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

Good afternoon and welcome to the Trevi Therapeutics Second Quarter 2024 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 act -- 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-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 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 over to Jennifer Good, Trevi's President and CEO. Please go ahead.

Good afternoon and thank you for joining us for our Second 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. I will give an update on the progress in our clinical trials and Lisa will give a brief financial update. Then the three of us are happy to answer any questions that you may have. This has been a fun but busy quarter at Trevi as we continue to execute against our clinical development plans for both chronic cough in idiopathic pulmonary fibrosis or IPF as well as refractory chronic cough or RCC. We have a number of data readouts expected by year-end and are hoping to build on the strong efficacy data we saw in our Phase IIa trial in IPF chronic cough. To support this fast pace and focus on execution, we continued to bolster our team; and were happy to announce in April the hire of Dr. Meg Garin, who was key in progressing the clinical development of camlipixant while at BELLUS Health. Meg is overseeing our RIVER trial day to day and has already started looking ahead to planning for our next trial. She has been a great addition to the team. Let me provide a brief update on our clinical trials, beginning with our Phase IIa RIVER trial in RCC, which is expected to read out in the fourth quarter of this year. RCC is a debilitating disease that affects approximately 2 million to 3 million U.S. adults and is defined as a persistent cough lasting greater than 8 weeks despite treatment for an underlying condition or where no underlying condition exists. With the lack of any approved therapies for RCC in the U.S. and several drug candidate failures, there continues to be a significant unmet need and an urgency from patients and providers for new therapies. We believe our key point of differentiation for Haduvio is the mechanism of action which works synergistically both centrally in the brain and peripherally in the lungs. We believe this mechanism has the potential to work more broadly in RCC patients and potentially have a stronger effect across the broader range of baseline cough counts than peripheral-only mechanisms. Our RCC trial is a standard Phase IIa crossover design that has been conducted across several cough trials run to date and is planned to enroll approximately 60 patients. These patients will be randomized with a 1:1 stratification or approximately 30 in each arm between those with 10 to 19 coughs per hour, moderate cough; and those with greater than or equal to 20 coughs per hour, high cough. This trial has been progressing nicely and we now have approximately 80% of the subjects enrolled. Based on the current run rate, we expect to report data from this study in the fourth quarter of this year. However, I want to note that we currently have an imbalance in the enrolled subjects between the 2 stratification arms, i.e., the 10 to 19 and greater than 20 cough counts. The enrollment between the 2 arms has fluctuated throughout the study. This is important data to inform future development. And there may be a scenario where we get to our overall planned N of 60 but keep the study open a little longer to balance the arms. We are excited to complete the enrollment of this study and report the data in this important chronic cough condition. 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 have significant physical, psychological and social impacts. Cough may also be a risk factor that plays a role in the progression of the underlying disease. The constant lung injury, micro tears and inflammation caused by persistent coughing may lead to worse health outcomes for patients. With no currently approved treatment options for chronic cough and IPF, patients and providers have an urgent need for new therapies. Our IPF chronic cough trial CORAL is a Phase IIb parallel arm dose-ranging study that will investigate 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 now have the majority of our sites activated, and enrollment is progressing nicely. We have great relationships with the investigators in the trial and are communicating with them frequently to ensure our study is top of mind. The next milestone in this study is to conduct a sample size reestimation, SSRE analysis, when 50% of the patients complete. This analysis will be done by an unblinded statistician external to the company who will rerun the power calculations using actual data. We will get very limited information back, but we will be informed of 1 of the following 3 outcomes: one, continue on as planned with the current planned number of patients, reconfirming the original powering assumptions. Two, the drug is working within the prespecified promising zone but will require an upsize in the number of patients to maintain the power. Or three, the drug is not working in the prespecified range and the company should consider stopping. We will announce the results of this analysis when we have the information, which we expect in the fourth quarter of this year. We continue to expect top line data for the full study in the first half of 2025, subject to the result of the SSRE. We also are conducting 2 important supportive studies this year, the human abuse potential or HAP study as well as the respiratory physiology study. I will give you a quick update on both. The HAP study is currently 95% enrolled and will require one more cohort of dosing to complete. We expect to complete enrollment and dosing in the third quarter, with data from this study reported in the fourth quarter. Finally, we have initiated a Phase I respiratory physiology study, which is being conducted to systematically measure respiratory function in varying levels of disease severity in IPF to help determine our Phase III patient population. To date, we have excluded sleep-disordered breathing patients in our clinical studies and we want to better characterize the safety overall in the patient population. The protocol has been approved in both the U.S. and the U.K. and the study has initiated patient screening. We expect to enroll approximately 25 patients that will be inpatient for 10 days. The primary end point of the trial is the effect of escalating doses of Haduvio on respiratory function as measured by minute ventilation. Secondary end point measures of additional respiratory functions are also included. As you can see, these studies have progressed nicely. And data from these trials will be important to inform the development path forward for Haduvio in chronic cough conditions. I want to thank our team who have worked hard to keep the enrollment on plan. We look forward to completing these clinical trials and reporting out the data, beginning in the fourth quarter of this year. 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 3 months ended June 30, 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. For the second quarter of 2024, we reported a net loss of $12.4 million compared to a net loss of $7.1 million for the same quarter in 2023. R&D expenses were $10 million during the second quarter of 2024 compared to $5.8 million in the same quarter in 2023, which reflects the strong clinical activity across all 4 of our trials. G&A expenses were $3.3 million during the second quarter of 2024 compared to $2.5 million in the same period of 2023, primarily due to increases in personnel and related expenses, market research costs and information technology services. As of June 30, 2024, our cash, cash equivalents and marketable securities totaled $69.5 million compared to $83 million as of December 31, 2023. During the quarter, we issued approximately 1.5 million shares from our ATM, which was purchased by a single buyer. This cash inflow strengthens our runway post data readouts on our current clinical trials. We continue to expect that our cash burn, excluding the proceeds from the share issuance, will average $9 million to $12 million per quarter in 2024; and we will have cash runway into 2026. This concludes our prepared remarks. I will now turn the call back over to the operator for Q&A.

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

This is [ Ji Adam ]. I'm calling in for Annabel. Congrats on the progress this quarter. I had 2 questions. First is related to RIVER and chronic cough. When you guys are designing a trial, would you use different powering assumptions for the different severity groups being studied? Or are they [ powered with the ] same treatment effect? And then the second question is related to the human abuse potential study. Can you reconfirm that nalbuphine is not a scheduled drug while butorphanol is Schedule IV? And if that's the case, is there any reason that you would expect any -- would there be any reason to expect that there would be dose response to likability for the ER formulation? Has there been any indication from the FDA [ there was a plan ] to potentially reschedule nalbuphine [ ER ]?

Yes, thank you, [ Adam ]. I'm going to let David answer the powering assumptions for each arm. And then I'll take on the HAP question.

Yes. No, thank you for the question. So as you know, the primary end point in RIVER is the total population's N of 60. So that's the primary analysis, but what you really request, what you're asking about is the subgroup analyses. We made the same assumptions for the effect size in those subgroup analyses.

And then for the human abuse potential analysis, [ Adam ], I mean, nalbuphine has been around for decades. It's been unscheduled by the DEA. And it gets looked at regularly and they continue to unschedule the drug. We also have a lot of information on it. The preclinical work was done. We have our whole clinical database, et cetera, so we feel, based on what we know, the drug should remain unscheduled. There is sort of this last piece to bring it up to current standards, the human abuse potential study. I guess we'll run the study. We'll see the data. It will be part of the analysis. They look at sort of 8 different factors, of which that's 1, but I would just sort of bring everyone back to there's 2 pieces of the mechanism in our drug, a mu antagonist, none of which are scheduled; and kappa agonist, none of which are scheduled. So it seems a little bit unusual. Butorphanol, just to draw that comparison, is a weak mu agonist, kappa agonist. We're a mu antagonist, kappa agonist. So I don't want to say there's no scenario where that happens, but we're feeling pretty good about our drug and have not sort of seen issues with that. But clearly you have to run the study and see the data and then we'll submit everything when we get it.

The next question comes from Thomas Smith from Leerink Partners.

Congrats on the progress. Just on the respiratory physiology study. I was wondering if you could comment on your expectations on enrollment in terms of patient disease severity that you're enrolling into the study. And then also just comment on the doses that you'll be evaluating in that study and how that compares to what you're looking at in the IPF and RCC studies.

Sure. I'm going to let David take that.

Thank you very much. And thank you for the question. So the doses we're studying are the same that we have in both RIVER and CORAL. We're studying up to 108 milligrams BID in that inpatient study -- and sorry. The first part of your question was...

The severity, [ how it compare ].

So we start the study, in essence, in the same population in which we are studying in CORAL, so the IPF diagnosis and in essence the same population. And then once we have data from that initial group, we would expand the population, as we've disclosed previously, to include sleep-disordered breathing subtypes. So that will be added onto the study and including all varieties of sleep-disordered breathing in that study so that we can address the primary question which is for Phase III. We would like to include a broad range of IPF patients in Phase III so we can address that question.

Got it. That's helpful. And then just if I could ask a follow-up on RIVER, I was wondering if you could just elaborate on the enrollment balance between the moderate and severe patients that you're seeing. Are we seeing more moderate or severe? And are there any other baseline characteristics that you have visibility into that maybe differ from your initial expectations or some of the other contemporary Phase II RCC studies?

Yes. So we don't comment, Tom, on all the sort of specifics within the trial midstream because things go back and forth. I would say this is there's sort of a bit of an imbalance, but that's gone both ways. At one point, one arm is a little further ahead than the other, so we'll sort of lay all that out by subgroup when we get to the end. I would say, as far as baseline characteristics, I can tell you, when Meg came in, she went through sort of all the subjects enrolled and sort of all their medical information -- and David, you can comment as well -- and felt it looked good, good diagnoses, nothing unusual based on what she saw.

Absolutely, right, I mean, and which is what we expected. We -- it's one of the advantages of the smaller Phase IIa studies. You can go to really very super expert centers via trial. And so that's what we expected and that's what we've seen.

Yes. Thank you, Tom, for the questions.

Got it. That's helpful, yes. And looking forward to the Q4 updates.

Great.

The next question comes from Leland Gershell from Oppenheimer.

Just want to ask as you think about the evolution of the development programs and we're coming up on the RCC top line data. And as you continue developing Haduvio in IPF chronic coughs, would the outcome of the RCC trial impact upon your plans in IPF? In other words, would you look to prioritize Haduvio in RCC? Would that alter kind of the weight you put on the IPF opportunity? I'm just wondering how you think about those two side-by-side should RCC print out a strong data set.

Yes, it's a good question, Leland. We talk about it a lot as a team and a Board. There's a big commitment inside Trevi to that IPF is our lead indication: severe unmet need, not a lot of options for those patients. Cough is a big problem. We -- also as I laid out in my comments, we believe that cough is potentially contributing to the underlying disease. And so how we might sort of look at some of those end points in an exploratory way. RCC is interesting because there is unmet need there, and how that eventually merges with IPF is sort of the -- a question we'll have to wrestle with. I think, as Trevi, we would look to probably pick up sort of the most -- assuming the P2X3 camlipixant gets approved, we would probably look to be third-line therapy behind that for the failures because we want to maintain the pricing we have in IPF. We think today that's probably the optimal way to maximize the value of the drug. Now in somebody else's hands that's got a bigger sales force, that may not be the case, so I would think about this, assuming the data supports it, that Trevi is going to be leading with its IPF program; and looking at and studying RCC, with an eye towards picking up the most severe coughers that aren't getting relief anywhere else. And that could be, by the way, in this moderate cough count if they're not able to be treated, but that's -- we've done some modeling this summer. And I think that's how we believe we can best optimize it.

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

Congrats on the progress. On the Phase IIa RIVER protocol, could you please just remind us how that differs from the Phase IIa CANAL that you previously executed on very successfully? And then I have a quick follow-up.

Thank you so much for the question. So the design, as you know, is in essence the same. The only difference we made is, based on the early efficacy signal that we saw in the CANAL design where we went up to 162 milligrams BID, we capped the dose at 108 milligrams BID. So the dose, we reduced compared to CANAL. And we increased the washout period up to 3 weeks. There's another minor difference as well. CANAL was run when COVID was very active, and we could only get the objective cough end point at baseline [ and ] week 3. Here we've gone back to the more -- we were able to get weekly objective cough data, which was always the aim in CANAL but COVID got in the way.

Very helpful. And then on the PROs, which we all know is an important regulatory topic also, could you just remind us what you are looking for in CORAL, obviously? And then is RIVER also going to give us some more information on some of these PROs? Is -- and then I'll have one more question after that.

Yes...

Yes. So we increased the range of PROs. And I'll start with the CORAL study, first, compared to the CANAL study. So in CORAL, we basically have the opportunity to profile both with cough frequency score -- that's we're using the exact, which were the same end point we used in Phase IIa in CANAL, but we've also expanded quite broadly: Living with IPF, a lot of PROs which allow you to get a good feel for the overall clinical characteristics and the improvements, including functional improvements that you get. So we've got a broad range of PROs, so Leicester Cough Questionnaire you would expect. Living with IPF is a very good instrument; and then standard anchor measurements, patient's global impression of severity and change in cough and IPF, those sorts of measures. Those are some of the most important PROs we added there. And we took a similar approach, frankly, even in the small RIVER study. So there the important secondary end points of PROs would be cough frequency, again, living -- the Leicester Cough Questionnaire and cough severity. We're using the VAS measurement because that's used in the majority of our CC programs. So it's a good comp compared to other programs. We may at some stage switch to the cough severity NRS measurement because regulatory-wise that will probably be a better end point for approvals, but that's a relatively small detail. So -- and then again, good anchor with patient global impression of severity and change in cough in the RIVER study as well.

Very helpful. And then lastly, on your earlier comment, Jennifer, on the focus on severe cough cohort or maybe refractory to P2X3. Is that a more recent development? Or is that something that you're just going to be data dependent on what you learned from RCC? And I just ask that because the final dose-ranging work will -- could give you a different dose in those 2 different indications. So I was just curious how tied you are to the idea of pegging yourself to the IPF chronic cough indication.

It's a good question, Mayank. Like I said, it's something we debate a lot. I would say it's been -- it's come out of a bit of work this summer. And you are right. This is all going to be data-driven. So obviously these are 2 big indications, a lot of unmet need in both, so lots of opportunity here. I think what we've been wrestling with a bit as a small company -- IPF is there. We can take that all the way through approval. And if we had to commercialize it, it's a very specialty sales force, so we feel really comfortable with that model. RCC starts to open sort of that can of worms a lot broader, so the work that our colleague has done a lot this summer is trying to figure out how you could maintain the premium pricing that we think we can get in IPF into an RCC population, but those decisions are by no means final. I would just say that's probably out of some research this summer and thinking about how to optimize it without cannibalizing IPF. That's our current thinking, but on the other hand, the RCC market is big enough. And that's what I say. In somebody else's hands that's already got an existing sales force, you could see them launch much more broadly because they don't have the costs sort of associated with building that. So you're right. It will be data dependent, really not something we have to decide for a while. I mean we'll continue on. We'll run the next study, but at some point, somebody has got to wrestle with that question.

Yes. Makes a lot of sense. And good to be ahead of that. And look forward to your 4Q updates.

Yes.

The next question comes from Brandon Folkes from Rodman & Renshaw.

Congratulations on all the progress. Maybe, just firstly, on the HAP data readout. In terms of a positive outcome -- or is it really as long as we don't see a dose-dependent likability that that's a positive outcome for you and strengthens your discussions with the agency? So that even if we see high likability in one of the groups -- I'm sure we'll see some likability, but as long as it's not dose dependent, should we interpret that as a positive and strengthening your discussion with the agency?

So Brandon, it's a good question. Like all data, it's sort of the gestalt of what you see. I would say -- there's a published paper Cara did with their kappa agonist where they showed separation from placebo, but they were less likable than their comparator, pentazocine. They only had one dose, so the dose response question wasn't there. That drug was left unscheduled. So I think, at a baseline on data, we will likely separate from placebo but, hopefully, be less likable or similar to our comparator. I think that puts us in a strong situation. Now having said that, you are right that what -- the FDA really has concerns that there's a little bit of signals and likability that you don't see the dose dependence. Because you don't want to see somebody like it a bit and then you take sort of 3x the dose and they like it 3x more. So it's a bit of all of that combined, so it's certainly something we'll look at, but our expectation is this drug should not be all that likable. I mean you've looked at our adverse events profile. And we just don't see that. So when we get all the data, we'll lay it out for the Street and also have an expert to help sort of interpret what we've seen and our own conclusions around it.

Great, very helpful. And then maybe just shifting gears into the respiratory study. Any way to characterize what you think the hurdle rate here is to include sleep disorder patients going forward? Or is it also a case of generate the data and then have the conversation with the agency in terms of whether it's enough to get these sleep disorder patients? Or do you think there's a finite hurdle here that the agency wants to see?

[indiscernible] regards the respiratory physiology study. I think there are well-established end points and markers of what is a clinically relevant change in ventilation, which -- for example, which is the primary end point, which we can utilize. So actually we think the signal of the study will be relatively interpretable ourselves when we get this because in clinical practice there are fairly clear guidance as to what is a clinically relevant change in all the end points we're looking at. So we believe that the results of the study will be interpretable by ourselves. And I don't -- it's definitely not our thinking that we have to -- it's mandatory that we have to go back to the FDA and have some discussion. As part of an end-of-Phase II meeting, we'll have this data set, but we think it will be more straightforward than now here's a detailed discussion about the relevance of all these findings.

That's very helpful. And then maybe lastly, just following up on a few of the earlier comments. Just on the RIVER imbalance between the 2 arms, you talked about sort of how this has fluctuated throughout the study. Is this just a normal part of the fluctuation and of that cycle? Or has one patient group become a little bit more competitive to enroll going forward? I know you're not giving color on which patient group, but is there sort of a fundamental competition for one of these patient groups? Or is it just normal fluctuation?

So we always expected -- thank you for the question. We always expected you're always going to get one group is going to recruit a little bit faster than the others when you -- but we expect -- we didn't -- weren't predicting which one, frankly. The difference here that Jennifer was speaking to is the difference was a little bit larger than we expected. And that's why, as we've always explained, we think approximately 30 subjects per group in these 2 subgroups, the 10 to 19 and the greater than 20 patients, will allow us to detect a clinically meaningful effect size. We've got more than 80% power in both of these subgroups with about approximately 30 subjects to detect a mid-30% effect size on top of placebo. And for that reason, we think it's important to stick with that stated aim. And that's what Jennifer was speaking to. So the difference was -- the difference -- the imbalance was a little bit larger than we were expecting when we started the study, but we always knew there'll be one group that will recruit quicker.

And it's a difference of a month or 2 of recruiting. So we'll just see how it comes together. This issue could go away. I'm just reminding people of the protocol and that, that could come up at the end of the study.

The next question comes from John Gionco from Needham & Company.

This is John on for Serge today. First, surrounding the IP for nalbuphine ER, can you provide an overview of the current patent coverage and if any additional applications are outstanding at this time and whether the existing method-of-use IP applies equally to both IPF and RCC?

Yes. Good question, John. Thank you. So we have issued method-of-treatment patents. We have a set of formulation patents that protect the product till roughly 2030, but we have issued method-of-treatment patents, which is really the core of the protection, that are issued through 2039 for IPF cough. We do have worldwide rights and patents that we've prosecuted around that. There are some additional applications being prosecuted as well concerning other clinical work we've done around the label, things like dosing and the elderly or hepatically impaired, renally impaired, probably get some IP maybe out of our human abuse potential study. So those kinds of patents that are being prosecuted now would actually extend this out to -- one group is 2041 and on group is 2043, but I think of this sort of the core of the patent coverage through this method of treatment 2039. As for refractory chronic cough, that broadly follows under the same umbrella. We're waiting for our data out of this RIVER study. And then we'll prosecute the actual claims around the data we saw, file them as Track One claims; and those should be issued as well. We wrote the overall [ invention ] with it in mind, that we would be looking at IPF, other interstitial lung diseases and refractory chronic cough. And we pull from that application, when we get actual data, to get the claims issued.

Great, sounds good. And just a quick follow-up, if you could discuss the current patient population with regard to RCC, in terms of how many are diagnosed and how many are currently seeking treatment, just to provide a little granularity on that.

Yes. It's a good question. We have some of this in our corporate deck. And I don't have my commercial colleague on. We believe there's about 2 million to 3 million treatable patients in the U.S. It's a big indication. I think there's roughly 7 million patients diagnosed in the U.S., but when you sort of work that down of people who aren't -- who are looking for treatment and not getting proper care, sort of it brings its way down to about 2 million to 3 million patients. But if you want to, John, we can follow up on that. And I can have Farrell join the call and we can give you a better walk-down.

Great. That sounds good. And congrats again on the progress.

Thank you for the questions.

The next question comes from Debanjana from -- Chatterjee from JonesTrading.

Are you able to hear me?

Yes.

Yes, okay. I was kind of curious. Like how long of a delay do you anticipate to the RCC readout because of this imbalance? And I have a follow-up question.

I don't -- I mean, sitting here today, I don't expect any delay. We've confirmed -- reaffirmed our guidance for the fourth quarter of this year. And we're 80% enrolled. So I just only bring up the issue because, if we get to the end and want to hold the trial open for -- I mean we're not going to hold it open for more than a month, or 2 at the most, to get these arms in balance. And it may not even -- that may not even be required. So at this point, I don't expect any delay. I'm just pointing out that, that was a part of our protocol we really wanted to try to execute on to get the information.

Yes. That's very helpful. And maybe one other question: As you mentioned that it's -- I mean, in case you decide to lead, I mean, and execute like the RCC program on your own, like, you could be considering like in third line. How big do you think the opportunity size is there? How many -- like what's the number of patients?

Yes. So we have not shared all of that. We're doing a lot of work this summer. It's a big patient opportunity. I mean you know with a lot of the P2X3s. I know you follow that space, Debanjana. They don't work in sort of 30% to 40% of the patients. Some of the patients they work in have very severe cough. And even then with the reduction in cough, it's not completely reduced, so there's a pretty big opportunity here for this group with really not a lot of options. So we are finishing up our market research. And at some point, we'll share sort of our views on that and how that walks down, but we view that as a very significant market opportunity, particularly in light of the fact there is very little -- there's not a lot of competitors left in the space.

This concludes our question-and-answer session. I would like to turn the conference back over to Jennifer Good for closing remarks.

Thank you for joining us. We are expecting steady news flow of data in the upcoming months with regards to our clinical trials data, and we look forward to sharing this with you. We will be participating in several investor conferences over the next couple of months, as listed in our press release, and hopefully, we will see some of you there. Thank you for joining the call. And we're available afterwards for any questions you may have.

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