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spk01: Good afternoon and welcome to the Trevi Therapeutics Q3 2023 Earnings Conference Call. At this time, all participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your phone. To withdraw your question, please press star then two. Please note, this event is being recorded. Various remarks that management makes during this conference call about the company's future expectations, plans, and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed previously. in the risk factor section of the company's most recent quarterly report on Form 10-Q, which the company filed with the SEC this afternoon. In addition, any forward-looking statements represent the company's views only as of today and should not be relied upon as representing the company's views 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.
spk04: Good afternoon, and thank you for joining our third quarter earnings call on business update. Joining me today on this call are my colleagues Lisa Delfini, Trevi's chief financial officer, and David Clark, Trevi's chief medical officer. Lisa and I have some prepared remarks, then we will open it up for questions. We have continued to advance our clinical development plans for Heduvia in both of our chronic cough indications, including idiopathic pulmonary fibrosis and refractory chronic cough, as well as the human abuse potential study. Let me provide a brief update on each of these programs. I will begin with our Phase IIa refractory chronic cough study that was recently initiated. We have named this the RIVER study. Refractory chronic cough or RCC 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 or when no cough associated conditions can be identified. RCC is caused by cough reflex hypersensitivity in the central and peripheral nerves and has a significant impact on patients physically, psychologically, and socially. 72% of high and moderate coughers report their cough being uncontrolled. There are currently no approved therapies for RCC in the US, EU, or UK. The key point of differentiation for Heduvio and chronic cough is the mechanism of action, which works both centrally in the brain and peripherally in the lungs. We believe Heduvio's central and peripheral mechanism has the potential to work in more patients than peripheral-only mechanisms, like the P2X3s. and potentially provide a stronger response and cough reduction. When we look at the competitive landscape in RCC, a number of other mechanisms have been studied with little success. Even the P2X3 inhibitors have mixed results, but there are two P2X3 therapies in late stages, one being reviewed by the FDA and the other in phase three trials. However, importantly, both of these compounds have been shown to have non-statistically significant effects in RCC patients with moderate cough frequencies of 10 to 19 coughs per hour. We believe that based on the data from our IPF cough trial and the drug's mechanism of action, that Heduvio may work in both the moderate and high cough frequencies. When you look at the RCC patient distribution, 44% of the patients are estimated to have moderate cough frequency, whereas only 29% have high cough frequency. So there's a potential Heduvia may address close to three-quarters of the RCC market, whereas P2X3s may only be effective in less than a third of the market. The RIVER trial is the standard Phase IIa crossover design that has been run in all the cough trials. It is a double-blind, randomized, placebo-controlled, two-period crossover study evaluating the reduction of cough in approximately 60 subjects. These subjects will be randomized with a one-to-one stratification between those with 10 to 19 coughs per hour, moderate frequency coughers, and those with greater than or equal to 20 coughs per hour, high frequency coughers. Each treatment period will last 21 days, separated by a 21-day washout period. Subjects on Heduvia will have the twice a day dose titrated weekly from 27 milligrams up to 108 milligrams across the dosing period. The primary efficacy endpoint is the relative change in the 24-hour cough frequency at day 21 from the treatment period baseline for Heduvia 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 report top-line data in the second half of next year. Next, a brief 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 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 and IPF, patients and providers have an urgent need for new therapies. 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 Heduvia and placebo. We are planning for a six-week trial in approximately 160 subjects. We plan to conduct this study in multiple countries and sites to be able to complete enrollment in a timely manner. We are on schedule with our regulatory interactions and have received approvals to proceed in some of our planned countries. We expect this trial to be initiated in the fourth quarter of 2023 and will provide top line guidance when we announce the trial. In parallel, we are planning for a phase 1B respiratory physiology study in IPF patients that have varying levels of disease severity. The purpose of this study is to determine if we see clinically significant impacts on respiratory depression in any subgroups. This study will help define the patient population for our pivotal program and ultimately the label. We expect to initiate this study in the first quarter of 2024. Finally, we were able to make progress on reinitiating the human abuse potential study, which is required for the NDA filing. Recall that we had two hurdles we had to clear. The first was getting FDA's agreement with the proposed IV butorphanol dose we plan to dose in the likability portion of the study. We received that agreement from the FDA during the quarter. Second, we were working to secure supply of IV butorphanol from the single source supplier in the U.S., which we were also able to do. The final portion of the HAP 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. The primary objective is to evaluate the likability of nalbufine as compared to both placebo and butorphanol, and the primary endpoint is a drug-liking VAS scale. We expect to begin dosing the study in the first quarter of 2024 with data expected in the second half of 2024. As you can see, it is a busy time clinically for the company bringing up these four studies, and we look forward to conducting and reporting results on all of these trials. 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.
spk03: Thank you, Jennifer, and good afternoon, everyone. The full financial results for the three months ended September 30th, 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 third quarter of 2023, we reported a net loss of 7.7 million compared to a net loss of 8.3 million for the same quarter in 2022. R&D expenses were 6.3 million during the third quarter of 2023 compared to 5.8 million in the same quarter in 2022. The increase was primarily due to startup costs and consultant services associated with our chronic cost program, as well as an increase in personnel related expenses. These increases were partially offset by a decline in clinical development expenses related to our completed Phase 2B3 PRISM and Phase 2 canal trials, as well as decreased purchases of clinical trial supplies. G&A expenses were $2.7 million during the third quarter of 2023, essentially flat compared to $2.6 million in the same period of 2022. Offsetting these increases in expenses was an increase in other income net. which was 1.3 million in the third quarter of 2023 compared to 100,000 in the same period of 2022. This change was primarily due to an increase in interest income and reduced interest expense due to the payoff of the SVB term loan in May of 2023. As of September 30th, 2023, our cash, cash equivalents, and marketable securities totaled 88.9 million compared to 120.5 million as of December 31st, 2022. We expect cash burn to ramp a bit over the next several quarters as we conduct the trials that Jennifer discussed today. 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 gives us good cash runway after the last readout. This concludes our prepared remarks and I will now turn the call back over to the operator for Q&A.
spk01: We will now begin the question and answer session. To ask a question, you may press star then one on your touch-tone phone. If you're using a speaker phone, please pick up your hands up before pressing the keys. To withdraw your question, please press star then two. The first question comes from Annabelle Samimi from Stiefel. Please go ahead.
spk00: Hi. Thanks for taking my question. So, just on, first on the RCC trial, what do you see as a typical ramp-up time for RCC How competitive is the enrollment and the development landscape here outside of the trials that you just mentioned? And I guess the same goes for IPF. Just as you're waiting to start these trials, are you seeing any competitive development that might take patients away from the trials and then slow enrollment?
spk04: Thank you, Annabelle. I'm going to let David go ahead and answer that since he's leading this charge.
spk06: Thank you very much, Jennifer. Important question. So in terms of the ramp up for the river study in RCC patients, we are on targeting having all of the planned 14 studies up and running in early first quarter. And actually a substantial number of these sites would be targeted to be online at the end of fourth quarter. It's a small study. It's 60 patients, and we have heard from many of the PIs, a lot of whom are also involved in other Phase III RCC work right now. They certainly do not anticipate issues with competition from ongoing other RCC studies. One of the factors there is, as we have publicly disclosed, the enrollment will be a one-to-one enrichment strategy. Half the subjects, at least 20 per hour cough frequency, and half of them in the 10 to 19 category. So that, I think that is one factor that will help us with recruitment for this study. So we're not anticipating problems there. Moving on, does that answer your question on the RCC before I move on to the CORAL study?
spk04: Yes, it does.
spk06: So for coral study, can you reiterate, Annabelle?
spk04: She wanted the same question, basically.
spk06: Yeah. Yeah. So what we've heard so far for the coral, for the Phase IIb in the IPS COF subjects is what we're planning there is to have the majority of studies, the study centers, up and running by the end of first quarter. So as we've announced, we will be start initiating that study in the near future in Q4, but with the majority of centers active in Q1. What we've heard again, we've been in discussion with a lot of the investigators for that study, and what we've heard and what has been reflected from the individual investigators is usually In an IPF cost study, it would usually be a better recruitment scenario than recruiting for an IPF disease modifying program study. And that's what the investigators would anticipate for this study. So right now, we are not, to come back to your question, we're not expecting significant issues compared to other disease modifying programs. If anything, expectation is for enrollment to be higher than those disease modifying programs.
spk04: Yeah, and Annabelle, I would just add, I think we've been really thoughtful having struggled with difficult to recruit conditions in the past of having plenty of sites. We have about 60 sites for IPF to enroll 160 patients sort of spread across 10 countries. So I hope that we've got sort of some good strength behind it to be able to get enrollment done in a timely manner.
spk00: Okay, great. And if I could just ask a follow-up on the On the PN program, we saw the safety data from the OLE and the comment that the patients continued to see benefit on the WINRS score. Is there any magnitude that you can share with us? And do the placebos have any chance to cross over in this trial? I can't remember if that was one of the components. And can you share whether there is any healing evidence?
spk04: So that was a teaser, that little efficacy comment. So yes, what happened at the end of the, when you finished the double blind, everybody rolled on to drugs. So the placebos did have a chance to come into the study. We are at a future meeting going to put out the efficacy data around this, which will have skin healing data. We've got some pictures. We've got quality of life data. And as you might imagine, when you have your itch go down consistently over a year and people stay on it for a year, sort of the other measures, as you saw in our double blind study, tend to follow. But we didn't want to put that out at this meeting because we want to be able to do that at a future meeting.
spk00: Okay. And are you close to an end of phase two meeting now with FDA?
spk04: So as you heard, we've been very busy. So I would say the end of phase two meeting slipped a bit. We plan to request that in the first quarter, but we want to make sure we have a full briefing document ready to go when we do that request, which will also actually drop on questions we may have even related to our cough program because the underlying molecule is the same. So we anticipate requesting a meeting in the first quarter, and it takes roughly 70 days to get a meeting from there.
spk00: Okay, great.
spk04: Thank you. Yeah, thank you, Annabelle.
spk01: The next question comes from Rohan Mathur from Oppenheimer. Please go ahead.
spk02: Hey, everyone. Thanks for the update. I'm speaking for Leland Gershaw. Just two questions for me. As you see Heduvia advance in IPF chronic cough, how should we think about where Heduvia will fit in the IPF patient treatment regimen? And also, could you maybe remind us, are there any differences between the results in moderate versus severe cough observed in the canal trial? And if so, do these data point would more likely benefit in moderate to severe cough and refractory caudic cough? Thanks.
spk04: Yeah, so I'll take the first part. David, you want to comment on the second part? Sounds good. So the treatment regimen, it's interesting. I sat through a lot of calls. We did a lot of research last summer with not only patients, but also treaters and payers around this exact question. And, you know, the... Antifibrotics, they're challenging for patients. A lot of patients discontinue early because a lot of the GI side effects. And the other thing we also heard is a patient, they can't detect the fact that they're progressing slower. I mean, it's been shown they do extend life, but they still do decline. So it's hard for a patient to really detect the fact they're declining slower than they would. And one of the things we heard from a lot of the investigators is because the response from our trial was so dramatic and really a difficult aspect of this disease, that a lot of these treaters would probably start actually with prescribing our drug, get a win with these patients so they're feeling better, coughing less, and then move them on. They thought they might have a better success rate of keeping patients on the anti-fibrotic. So basically what we heard is cough is present in this disease from the beginning. it stays there all the way through the end. So it was really seen as a treatment that would be used early on and continued throughout the course of the disease. And I'll let David speak on the cough counts and why we think it could work in both moderate and severe.
spk06: Happy to do that. So in the canal study, the IPF cough subjects, what we basically looked at post hoc analyses looking at does baseline cough frequency affect the efficacy signal, and there was not a relationship. So even those subjects who fell into the lower baseline cough frequencies had the same efficacy signal as the higher baseline cough frequency subjects. That was one of the rationales when we were looking at the enrichment strategy that we've just disclosed for the RCC river study, why we're going for the one-to-one enrichment, so that we can, in essence, assess both the moderate cough frequency population with 10 to 19, and the high cough frequency that are being focused on with the P2X3 programs equally. We really want to get a good look. And that lack of a baseline cough frequency to efficacy effect in canal we think is supportive of that approach.
spk04: And we think because the drug works centrally at the brainstem, which mediates coughing and breathing, that it really should work across cough counts, you know, as long as you get to some minimum level where there's not so much variance.
spk09: Thanks so much. Thank you, Rohan.
spk01: The next question comes from Thomas Smith of Larrink Partners. Please go ahead.
spk09: Hello, Thomas. Are you there? The next question comes from Shawn Kim of Jones Trading.
spk01: Please go ahead.
spk10: Hi, thank you for taking my questions. The first question that I have is on the RCC trial. So given that you are stratifying for moderate versus severe, I'm just curious to hear the potential statistical plan for those two groups, whether you're going to be seeking statistical significance in moderate and also severe individually and also combined. And beyond the statistical significance of what you think will be clinically meaningful reduction, especially for the moderate group. Thank you. Yeah.
spk06: David? Thank you for that question. So with the N of 60 that we're studying in the river, we have powered it for a 45% treatment effect. with nalbuthine, okay? So a 25% effect greater than our anticipated placebo effect, which we expect to be, we've assumed to be 20% in that study. So that's for the total population of 60 subjects. We think that is appropriately conservative. Clearly, we saw much greater than a 25% separation from placebo. We saw double that in the canal study, as you know, in the IPF population. So we think we've been conservative. What that means is if we get an effect size which is larger than 25% versus placebo, we would actually have 80% power in both subgroups. So if we increase more than our conservative 25%, versus placebo effect size, and we would be powered in both of the groups of approximately 30 subjects each.
spk08: Does that address your question?
spk04: And David, he also asked about clinical meaningfulness, you know, what was defined as clinical meaningfulness.
spk06: Yeah, and that really sets about, as you know, 20 to 30% is believed by the majority of experts to be the sort of range that is clinically significant if you're looking at these reductions in cough frequency. And that was one of the reasons that we've set this, you know, the ability to power the 60 subjects to detect a 25% effect size, because that is clinically relevant to patients or is believed to be by experts in the field.
spk08: Okay, great. Thank you very much.
spk09: Thank you, Sean.
spk01: The next question comes from Serge Ballinger from Needham and Company. Please go ahead.
spk05: Hi. Good afternoon. Thanks for taking the questions. I have two. I guess first on the cough program, you maybe talk about the pathology differences between IPF cough and refractory chronic cough and whether you think adjuvant mechanism of action to be more effective in one disease or another. And then on the PN program, I'm just curious if you've had any discussions about partnering and how you would describe the level of interest for that program. Thanks.
spk04: David, why don't you take the first one? I'll take the second one.
spk06: Yeah, no, it's a really important question. So cough hypersensitivity is a key driver in both IPF and refractory chronic cough, as you know. So there's a similarity in terms of underlying what is driving both of these conditions, even though the pathophysiological initiation is different in these two conditions. But it leads to the same sort of degree of cough hypersensitivity. I mean, our key differentiation factor, as Jennifer talked about during her presentation that you've heard from us before, is the key here. So we've got peripheral activity, which is good. We also have the central activity, which differentiates us. And in essence, it's that activity suppressing medullary, so brain basal cough reflex center and the cerebral, the higher level cerebral control of it. That is the key differentiation so that in essence, we believe that central activity and its ability to be independent of what the triggering mechanism is, is going to drive effects in both of these indications and other cough indications.
spk04: Thank you, Serge, for the PN partnering question. Yeah, we continue to be in touch with parties interested. Our colleague Farrell was off at Bio Europe this week continuing those discussions. So we're clear on where the interest lies here, who's interested. As we've always said, we would like to get through the FDA meeting and be clear about the path forward and what's left. And then we'll make decisions at that time about whether we license the drug or not at that time. So yeah, good interest still.
spk09: Thank you.
spk01: Thank you. As a reminder, if you have questions, please press star, then one. The next question comes from Mayank Montani from B Riley Securities. Please go ahead.
spk07: Good afternoon, team. Thanks for taking my question. So appreciate the helpful comments on the RCC landscape. I was just curious what you might be looking for at the FDA adcom coming up closer to the end of the year for one of the P2X3 that you mentioned. And then the second question was on the IND filing, if you could sort of remind us where we are with that process.
spk04: Yeah, so the ad comes a great question, and David, you should add any color. I'm going to watch the whole day. I think it'll be really telling, you know, what the FDA or how they focus on with jefapixan. As you know, it was a small sort of placebo-adjusted change, but they did have statistical significance They were required to go back and do some work. So my expectations are the drug likely gets approved. Merck's certainly putting a lot of resources behind getting ready to launch it. But I think we'll be watching it just to learn sort of what the position is, how people view it. I don't know, David, if you have anything else regulatory-wise you're looking for.
spk06: No, similar to what you've said. I mean, surely I would just make my own personal comment from listening to a lot of experts in this field. I certainly share your view. I hope they get approved because of the medical need in this field. Yeah, that's true.
spk04: IND, you want to take that one? Where are we with getting an IND open?
spk06: So the IND is progressing for the respiratory physiology study. So we would expect to make an announcement on that and timing for that in the near future. But we're on track for having that submitted in the near future.
spk07: Got it. And maybe just one quick runway question, if you could clarify if that assumes any incremental spend on CN or, you know, any cash inflow you may have from a potential partnership discussion.
spk03: No, the cash runway includes our existing cash. So no additional cash influx assumed.
spk07: Or in flow. Okay. Okay. Thanks for that clarification. Appreciate you taking that question.
spk04: Yeah.
spk09: Thank you, Mayak.
spk01: 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 closing remarks.
spk04: We would like to thank everybody for participating in today's call. We will be attending the STPO Conference next week and we hope to see some of you there. Thank you.
spk01: The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.
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