Trevi Therapeutics, Inc. Q4 FY2023 Earnings Call

Good afternoon, and welcome to the Trevi Therapeutics Fourth Quarter and Year-End 2023 Earnings Conference Call. At this time, all participants will be in listen-only mode. After today's presentation, there will be an opportunity to ask questions. Please note, this event is being recorded. Various remarks that management makes during this conference call about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of the company's most recent quarterly report on Form 10-K, 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 of subsequent dates. 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 Good, Trevi's President and CEO. Please go ahead.

Good afternoon, and thank you for joining our fourth quarter and year-end 2023 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. Lisa and I have some prepared remarks, then we will open it up for questions. The fourth quarter of 2023 and the start of 2024 was a productive time for Trevi with the initiation of three clinical studies. Let me provide a brief update on each of these trials. I will begin with our Phase 2a RIVER trial in Refractory Chronic Cough that was initiated in the fourth quarter of 2023. 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 an underlying condition. RCC is caused by cough reflex hypersensitivity in the central and peripheral nerves and has a significant impact on patients physically, psychologically, and socially. With multiple drug failures in the space and 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 treatments. The key point of differentiation for Haduvio and 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 central and peripheral 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. RCC patients have been stratified for clinical trial purposes into three categories of frequency: very high, greater than 20 coughs per hour; high to moderate, 10 to 19 coughs per hour; and low frequency coughers. The very high and high to moderate frequency coughers are all considered as having severe cough by the Key Opinion Leaders. The P2X3 to date only demonstrated statistical significance in the very high cough counters and have not shown successful results in the cough frequency of 10 to 19 coughs per hour. We believe that based on the data from our IPF cough trial, which showed a strong drug effect across all baseline cough counts and the drug's central and peripheral mechanism of action, that Haduvio has the potential to work in patients broadly across varying cough frequencies. When you look at the RCC patient distribution, 44% of the patients are estimated to have moderate to high cough frequency, whereas only 29% are estimated to have very high cough frequency. So there's potential Haduvio may address close to three-fourths of the RCC market, whereas P2X3 may only be effective in less than a third of the market. On to the details of our RCC trial, which is the standard design across several cough trials run to date. The RIVER trial is a Phase 2a double-blind randomized, placebo-controlled, two-period crossover study evaluating the reduction of cough in approximately six patients. 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 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 at day 21 from treatment period baseline for Haduvio compared to placebo, 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 are excited to have initiated this study and expect to have substantially all the sites activated by the end of this month. 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 idiopathic pulmonary fibrosis or 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 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 in 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, one of the primary complaints of these patients, elevating the unmet need. At the end of 2023, we initiated a Phase 2b study in chronic cough in IPF, the CORAL study. CORAL is a four-arm Phase 2b dose-ranging trial that will study three active doses of Haduvio and placebo. The study is a six-week trial involving approximately 160 patients. We plan to conduct this study in multiple countries and sites to complete enrollment in a timely manner. Site activations are moving along in multiple countries and enrollment is in the early stages. We reconfirm our guidance for this study for top-line data in the first half of 2025, assuming no changes from our sample size re-estimation results, which are expected in the second half of this year. Finally, we initiated dosing of the final part of the human abuse potential or HAP study in January of this year. The final portion of the HAP study is a randomized, double-blind, double-dummy five-way crossover design to determine the abuse potential of three doses of oral nalbuphine relative to the selected dose of IV butorphanol and placebo. The primary objective is to evaluate the likability of nalbuphine as compared to both placebo and butorphanol, and the primary endpoint is a drug-liking visual analog scale. Recall that parenteral nalbuphine is unscheduled by the DEA. This study is moving along nicely, and we have passed the 50% enrollment mark. We continue to expect top-line data from this study in the second half of this year as well. 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 and chronic cough conditions. We are motivated by the potential to offer an effective treatment to patients with these serious conditions and chronic coughs. I will now turn it over to Lisa to review our financial results, then we will open it up for any questions you may have.

Thank you, Jennifer, and good afternoon, everyone. The full financial results for the three months ended December 31, 2023, can be found in our press release issued ahead of this call and our 10-K, which was filed with the SEC today after the market closed. For the fourth quarter of 2023, we reported a net loss of $7.8 million compared to a net loss of $5.5 million for the same quarter in 2022. R&D expenses were $6.5 million during the fourth quarter of 2023 compared to $4.3 million in the same quarter of 2022. The increase was primarily due to increased clinical trial costs in our Phase 2b CORAL trial and our Phase 2a RIVER trial, both of which were initiated in the fourth quarter of 2023. G&A expenses have remained essentially flat at $2.4 million during the fourth quarter of 2023 compared to $2.3 million in the same period of 2022. We take a very disciplined approach to cash management and as a result, while R&D expenses increased as we are starting up four clinical trials, G&A expenses have remained consistent. Other income net was $1.1 million in both the fourth quarter of 2023 and 2022 and primarily consists of interest income on our cash balances, offset by any interest expense. We paid off our term loan in May of 2023, so interest expense was negligible in the fourth quarter of 2023. As of December 31, 2023, our cash, cash equivalents, and marketable securities totaled $83 million compared to $120.5 million as of December 31, 2022. Our cash runway guidance that we will have cash, cash equivalents, and marketable securities into 2026 remains unchanged, and we believe is enough to fund all of the trials Jennifer just discussed and gives us good cash runway after the last readout. In 2024, we expect average cash burn of about $9 million to $12 million per quarter and our fully diluted shares outstanding at December 1, 2023 is $114.5 million. This concludes our prepared remarks. I’ll now turn the call back over to the operator for Q&A.

We will now begin the question-and-answer session. Our first question comes from Leland Gershell with Oppenheimer. Please go ahead.

Good afternoon and thanks for taking our questions. Two from us. First, with respect to IPF did the CORAL design. Just wanted to have clarity on the primary endpoints. You're testing three dose levels and then you have placebo. So will that primary endpoint in terms of 24-hour cough frequency be the aggregate cough frequency across all three doses versus placebo, or would it be to analyze on an individual basis with each dose level versus placebo? Thank you.

Go ahead, David.

So Leland, thank you very much for the question. So the analysis will be per dose level. So high dose, mid dose, low dose, all compared independently with placebo. It's important for us to get a good feel for the dose response and that analysis allows us to do that.

Okay. Thanks. That's very helpful. And then my other question, just wondering, maybe Jennifer, if you could comment on the recently published data from a short-term trial of low-dose controlled morphine used in the IPF offsetting, which has shown a 40% reduction in cough related to placebo. But in the context of the fact that it was only a two-week trial and then, of course, morphine versus nalbuphine? Thank you.

It's a good question. The PAciFy trial conducted in the U.K. confirmed our expectations. We believe in the mechanism and the effectiveness of the opioid pathway. Additionally, we think the combined action of targeting both kappa and mu receptors with our drug is significant. This is reflected in the observed 40% reduction in morphine and a 74% to 76% reduction in nalbuphine. We were confident that it would be effective, and we anticipated that our drug would likely outperform others. One of the limitations of morphine is its potential for respiratory depression, which restricts dosage levels and ultimately limits its effectiveness.

Okay. Thanks very much for the added information.

Thank you.

The next question comes from Thomas Smith with Leerink Partners. Please go ahead.

Hi. This is on behalf of Tom Smith. Congratulations on the progress you've made in 2023. We have a couple of questions. First, you plan to conduct a sample size estimation for the CORAL trial. Can you explain the rationale and details behind the sample size? Also, could you remind us of the number of targeted clinical sites and the distribution between the U.S. and international sites?

Yeah. I'm going to let David do this.

Yeah. No. Thank you very much for the question. So the rationale is really to protect the study. We believe we've seen a very clinically relevant effect, as we've described in the Phase 2a study. So we want to be protected from the situation where the estimates that we have for the effect size going into the CORAL study we've assumed a 36% effect size. We believe we've been appropriately conservative compared to the placebo-corrected more than 50% effect size that we saw in the Phase 2a study. But we wanted to protect ourselves from the situation where the effect size could still be clinically relevant because, as you know, from experts in this field, a 20% to 30% effect size on objective cough is believed to be clinically relevant. So if we have, and what we've done with the powering and the sample size re-estimation supports this is, if we have an effect size that is not as large as we saw in the Phase 2a, but it's still clinically relevant, for example, 25%, we can detect that with an increased sample size.

Got it.

Yeah. I would just add too, David, there hasn't been a lot of work done in this area, right? There was one other good-sized study in our small CANAL study. Everything else has failed or been too little. So you're powering with not a lot of information. So it made sense, I think. Do you want to take this question too, a number of targeted sites and do you ask ex-U.S.?

Yes. So we'll be approximately 60 sites or so our plan for the CORAL study. And right now, the majority of those sites are ex-U.S. So they're primarily in the EU and the U.K. We also have sites starting up in Australia and other regions, so Australia, Chile, and Canada. Those are the main regions and countries we're in at the present time and planning.

Got it. Very helpful. And one last question, do you have an end-of-Phase 2 meeting with the FDA for Haduvio in prurigo nodularis and what's the feedback from the meeting and the progress on partnership discussion? Thank you.

No, we have not yet filed a request for an end-of-Phase 2 meeting. As you can tell from late in the year, David and his team were quite busy getting these studies up and running. We have one more study we want to get started, and we are finalizing all the reports and writing what we need to. We will file for an end-of-Phase 2 meeting sometime this year, but it has not been a priority thus far. We haven’t done so yet, but we will get there eventually.

Got it. Thank you so much.

Yeah. Thank you for the questions.

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

Hi. Good afternoon. Thanks for taking the question. I guess for Jennifer and David, just curious what kind of takeaways or KOL feedback you've gotten following the FDA advisory committee for Merck's P2X3 candidate and the second CRL. Just curious if there's been any change regarding the approach to clinical development or how they view the market opportunity for refractory chronic cough? Thanks.

David and I are looking at each other because we can both answer this. I'll give a couple of comments and then let David comment. I mean, fundamentally, I think at the end, not only sort of what everybody saw in the briefing book and listening to the meeting, but we also followed up with KOLs at our own advisory board to make sure we weren't missing something. I think fundamentally, the Merck drug just didn't have good enough efficacy to clear the hurdles and got hung up in the primary endpoint didn't correlate with the pros, etc. So I think at the end of the day, that was it, I would say, and then I'll let David comment. The other takeaway that I certainly had from listening to the advisory committee was just how compelling the patient stories were about how disruptive RCC is to their lives. That made a huge impact on me. And I think you heard it from the panel and from the FDA that they recognize that this is a serious disease. Having watched that journey over the last five years when there was some debate about whether this was a real condition, I think that ship has clearly sailed. I left that call feeling that the FDA has bought in and the patients did a really good job of making the case. So David, from the drug developer's perspective, what do you hear?

I agree with what you've said. The only pieces I would add are two points. I think effect size, what we hope will be a differentiating factor for our program is the effect size. If we get a translation from the effect size we saw in the IPF cough population into the RCC population when we see in Phase 2a and hopefully subsequent studies. So we think that will be a differentiator, really protecting us from what happened to that Merck program, as you said, Jennifer. The only other piece I'd add is that there are so many learnings you were aware of from the Bellus now GSK program that are in place. I think also as a field, a lot of the KOLs were reflecting to us that a lot of lessons have been learned from these multiple programs being run, which we utilize. Hopefully, we're successful in Phase 2a and RIVER, and we're expanding into the larger studies. There's a lot of good learnings to be gained, which are to our advantage.

Yes. It's never easy to be the first guy over the wall in a new condition. But it makes our job easier for sure.

Thank you.

Thank you, Serge.

Our next question comes from Mayank Mamtani with B. Riley Securities. Please go ahead.

Hi. This is actually William on for Mayank here. Thank you for taking our questions and congratulations on the nice year-end quarter. On your Phase 2a RIVER and HAP trials, do you plan on announcing full enrollment or last patient dose to give some refinement as the time frame expectations surrounding these readouts? And should we expect the HAP trial to read out first, given that it's already over 50% enrollment? I have a couple of follow-ups.

Yeah. Thank you for the questions, William. I think what you should expect is, we'll let people know when the study initiates, we'll give guidance around what we think the top-line data readout is. I think we'll also let people know when we hit the 50% enrollment mark so that investors and analysts will know whether we're on sort of the front end of enrollment or the back end of enrollment, and we would announce last patient in, that's a pretty big milestone. So what we're going to avoid doing is providing update by update of sort of where we are in enrollment, that just gets painful all around for everybody. So that's our current thinking.

That's helpful. Also, can you provide an update on your plans to meet with the FDA regarding the next steps, particularly for the HAP trial? Will these discussions include REMS or other regulatory matters based on the readout? How should we expect this to unfold? Will it be addressed in a single meeting, and how will these insights be integrated into future trials?

Correct. So our current thinking is we're doing the preparations right now with experts in the abuse liability field, so that we are ready when that data comes in to really interrogate it with them and get their expert opinion. And then with that, you're quite right, then we'll make our decisions on what we think are the logical next steps for any further discussion with the regulators, so that's what we're currently planning.

And probably, David, that goes into, at a minimum, the end-of-Phase 2 discussion around IPF, right? Because that will be a defined meeting. I think whether we choose to do something separate from that is probably really only relevant if there's something in the data we want to flag. So I would expect, William, at the end-of-Phase 2 meeting for IPF, we'll bundle all that up and probably discuss it then.

Okay. No. That's…

I didn't answer your question. By the way, I remember that you had asked which we thought would come first. And you're right. I think with the HAP study only needing 56 subjects and we're more than 50% enrolled. I imagine that trial will report out first.

Okay. I appreciate that. And then maybe last, just on the RIVER trial that it's stratified, obviously, as you said, the primary endpoint with a reduction of cough. Should we be expecting that breakdown at the time of top line to better understand the efficacy in these sub-populations, or I guess just some better color on what we should be expecting at the top line readout when that occurs? Thank you.

You are right in that assumption. We plan to analyze the overall population as well as these two subpopulations, and we intend to announce those results alongside the top line data readout.

Awesome. Appreciate it and thank you for taking our questions. I’ll turn back in the queue.

Thank you, William.

I am 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 any closing remarks.

Thank you. We are expecting a milestone year with regards to our clinical trials data for Haduvio. We see an exciting road ahead for Trevi and look forward to focusing on the execution of our clinical trials to get to data in these important indications beginning in the second half of this year. We would like to thank everybody for participating in today's call and are available after the 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.