete enrollment this summer. The objective of this study is to determine the abuse potential of oral nalbufine relative to butorphanol and placebo, and was designed and agreed upon with FDA input. Recall that parenteral nalbufine is unscheduled by the DEA and was recently rereviewed by the DEA and left unscheduled. It's also important to note that the two parts of nalbufine's mechanism are also unscheduled, whether it be kappa agonists such as Corsuba or mu antagonists in products such as naloxone and naltrexone. This study will be submitted with our NDA as part of an eight-factor plan, which includes all the preclinical work done to date the mechanistic rationale for why this drug is unscheduled, our clinical data generated in our development programs, the results of this HAP study, as well as a public health rationale. Our goal is to have oral nalbuphenia remain unscheduled as the parental form has been all these years. We continue to expect top line data from this study in the second half of this year as well. Finally, our IND for IPF cough was cleared by the FDA And we expect to initiate our respiratory physiology study in the third quarter of 2024. We anticipate this study being conducted in the U.S. and in the U.K. The goal of this study is to systematically measure the impact of nalbuphener on respiratory depression in varying levels of disease severity and IPF to determine our phase three patient population. To date, we have excluded sleep disordered breathing patients in our studies and we want to better characterize the safety in this group as we move forward. As you can see, it is a busy time clinically for Trevi, and we believe the data from these trials will be important to inform the development path forward for Heduvia across chronic cough conditions. We are excited to begin completing these studies in the second half of this year and reporting the data. On a final note, our management team will be attending several medical conferences over the next few months, including the American Thoracic Society meeting in San Diego in a couple weeks, the London Cough Conference in July, and the European Respiratory Society meeting in Austria in September. Please let us know if you plan to attend, as we would love to meet with you. I will now turn it over to Lisa to review our financial results, then we will open it up for any questions.
spk08: Thank you, Jennifer, and good afternoon, everyone. The full financial results for the three months ended March 31st, 2024 can be found in our press release issued ahead of this call and our 10Q, which was filed with the SEC today after the market closed. The first quarter of 2024 was a quiet quarter for finance as the rest of the company is operationally focused on the enrollment and execution of our four trials that Jennifer discussed today. For the first quarter of 2024, we reported a net loss of $10.9 million compared to a net loss of $6.4 million for the same quarter in 2023. R&D expenses were $8.8 million during the first quarter of 2024 compared to $5 million in the same quarter of 2023, primarily due to increased clinical development expenses for our Phase IIb choral trial, our Phase IIa river trial, and our HAP trial. These increases were partially offset by decreased clinical development expenses for our Phase IIb-3 PRISM trial. G&A expenses were $3.1 million during the first quarter of 2024 compared to $2.6 million in the same period of 2023, primarily due to increases in information technology and finance staffing and activities as well as professional fees. Other income net was $1 million in the first quarter of 2024 compared to $1.2 million in the same period of 2023. As of March 31st, 2024, our cash, cash equivalents and marketable securities totaled $72.8 million compared to $83 million as of December 31st, 2023. We used about $10.9 million in cash in Q1-24, offset by about $700,000 of interest received. This is within the range of our expected cash burn for the year of $9 to $12 million per quarter. Our cash runway guidance remains unchanged, and we have cash, cash equivalents, and marketable securities into 2026. This concludes our prepared remarks, and I will now turn the call back over to the operator for Q&A.
spk06: Thank you. We will now begin the question and answer session. To ask a question, you may press star, then one on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then two. The first question comes from Leland Gershow from Oppenheimer. Please go ahead.
spk01: Leland Gershow from Oppenheimer. Good afternoon. Thanks for taking our questions. Just two from us. First, in terms of the upcoming ATS meeting, we look forward to, I believe we'll be hearing a coughed out analysis from Canal by Dr. Jackie Smith from the UK. As we look forward to those data, if you could maybe, Jennifer, kind of discuss what the formal definition of a cough bout would be, at least in this setting, and to what extent do cough bouts impact patients with IPF? And then I have a second question. Thanks.
spk07: Yeah, sounds good. I'll kind of tee it up, and I'm going to let David give you the specifics because he was deep into the paper. The reality is this whole concept of cough bouts, it reminds me a lot of itch in that you know, when we talk about average cough, that's sort of averaged over time. But there's a belief that when people have these severe bouts, that's what's doing a lot of the damage. So people are starting to get interested in looking at what that looks like. Unfortunately, there's no agreement in the field as to how you define a cough bout. So that is sort of part of the debate. And there's two very leading KOLs who have taken our data and done the analysis. So Dr. Smith will present that, and I'll let David speak exactly to sort of her methodology at this meeting. And then I think in the fall, one of the other KOLs is going to present it sort of using a different methodology. But David, can you explain sort of Jackie's methodology and how that will be presented?
spk00: Absolutely, I can. So the methodology that Dr. Smith prefers is a cough bout is defined by two coughs. a minimum of two coughs, and then you have to have an off period. And the off period is so that a bout is if you have a cough, and typically if the off period is a two-second duration. So if you have a cough within two seconds, that bout is ongoing. Now, in an exploratory way, she likes to look at cough bout periods of periods of one seconds up to 10 seconds. So what you'll see in the paper is looking at the definition of this cough bout. So that's a cough within this duration that varies between one and 10 seconds. And that sort of cough bout definition, as Jennifer Good said, there's not complete consensus in the field, but the methodology that Dr. Smith uses is probably amongst the commoner of the cough bout definitions. And then we have, as we say, we have this other methodology that will be presented later in the year.
spk01: Thanks, David.
spk03: Thank you, David.
spk01: And then I just wanted to ask, with respect to the HAP study, I know you're looking at a few different doses there, and it's obviously encouraging to hear, you know, recent support for lack of scheduling for nalbutene from the FDA. If we were to see significant liking At, I guess, any of those dose levels, would that be incremental concern that we could see some form of DEA scheduling? What would be kind of the sensitivity if you have that, you know, in any sort of way that you can quantify for us to the risk of scheduling based on the HAP study content?
spk07: Yeah, so the scheduling decision will be made. It'll be a review decision, you know, first by the division that gets deferred to the DEA. They do look at sort of the gestalt, if you will, of the eight-factor plan. So the mechanism of the drug, what they know about it from epidemiology, what you saw in your own clinical trials, just there's sort of a whole big picture they look at. Now, the HAP is not, the preclinical data is also quite important, which has all been done, and that's all clean. The HAP, though, is not insignificant, I think. it's not that you can't see anything in your data. It's all going to be, you know, in theory, you're going to be a little more likable than placebo. I think if you're significantly more likable than butorphanol, it opens up the conversation. I think it'll just depend. We'll have to look at that data sort of in context of everything else. I will tell you, though, when I sat through the original discussions of what the FDA focuses on, it's not that you can't have sort of any signs of this. What they really get worried about is a dose response to likability. So if you have some likability at call, your low dose, and that doubles and then triples with sort of your high dose, that's where you get into issues because they obviously worry people take, you know, 10 of your tablets and that's a problem. So it's a hard question to answer, Leland, and internally we've been grappling with. I think when we have the data, we'll put it out as clear as we can and have an expert join the call so that people can, you know, interrogate the data themselves and ask the questions.
spk01: Fair enough. Thank you for the incremental college.
spk03: Yes, thank you. And we'll see you at ATS.
spk06: The next question comes from Jack Padovano from Stiefel. Please go ahead.
spk02: Hi, this is Jack on for Annabelle. Thanks for taking our questions. So when you arrive at this sample size re-estimation for IPS, what might the chances be that the study has already hit statistical significance at that point? And if that occurs, would you just continue as planned until final readout, or could you potentially halt the trial early in that case? And then kind of to follow up on that, just recalling the magnitude of effect that we've seen in IPF already, if those kinds of effects persist in upcoming trials, are there any opportunities for you to move straight from POC into Phase III?
spk03: So, David, I'll let you answer both of those.
spk00: Yes. So with the SSRE we are utilizing, it is not acceptable with regulators, particularly the FDA, to use the success criteria such as you've outlined. So you've got 80 subjects completed at the primary time point, and you've separated with several doses from placebo. The FDA will not allow you to build that sort of success criteria into this sort of a standard SRE. So there's the answer to the first question. first question. It really just, in a closed-loop system, you say, is your variance and your effect size sufficient for your assumptions going in? So your sample size cannot fall below 160. And what was your second question? I'm sorry.
spk07: The second question, I can jump in, David, and then you can add color. He wanted to know if the magnitude of effect is strong, can we go straight from POC to pivotals? And I think You know, in IPF, we're doing a phase 2B to select dose, and the intent is to roll into our pivotal program. I think with River, the phase 2A, the internal consensus is, and David, this is where you can add some color, is we are planning for a phase 2B that is structured to look like a pivotal. So we still are probably going to need to do some dose-ranging work to make sure we're clear in that patient group, but we will try to structure it to look like a pivotal study, and then depending on the data. can hopefully have discussions. But David, any color you want to add on that?
spk00: No, I think that addresses it very well. Thanks, Jennifer.
spk02: Great, thank you.
spk03: Thank you, Jack.
spk06: The next question comes from Tom Smith from Laring Partners. Please go ahead.
spk04: Hi, this is Tom Smith. We have a couple of questions on the reverse study. So first, what's the rationale for shooting 21-day duration while the other late-stage trials look at endpoints at 12 or 24 weeks and have a follow-up.
spk07: Yeah, I mean, the rationale is all phase 2As. I mean, for the compounds you currently see in development, they all ran this phase 2A crossover design as a proof of concept, sort of to show that your drug is working. It takes away some variability. As you exit the proof of concept, that's when you get into the longer trials.
spk04: Got it. And what's your expectation on the data expected in second half 24? Do you anticipate to see different levels of efficacy in patients with moderate versus severe cough frequency as you look at where to change in cough frequency rather than the absolute changes?
spk07: Yeah, David, do you want to talk a little bit about sort of the hypothesis around the study and what we're trying to show with the different cough levels and things?
spk00: I'd be happy to do that, Jennifer. So the information we have so far, and it is as you mentioned, you know, it's only from the canal study in IPF chronic cough population, is that baseline cough frequency did not influence the efficacy signal. It was as robust in the subjects independent of that cough frequency. So that's the only information we have going into this. And as you're aware, there has been difficulty with peripheral-based mechanisms of action, getting the signal in that moderate population. But our information going into the study is that based on the IPF chronic cough, we didn't see any evidence of a difference, a change based on baseline cough frequency.
spk04: Got it. And do you plan to include efficacy in points that can capture, for example, a cough cluster or cough episode which appears to burden patients with RCCs? I'm sorry, can you repeat that question?
spk07: Is that the COP clustering you're asking about, and are we capturing some of that data?
spk00: Yes.
spk07: Yeah. And David, I think we have an ability to go back and do that analysis, correct?
spk00: We do. Actually, we have that pre-specified as analysis, which we will be conducting. Because as we have mentioned before, we believe We think the primary endpoint for cough programs, we believe, will stay the same as it is right now, using 24-hour cough frequency. But there's clinical relevance to these cough bouts by these different definitions. So we really want to study them in all of our studies moving forward so we understand what sort of effects we're having there, in addition to what we believe will be the registration endpoint.
spk04: Got it. Thank you so much.
spk06: Thank you. As a reminder, if you have a question, please press star 1. The next question comes from Mayank Mamthani from B. Reilly Securities. Please go ahead.
spk05: Good afternoon, team. Thanks for taking your question, and congrats on the progress. So just maybe on the SSRE for the CORAL trial, if you could just maybe clarify the statistical assumptions for CORAL. placebo as well as, I guess, the top dose you're looking to show separation against? Just maybe, you know, how many patients, what sort of effect size and p-value? And also, are there any baseline characteristics that could be different between coral than canal that we should be aware of? And then I have a quick follow-up.
spk07: David, you want to take that?
spk00: I'm happy to do that, Jennifer. So in terms of the inclusion criteria, we did not change them. So the way we are selecting the IPF chronic cough population is the same as we utilized in canal. I mean, the main difference, as you know, is it's a global program. So there is the potential for some differences there. We will see in the study. So the assumptions we made for the SSRE, the N of 160, so that's 40 per group. That is based on an effect size of active drug above placebo on top of the placebo effect. So the separation on top of placebo effect of 36%. We've got more than 80% power going into the study with the N of 160, 40 per group. The top end of the sample size that we are allowed to go to, we set at 160 we can go up to 400. And that's if we either have a variance which is not, is higher than we expected, or the effect size is smaller. So for example, if the effect size, the increasing it to the top sample size of 400, that's 100 per group, if that is necessary, that would allow us to detect a clinically relevant effect size of 25% on top of placebo. So that's how we framed the SSRE characteristics.
spk05: Super helpful. And then on the phase two reverse study, moderate versus severe cohorts, are they equally split in terms of enrollment? And would you be looking to present data in second half, you know, in both of those cohorts, or you do a sort of a total pooled analysis? And then lastly, what's the forum for this half-study presentation. Obviously, great to see the 75% enrollment achieved, but it does have a relatively short follow-up. So just curious if that would be a press release or an event, a KOL event, if you could clarify that. Thanks again for taking your questions.
spk07: Yeah, thank you, Mayank. So far, so good on the enrollment in RIVER. We're seeing sort of equal numbers in both moderate and severe. Obviously, we won't finish the study until we get everybody in. We do plan to report that out as part of our top line data, so that won't come later. That'll be part of our top line data reported out. As far as the forum for human abuse potential, we're sort of working through that, but I think what we're working towards is a press release and then also doing a call with probably an expert or two on the phone that works in this area regularly. So we'll present the data on our end, but then also open up the call to folks like you to be able to ask whatever questions you'd like around the data. I mean, hopefully it's clear and sort of not a lot to discuss, but that's also encouraging and allows you guys the opportunity to sort of confirm that yourself. So that's the current plan that we are working against.
spk03: Understood. Looking forward to it. Thank you. Good. Thank you. I am not showing any further questions.
spk06: This concludes our question and answer session. I would like to turn the conference back over to Jennifer Good for closing remarks.
spk07: Thank you. We are expecting a data-rich year with regards to our clinical trials for Hadovio. We see an exciting road ahead for Trevi, and we are locked down on executing good quality trials on time. We will be participating in several investor conferences over the next couple of months, as listed in our press release, and look forward to seeing many of you there. Thank you for joining today's call, and we are available after the call for any follow-up questions you may have.
spk03: The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.
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