Trevi Therapeutics, Inc. Q1 FY2024 Earnings Call

Good afternoon, and welcome to the Trevi Therapeutics First Quarter 2024 Earnings Conference Call. 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. Actual results may differ materially from those indicated by these forward-looking statements due to various important factors, including those discussed in the Risk Factors section of the company's most recent quarterly report on Form 10-Q, which was filed with the SEC this afternoon. Additionally, any forward-looking statements reflect the company's views only as of today and should not be relied upon as representing the company's views at any later date. While the company may choose to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so even if its views change. I would now like to turn the conference over to Jennifer Good, Trevi's President and CEO. Please go ahead.

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 6 weeks ago. So Lisa and I will give a brief update then the 3 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 8 weeks despite treatment for the underlying condition. With the 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 Haduvio in refractory chronic cough is the mechanism of action, which works synergistically both centrally in the brain and peripherally in the lungs. We believe Haduvio'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, 2-period crossover study, evaluating the reduction of cough in approximately 60 patients. This design is similar to other Phase IIa cough trials run to date but does incorporate a meaningful difference. These patients will be randomized with a 1:1 stratification between those with 10 to 19 coughs per hour and those with greater than 20 coughs per hour. Each treatment period will last 3 weeks separated by a 3-week washout period. Patients on Haduvio 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, microtears and potential inflammation caused by persistent coughing may lead to worse health outcomes for patients such as increased respiratory hospitalization, 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 3 active doses of Haduvio and placebo. The study is a 6-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 reestimation 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 sample size reestimation is conducted when 50% of the subjects complete the study. We intend to share the sample size reestimation results once it is complete, which will either confirm our current study sizing assumptions, recommend upsizing within a prespecified range or indicate utility. 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 nalbuphine relative to butorphanol and placebo and was designed and agreed upon with FDA input. Recall that parenteral nalbuphine is unscheduled by the DEA and was recently re-reviewed by the DEA and left unscheduled. It's also important to note that the 2 parts of nalbuphine's mechanism are also unscheduled, whether it be kappa agonists such as Korsuva or mu antagonists in products such as naloxone and naltrexone. This study will be submitted with our NDA as part of an 8-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 nalbuphine ER remain unscheduled as the parenteral 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 nalbuphine ER on respiratory depression in varying levels of disease severity in IPF to determine our Phase III patient population. To date, we have excluded sleep disorder 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 Haduvio 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 of weeks, the London Cough Conference in July and 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.

Thank you, Jennifer, and good afternoon, everyone. The full financial results for the 3 months ended March 31, 2024, can be found in our press release issued ahead of this call and our 10-Q, 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 4 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 '23, primarily due to increased clinical development expenses for our Phase IIb CORAL trial, our Phase IIa RIVER trial and our HAP trial. These increases were partially offset by decreased clinical development expenses for our Phase IIb/III 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 31, 2024, our cash, cash equivalents and marketable securities totaled $72.8 million compared to $83 million as of December 31, 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 million 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.

Your first question comes from Leland Gershell from Oppenheimer.

Just 2 from us. First, in terms of the upcoming ATS meeting, we look forward to, I believe, we'll be hearing a cough bout analysis from Dr. Jacky Smith from the U.K. 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 the setting? And to what extent do cough bouts impact patients with IPF? And then I have a second question.

Yes, 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 reminds me a lot of itch and that when we talk about average cough, that 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 2 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 just 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 Jacky's methodology and how that will be presented?

Absolutely, I can. Dr. Smith defines a cough bout as occurring with a minimum of two coughs followed by an off period. The off period is established to indicate that a bout is ongoing if a cough happens within two seconds. Exploratorily, she examines off periods ranging from one to ten seconds. The paper will detail this definition of a cough bout, highlighting that coughs occurring within that fluctuating time frame are considered part of the same bout. While there isn't complete agreement in the field, Dr. Smith's approach is one of the more commonly accepted definitions of a cough bout. We also have another methodology that will be presented later this year.

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 recent support for lack of scheduling for nalbuphine from the FDA. If you 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 in any sort of way that you can quantify for us to the risk of scheduling based on the HAP study?

The scheduling decision will be made following a review by the division, which then defers to the DEA. They consider various factors, including the drug’s mechanism, epidemiological data, and the results from clinical trials. The preclinical data is also essential, and it is all clear. However, the HAP is noteworthy. While the data might not raise significant concerns, being more likable than placebo is expected. If it shows significantly higher likability compared to butorphanol, it could lead to further discussions. The interpretation of this data will depend on the broader context. In previous discussions regarding FDA concerns, the key issue is the dose response to likability. If a low dose shows some likability and that response doubles or triples at higher doses, it raises concerns about potential abuse. It's a complex issue, and we have been considering it internally. Once we have the data, we will present it clearly and have an expert available to address any questions.

The next question comes from Jack Padovano from Stifel.

This is Jack on for Annabel. So when you arrive at this sample size reestimation for IPF. 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 a 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 3.

So David, I'll let you answer both of those.

Yes. So with the sample size reestimation 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 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 sample size reestimation. So there's the answer to the 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.

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 in IPF, we're doing a Phase IIb to select dose and the intent is to roll into our pivotal program. I think with RIVER, the Phase IIa, the internal consensus is, and David, this is where you can add some color, is we are planning for a Phase IIb 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?

No, I think that addresses it very well. Thanks, Jennifer.

The next question comes from Tom Smith from Leerink Partners.

This is Nat Charoensook on for Thomas Smith. We have a couple of questions on the RIVER study. So first, what's the rationale for choosing a 21-day duration while the other late-phase trials look at endpoints at 12 or 24 weeks? And I have a follow-up.

The rationale is that all Phase II trials for the compounds currently in development used a Phase IIa crossover design as a proof-of-concept to demonstrate that the drug is effective, helping to reduce variability. Upon completion of the proof-of-concept, the trials transition to longer durations.

Got it. And what's your expectation on the data expected in 2024? Do you anticipate seeing a different level of efficacy in patients with moderate versus severe cough frequency, as you look at what change in cough frequency rather than the absolute changes?

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?

I'd be happy to do that, Jennifer. The information we have so far from the CANAL study in the IPF chronic cough population indicates that baseline cough frequency did not affect the efficacy signal. It was consistent among subjects regardless of their cough frequency. That is the only information we have at this point. As you know, there have been challenges with peripheral-based mechanisms of action in obtaining signals in that moderate population. However, our findings in the study suggest that in the IPF chronic cough context, we did not observe any evidence of a difference based on baseline cough frequency.

Got it. And do you plan to include efficacy endpoints that can capture, for example, cough cluster or cough episodes appear to burden patients with RCC?

I'm sorry, can you repeat that question?

Is that the cough clustering you're asking about? And are we capturing some of that data?

Yes.

Yes. And David, I think we have an ability to go back and do that analysis correct.

We have that prespecified as analysis, which we will be conducting because we believe the primary endpoint for cough programs will remain the same, using 24-hour cough frequency. However, there is clinical relevance to these cough bouts defined in different ways. Therefore, we want to study them in all of our future studies to understand the effects we are having in addition to what we believe will be the registration endpoint.

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

Congrats on the progress. So just maybe on the sample size reestimation for the CORAL trial. If you could just maybe clarify the statistical assumption for placebo as well as, I guess, the top dose you're looking to show separation against. Just maybe 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.

David, do you want to take that?

I'm happy to address that, Jennifer. In terms of the inclusion criteria, we have not made any changes. We are selecting the IPF chronic cough population using the same method as in CANAL. The main difference is that this is a global program, which could lead to some variations that we'll evaluate in the study. For the sample size reestimation, we plan to have a total of 160 participants, with 40 in each group. This is based on the expected effect size of the active drug over placebo, plus the placebo effect, resulting in a separation of 36%. We are confident with over 80% power for the study with this sample size. While we will start with 160, we are allowed to increase up to 400 if the variance is higher than anticipated or if the effect size is smaller. If we do increase to the maximum size of 400, that would mean 100 participants per group and would still enable us to detect a clinically relevant effect size of 25% above placebo. This outlines the rationale for our sample size reestimation.

Super helpful. And then on the Phase II RIVER study moderate versus severe cohorts, are they equally split in terms of enrollment? And would you be looking to present data in the second half in both of those cohorts or do you do sort of a total pooled analysis? And then lastly, what's the program 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 or KOL event. If you could clarify that.

Thank you, Mayank. We're currently seeing balanced enrollment in both moderate and severe groups for the RIVER study. We won't complete the study until all participants are enrolled, and we intend to include this information in our top line data report. Regarding the human abuse potential, we are working on that as well. Our plan is to release a press statement and hold a call with one or two experts who regularly work in this field. We will present our data and then open the call for questions from you and others about the data. We hope the information is clear and straightforward, but we also want to give you the chance to confirm it for yourselves. That's our current plan.

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

Thank you. We are expecting a data-rich year with regard to our clinical trials for Haduvio. 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.

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