TRVI - NASDAQ

Good afternoon and welcome to the Trevi Therapeutics’ Second Quarter 2023 Earnings Conference Call. [Operator Instructions] 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 annual report on Form 10-K which the company filed with the SEC this afternoon. In addition, any forward-looking statement represent the company’s views only as of today and should not be relied upon as representing the company’s views as of any subsequent date. While the company may elect to update these forward-looking statements at some point in the future, the company specifically disclaims any obligation to do so even if its views change. I would now like to turn the conference call over to Jennifer Good, Trevi’s President and CEO. Please go ahead.

Good afternoon. And thank you for joining our second quarter earnings call and business update. Joining me today on this call is Lisa Delfini, Trevi’s Chief Financial Officer. Lisa and I have some prepared remarks, then we will open it up for questions. During the quarter, we continue to advance our clinical development plans’ for Haduvio and our chronic cough indications. Let me provide a brief update on each of our programs, beginning with our lead program in chronic cough and IPF. IPF is a serious end-of-life disease. Chronic cough and IPF impacts patients physically, psychologically, and socially, decreasing their quality of life. With no currently approved treatment options for chronic cough, there is an urgent need for new therapies. Chronic cough 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 worsening of disease and potential worsening of outcomes for patients. We are planning to conduct two studies in parallel during this next phase of development in our IPF chronic cough program. The first is a forearm phase 2b dose ranging trial that will study three active doses of Haduvio and placebo. We are planning for a total end in the study of approximately 160 subjects and dosing for six weeks. We plan to conduct this study in multiple countries and sites to be able to complete enrollment in a timely manner. As you may be aware, there is a lot of development work going on with antifibrotics in IPF patients, so we expect that enrollment will be competitive. We feel we have a differentiated trial for patients and investigators as the only chronic cough study in IPF with previously reported positive data. We have finalized the protocol for the dose ranging study and are in the process of working through various submissions to regulatory authorities. We have also completed country selection and are qualifying the sites, working through budgets, and preparing sites for the start of this trial. We estimate this trial will be initiated in the second half of this year, subject to finalizing our regulatory interactions. In parallel, we are planning for a Phase 1b respiratory physiology study. Currently, there is class labeling carrying a generic risk of causing respiratory depression. This is not something we have seen in our safety data across our various studies to date, and there is literature that suggests that mixed agonist antagonist, which is the class nalbufine falls in, have a ceiling effect on the impact on respiration. However, given the pulmonary function of the IPF population, it is important that we characterize Hadubio’s effect, if any, on respiratory depression in IPF patients. Trevi is planning to conduct a Phase 1b inpatient study in IPF patients that have varying levels of disease severity to determine if we see any clinically significant impacts on respiratory depression. This study will help define the patient population for our pivotal program and ultimately the label. We have received FDA feedback on the planned Phase 1b study, have finalized a protocol, and are working through preparations with the two sites that will conduct the study. IND preparations are being finalized, and we expect to initiate this study in the second half of this year as well. In addition to the studies in IPF cough, we have also completed a protocol for a Phase 2 study in refractory chronic cough, or RCC. We believe that because Hadubio works both centrally in the brain and peripherally in the lungs, Hadubio has the potential to provide therapy across a range of chronic cough indications, regardless of what the underlying disease is. We expect that this trial will look a lot like the CANAL trial, which was a dose-escalating crossover design, and we plan to enroll approximately 60 subjects. There have been a lot of trials in RCC with only one mechanism which has seen some success, the P2X3s, which mechanistically work peripherally in the lungs. However, we believe there’s still a significant opportunity for a mechanism that works both centrally and peripherally to potentially provide strong and consistent efficacy in the most difficult to treat RCC patients, including those with high cough counts, but also among patients below the enriched level of 20 coughs per hour currently being used in RCC trials. We are leveraging the learning’s from other companies in our development plans in RCC as we design our own study. Our Phase 2 IPF cough data and mechanism continued to garner a lot of attention at medical conferences during the quarter, with oral presentations at both the American Thoracic Society meeting, as well as the American Cough Conference. We also had the data from the CANAL trial results published in NEJM Evidence. I think this speaks to the importance of the unmet medical need in these difficult to treat IPF cough patients and the medical community’s interest in our program across cough indications. The other indication we have on-going work is the treatment of prurigo nodularis, or PN. We are currently completing the data analysis from the one-year open label extension study that was associated with PRISM, and we intend to present that data at an upcoming dermatology conference. We also plan to seek an end to Phase 2 meeting with the FDA, which we expect to request later this year. After this meeting, we will determine next steps for the program. Finally, we are conducting a human abuse potential study, which is required for the NDA filing. Note that the parenteral version of nalbufine is currently unscheduled in the U.S. by the Drug Enforcement Agency, or DEA. The objective of this study is to compare the likability or abuse potential of oral nalbufine to an agreed upon active comparator, which is butorphanol, for this study. Butorphanol is a Schedule IV drug. The study is being conducted in two parts, with the objective for the first part to characterize various butorphanol doses and choose a dose appropriate for the comparison against oral nalbufine. We have completed Part I of the study and have selected the nalbufine and butorphanol doses for the second part of the study. We have submitted this data to the FDA to get their comments. The second portion of the study is a randomized, double-blind, active, and placebo-controlled five-way crossover design to determine the abuse potential of three doses of oral nalbufine relative to the selected dose of butorphanol and placebo. However, this portion of the study is now delayed a bit, as there is a nationwide shortage of IV butorphanol, the comparator drug in the study. We were working to secure supply from the single-source supplier in the U.S., but then the plant was recently damaged due to a tornado, and we will need to let the company work through that matter before resuming supply conversations. Once we are able to secure IV butorphanol and have input from the FDA on the recommended doses, we will commence the final portion of the study. Importantly, this study is not on the critical path for any of our planned clinical trials. In closing, we are focused on getting these three chronic cough studies up and running and opening good sites to support strong enrollment. We will announce studies as they are initiated and provide more details on the study design and expected timelines. 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 June 30, 2023, 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. For the second quarter of 2023, we reported a net loss of $7.1 million compared to a net loss of $8.1 million for the same quarter in 2022. R&D expenses were $5.8 million during the second quarter of 2023 compared with $5.1 million in the same quarter in 2022. The increase was primarily due to increased consulting and professional fees related to start up activities for the three planned chronic cough trials, as well as an increase in personnel related expenses. G&A expenses were $2.5 million during the second quarter of 2023 compared to $2.7 million in the same period of 2022. The decrease was due to a reduction in market research costs. Other income net was $1.2 million in the second quarter of 2023 compared to other expense net of $0.2 million in the same period of 2022. The change was primarily due to an increase in interest income due to higher cash balances and higher interest rates. As of June 30, 2023, our cash, cash equivalents, and marketable securities totaled $94.2 million compared to $120.5 million as of December 31, 2022. As I discussed on last quarter’s call, during the quarter we elected to pay off our term loan in full. The payoff amount was $6.5 million. The loan was with Silicon Valley Bank, now a division of First Citizens Bank, and we paid it off to free ourselves of restrictions imposed by the lender. 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 the trials Jennifer just discussed and give us good cash runway after the last readout. This concludes our prepared remarks. I will now turn the call back over to the operator for Q&A.

Thank you. We will now begin the question and answer session. [Operator Instructions] Our first question comes from Annabel Samimy from Stifel. Please go ahead.

Hi, everyone. Thanks for taking my question. I just wanted to go over really quickly the learnings that you got from the other trials in RCC. You went pretty quickly. How might this population behave differently from IPF? You mentioned that you’re going to have the same trial design, so I just wanted to understand the specifics around that. Thanks.

Yes, it’s a good question, Annabel. I think the learnings have been around, the endpoint. That’s where the objective cough monitor was sort of nailed down and obviously the validation of counting and all that. I would say the biggest debate that comes around is what how much to enrich or not enrich, and we’ve had a pretty healthy debate internally. As you know, the Bellus [Ph] study had a, I think, three to one enrichment strategy around greater than 20 coughers. In our data in IPF cough, though, we did not see any difference based on level of cough, and after attending some of these medical meetings and having our own advisory boards, there is a big unmet need for what physicians view as severe coughers that are in this 10 to 19 coughs per hour. They view that as severe disease, and the Bellus [Ph] data, and I’ve heard even the Merck data, really only works on sort of these higher cough counters, which is not a big portion of the market. So we’re going to stratify our trial and actually have half the subjects come from this 10 to 19 coughs per hour and greater than 20 coughs per hour, and we feel confident doing that based on what we saw in IPF cough and sort of how it responded in the various cough levels. So I would say that was sort of the biggest debate. Other than that, similar protocol, similar sort of inclusion exclusion criteria.

Okay, great, and then just want to confirm you said butorphanol is not a rate-limiting step for any of the trials, not IPF or RCC, correct?

Correct. It’s only a rate-limiting step to getting to our final human abuse potential data, but no impact on the clinical studies.

Okay, great. Thank you very much.

Thank you, Annabel.

The next question comes from Serge Belanger from Needham and Company. Please go ahead.

Hi, good afternoon. Just a couple quick questions for us. I guess first one, maybe the number of sites that you’re targeting for the Phase 2b dose screening trial. And I think in the past you mentioned that the enrollment process for this trial, about 200 patients, would be about 12 months. Just curious if you’re still in that same ballpark, given your comment that this could be a competitive enrollment. Thanks.

Yes, two good questions. The number of sites for the 2b, we’re still finalizing that. We’re doing a lot of the site qualifications, but it’s going to be approximately 60 to 70 sites. So we’re bringing on a lot of sites to be able to sort of move through this quickly. So that is underway. I think as far as the 12-month enrollment, one adjustment, when we initially started, we thought it’d be approximately 200. But as we fine-tuned our statistical assumptions, the end’s going to be 160. So that’s helpful. And yes, we do think it’s still a 12-month enrollment.

Great. Thanks.

Thank you, Serge.

The next question comes from Leland Gershell from Oppenheimer. Please go ahead.

Hi, good afternoon, and thanks for the update and taking our questions. I just wanted to ask, on the human abuse potential study, obviously you’re testing doses that are much higher than those in the work you’re doing in both IPF, chronic cough, and RCC. Just wondering, if you do start to see some liability at those higher doses that are beyond what would be contemplated for the potential indications, would that potentially have an impact on labeling or DEA restrictions? How should we think about what the potential scenarios would be from those data? Thanks.

Yes, it’s a good question, Leland. I get this question a lot about sort of what’s success here. And there’s no sort of silver bullet, because as you know, the DEA is going to look at a lot of things in totality. Our clinical databases, etcetera. But I think generally, we’re going to have a low dose of nalbufine, sort of the marketed dose of nalbufine, and then a high dose, which we’ve done all the work around that. It’s going to be sort of 3x the marketed dose. And we’ve already done work around characterizing all those doses. And interestingly, you do not see an increase in any kind of likability as you get to those high doses. It is tolerated, which is interesting. But not shockingly, the kappa [Ph] ends up sort of getting swamped that receptor. And so you get a lot of those dysphoric side effects that really sort of come in hard when you get up to those high doses. So we’re not expecting to see that. I think if you did, I mean, that’ll definitely factor in. And I think that’s somewhat what’s made butorphanol a schedule IV drug. So I think the real answer would be if you saw an increase in likability around nalbufine as doses got higher, you would compare what that high dose looked like to butorphanol. If they’re similar, then you could be talking about a schedule IV type drug, which, and the conditions we’re in, these are serious conditions. A lot of these patients are on opioids anyway. So we don’t see that as impacting the market.

Got it. Okay. And given the butorphanol shortage, it sounds like this is going to go past year-end. Do you have a sense of when we might be able to see these data, presumably first half 2024? Or I’m just wondering if you can share. Thank you.

Yes, no, it’s a good question. We definitely won’t get to year-end because we needed to be dosing in June, July, which is we were working that problem sort of last call. It just depends. This is Pfizer’s plan and when that can sort of play through. We are in conversations with them. They’ve actually been quite receptive and helpful. So I’m hoping when this sort of gets settled out that maybe we can get that in-house and we’ll keep people updated. For now, we haven’t put out any new guidance just because that’s very out of our control, as you can imagine.

Yes, understood. Sorry. Thanks very much for taking the questions.

Yes. Thank you, Leland.

The next question comes from Thomas Smith from Lear, Inc. Partners. Please go ahead.

Hi, this is Nat [Ph] Sharon on for Thomas Smith. So the first question is what are the gating factors to initiate these three chronic health trials and which trial will likely be initiated first? And I have a follow-up.

Yes, sure. So the gating factors really are primarily around just getting regulatory clearance. We’re pretty much ready to go. Protocols are written. We’re getting sites contracted, getting them all ready to go. It’s just a matter of getting final sign-off from the regulators and everything in place. My guesstimate of the first study ready to go is actually probably the RCC trial.

Got it. And what strategy do you plan to implement to compete with other competitor programs in chronic health IPS?

Yes. So there’s only one other competitor program in IPF chronic cough. It’s a NERI [Ph] drug. It’s a Phase 2 program that that drug did not have success in RCC. So we don’t view them as a big competitor. I think their overall study is only looking to enroll about 80 patients or so. So we don’t view them as a big competitor. I view the more competitive landscape is competing for the IPF patients because there is a lot of work going on in antifibrotics and IPF. So I think what our competitive advantage will be, we’re one of the only trials in cough. So for people that have severe cough, I think that’s going to be intriguing to them. We also are running a short study at six weeks. The antifibrotic trials, a lot of them are one-year commitments. So I think for a patient to be able to get into a six-week trial, they’re severe coughers, this could be an intriguing proposition for them. And we’re just quite frankly, bringing up enough sites that we can spread this out and get this done in a rapid time.

Makes sense. And maybe one last question from us. With Merck, recently we submitted the NDA for the RCC drug. Does it change your thought on how do we all plan in RCC? Do you still plan to find a partner to advance RCC beyond phase 1b?

It’s a good question, Matt. I think our plan is to do the development work here and understand the value of the asset and create optionality here. I do think you’re right that marketing and RCC is a different sort of animal than marketing in a specialty condition like IPF. But those are all things that can be sorted out later. There’s plenty of people interested in this cough space. I think if we can put up good data, especially, I really think it’s intriguing if we’re able to work more broadly in this patient population of severe coughers that doesn’t have to be so enriched. I think that all of a sudden makes this asset best in class. So we’ll work through the development work and sort out how we commercialize it best later.

Got it. Thank you so much.

Yes. Thank you, Matt.

Next question comes from Mayank Mamtani from B. Riley Securities. Please go ahead.

Good afternoon, team. This is William Wood on for Mayank. Thanks for taking our questions. When thinking about the butorphanol shortage, following the FDA feedback and depending on the timeline for the actual shortage, is there a scenario where you redo part one, proceed, or are there other options you are considering, sort of maybe worst case scenario?

I think worst case scenario. So the only way I think, I don’t think we’d have to redo part one. I guess there’s a chance that the agency says they want us to look at a different dose. We did look at multiple doses there. If for some reason they wanted us to look at a different dose, we would just have to dose a small cohort and generate that data. But I think the structure we put together is scientifically sound. But we do want that validated before we run a whole likability study. I think to your point, worst case scenario would be we’d have to pick another comparator that wasn’t butorphanol. And we’d have to get agreement with the agency that that was a good, Pentazocine is probably the likely other one. The problem is you don’t really get out of these issues. All these old IV drugs, they’re all sort of in short supply because there’s basically one manufacturer. So I’m hoping we don’t get to that point, but if we do, then we’d probably be talking with the agency about what would be another likely comparator, which like I said, it was sort of a coin toss between butorphanol and Pentazocine when we did it at the time. So I think either of those would be fine for us. And then we would have to repeat the dose work.

Right. No, that makes sense. And then additionally, when I know ERS is quickly approaching in early September, where we expect to see the pacify low dose morphine study readout will be presented there. How should we think about that data in terms of how it might read through to your nalbuphine ER?

Yes. And we’ll have a whole team at ER. So if anyone’s there, happy to connect you to our group there. Yes. So I mean, William, you and I have talked about this before. I mean, I’m going to be surprised. It’s a morphine trial. Morphines used now and cough low dose morphine more in the U.K., less here because of the whole opioid restrictions. I’m going to be surprised if it doesn’t work. The lead investigator on that is Dr. Molyneux [Ph] who was in our study as well. Great investigator. So I’m going to, I think the read through is the mechanisms, right? That opioids work in cough. I think low dose morphine is always going to have challenges. It is a schedule two opioid. It’s generic. You’re not going to probably be able to get IP around that at all. So I actually think it validates the mechanism and doesn’t compete commercially with what we’re doing.

Understood. And then one just very quick last one. It looked like in your past ER that, or from 1Q that RCC was slated for third quarter, now listed as second half. Should we read that as a pushback or more just a generalization?

It’s more just verbiage. I think in 1Q [Ph], you’ll see, we still say third quarter. I think in some of my remarks, I might say later this year, but it’s just more of a casual comment.

Yes. Appreciate it. Thank you for taking our questions.

Yes. Thank you, William.

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

We would like to thank everybody for participating in today’s call. We have several upcoming conferences that we are participating in starting next week with Stifel which are detailed in our earnings release issue today. We hope to see some of you at these meetings. Thank you.