Q1 2024 Trevi Therapeutics Inc Earnings Call

Operator: Good afternoon, and welcome to the Trevi Therapeutics First Quarter 2024 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 1 on your phone. To withdraw your question, please press star then 2.

Good afternoon, and welcome to the Trevi Therapeutics first quarter 2024 earnings conference call. At this time, all participants will be in a listen only mode.

Operator: Should you need assistance. Please signal conference specialist by pressing the star key followed by zero.

Operator: After todays 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.

Operator: Please note that 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-Q, which the company filed with the SEC this afternoon.

Operator: Please note this event is being recorded.

Operator: Various remarks that management makes during this conference call about the company's future expectations plans and prospects.

Operator: Constitute forward looking statements for purposes of the Safe Harbor Safe Harbor provisions under the private Securities Litigation Reform Act of 1995.

Operator: Actual results may differ material materially from those in Takeda by these forward looking statements as a result of various important factors, including those to start 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.

Operator: 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 at any subsequent date. While the company may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, even if its views change. I would now like to turn the conference over to Jennifer Good, Trevi's President and CEO. Please go ahead.

Operator: In addition, any forward looking statements represent the companys views only as of today and should not be relied upon as representing the company's views as any subsequent date, while the company may elect to update these forward looking statements at some point in the future.

Jennifer L. Good: The company, specifically disclaims any obligation to do so even if it's used change.

Jennifer L. Good: I would now like to turn the conference over to Jennifer could get Chevy's, President and CEO. Please go ahead.

Jennifer L. Good: Good afternoon, and thank you for joining us for our first quarter 2024 earnings call and business update. Joining me today on this call are my colleagues Lisa Delfini, Trevi's Chief Financial Officer, and Dr. David Clark, Trevi's Chief Medical Officer. We reported Q4 earnings just six weeks ago, so Lisa and I will give a brief update, then the three of us are happy to answer any questions.

Jennifer L. Good: Good afternoon, and thank you for joining us for our first quarter 2024 earnings call and business update.

Jennifer L. Good: Joining me today on this call are my colleagues, we sit Delphine <unk>, Chief Financial Officer, and Dr. David Clark Provost Chief Medical Officer, We reported Q4 earnings just six weeks ago, So Lisa and I will give a brief update then the three of US are happy to answer any questions.

Jennifer L. Good: This is a busy time at Trevi, advancing our clinical development plans for both refractory chronic cough, or RCC, as well as cough and idiopathic pulmonary fibrosis, or IPF. Let me provide a brief update on our various trials, beginning with our Phase 2a trial in RCC, which is expected to read out later this year. Refractory chronic cough, or RCC, is a debilitating disease that affects up to 10% of the adult population and is defined as a persistent cough lasting greater than 8 weeks despite treatment for the underlying condition. With 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 therapies.

Jennifer L. Good: This is a busy time at Tommy advancing our clinical development plans for both refractory chronic cough for RCC as well as cough and idiopathic pulmonary fibrosis or IPF.

Jennifer L. Good: Let me provide a brief update on our various trials beginning with our phase Iia trial in RCC, which is expected to read out later this year refractory chronic cough for 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.

Jennifer L. Good: Site, despite treatment for the underlying condition.

Jennifer L. Good: With 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 therapies.

Jennifer L. Good: The key point of differentiation for Hiduvio in refractory chronic cough is the mechanism of action, which works synergistically both centrally in the brain and peripherally in the lungs. We believe Hiduvio's mechanism has the potential to work in more patients and potentially have a stronger effect across a broader range of baseline cough counts than peripheral only mechanisms like the P2X3 inhibitors. Our RCC trial, RIVR, is a Phase 2a double-blind, randomized, placebo-controlled, two-period crossover study evaluating the reduction of cough in approximately 60 patients.

Jennifer L. Good: A key point of differentiation for Adobe O and refractory chronic cough is the mechanism of action, which works synergistically, both centrally in the brain and preferably in the lung. We believe her dubious 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.

Jennifer L. Good: Only mechanisms like the PQ extra inhibitors.

Jennifer L. Good: Our RCC trial River is a phase Iia double blind randomized placebo controlled two period crossover study evaluating the reduction of cost and approximately 60 patients.

Jennifer L. Good: This design is similar to other Phase IIa cost trials run to date but does incorporate a meaningful difference. These patients will be randomized with a one-to-one stratification between those with 10 to 19 costs per hour and those with greater than 20 costs per hour. Each treatment period will last three weeks, separated by a three-week washout period.

Jennifer L. Good: This design is similar to other phase Iia cross crowds run to date, but does incorporating meaningful difference.

Jennifer L. Good: These patients will be randomized with a one to one stratification between those with 10 to 19 cost per hour and those with greater than 20 cost per hour.

Jennifer L. Good: Each treatment period will last three weeks separated by a three week washout period.

Jennifer L. Good: Patients on Hiduvio 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 24-hour cough frequency as measured by an objective cough monitor. The study will also explore secondary endpoints, including patient-reported outcome measures for cough and quality of life. We now have all 14 sites activated for this trial and see almost an even split in the enrolled subjects between each arm, the 10 to 19 and greater than 20 cough counts in the study.

Jennifer L. Good: Patients on <unk> will have the dose titrated weekly from 27 milligrams up to 108 milligrams twice daily across the dosing period.

Jennifer L. Good: Mary efficacy endpoint is the relative change in the 24 hour cough frequency as measured by an objective cost monitor. The study will also explore secondary endpoints, including patient reported outcome measures for cost and quality of life.

Jennifer L. Good: We now have all 14 sites activated for this trial and see almost an even split in the enrolled subjects between each arm the 10 to 19 and greater than 20 cough counts in the study.

Jennifer L. Good: Enrollment is progressing, and we continue to expect top-line data from this study in the second half of this year. Next, an update on our LEAD program in IPF chronic cough. IPF is a serious end-of-life disease. Chronic cough is reported by approximately 85% of patients suffering from IPF and has similar significant physical, psychological, and social impacts to that of RCC but may also be a risk factor that plays a role in the progression of the underlying disease of IPF. The constant lung injury, microtears, and potential inflammation caused by persistent coughing may lead to worse health outcomes for patients, such as increased respiratory hospitalizations, mortality, or need for transplantation.

Jennifer L. Good: Enrollment is progressing and we continue to expect top line data from this study in the second half of this year.

Jennifer L. Good: Next an update on our lead program in IPF chronic cough IPF is a serious end of life disease chronic cough is reported by approximately 85% of patients suffering from IPF and has similar significant physical psychological and social impacts to that of RCC, but may also be a risk factor that.

Jennifer L. Good: The role in the progression of the underlying disease of Ips that concept 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.

Jennifer L. Good: 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, which is one of the most difficult aspects of IPF, elevating the unmet need. Our trial CORAL is a phase 2b parallel arm dose-ranging study that will study three active doses of Haduvio and placebo.

Jennifer L. Good: Treatment options for chronic cough in IPF patients and providers have an urgent need for new therapies.

Jennifer L. Good: While there are a lot of ongoing development programs in IPF current and in development therapies have not shown an impact on chronic cough, which is one of the most difficult aspects of IPF elevating the unmet need.

Jennifer L. Good: Our trial Coral is a phase two be parallel arm dose ranging study that will study three active doses of <unk> and placebo. The study is a six 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.

Jennifer L. Good: The study is a six-week trial in approximately 160 patients. We are conducting this study in multiple countries and sites to be able to complete enrollment in a timely manner. We expect to have the majority of our Plan 60 sites activated by the end of June.

Jennifer L. Good: We expect to have the majority of our planned 60 sites activated by the end of June enrollment is progressing and we are working with our sites to ensure our study is top of mind, we reaffirm our guidance for this study and which we expect to read out the results from our sample size re estimation analysis in the second half of this year and we.

Jennifer L. Good: Enrollment is progressing, and we are working with our sites to ensure our study is top of mind. We reaffirm our guidance for this study, in which we expect to read out the results from our sample size re-estimation analysis in the second half of this year, and we continue to expect top-line data for the full study in the first half of 2025. As a reminder, the SSRE is conducted when 50% of the subjects complete the study.

Jennifer L. Good: Continue to expect top line data for the full study in the first half of 2025.

Jennifer L. Good: As a reminder, the S. S. Sorry is conducted when 50% of the subjects complete the study we intend to share the SSR results. Once it is complete which will either confirm our current study sizing assumptions recommend upsizing within a pre specified range or indicate futility.

Jennifer L. Good: We intend to share the SSRE results once it is complete, which will either confirm our current study sizing assumptions, recommend upsizing within a pre-specified range, or indicate futility. We have also made good enrollment progress on our Human Abuse Potential Study, or HAP, this year.

Jennifer L. Good: We have also made good enrollment progress on our human abuse potential study or half. The share. This study is now approximately 75% enrolled and we expect to complete enrollment. This summer. The objective of this study is to determine the abuse potential of oral and there'll be a fine relative to <unk> and placebo.

Jennifer L. Good: This study is now approximately 75 percent enrolled, and we expect to complete enrollment this summer. The objective of this study is to determine the abuse potential of oral nalbufine relative to butorphanol and placebo, and it was designed and agreed upon with FDA input. Recall that parenteral nalbufine is unscheduled by the DEA, and it was recently re-reviewed by the DEA and left unscheduled. It's also important to note that the two parts of nalbufine's mechanism are also unscheduled, whether it be kappa agonists, such as Corsuba, or mu antagonists in products such as naloxone and

Jennifer L. Good: And was designed and agreed upon with the FDA input.

Jennifer L. Good: Recall that parental now be athene is unscheduled by the DEA and was recently reviewed by the DEA and left unscheduled. It's also important to note that the two parts of now but you're seeing some mechanism are also on schedule, whether it be kappa agonists, such as of course, Suba <unk> antagonist in products, such as naloxone and naltrexone.

Jennifer L. Good: This study will be submitted with our NDA as part of an 8-factor plan, which includes all the preclinical work done to date, the mechanistic rationale for why this drug is unscheduled, our clinical data generated in our development programs, the results of this HAP study, as well as a public health rationale. Our goal is to have oral nalbufenia remain unscheduled as the parental form has been all these years. We continue to expect top-line data from this study in the second half of this year as well.

Jennifer L. Good: This study will be submitted with our N D. A as part of an eight factor plan, which includes all the preclinical work done to date. The mechanistic rationale for why this drug is on schedule and our clinical data generated in our development programs. The results of this hap study as well as a public health rationale.

Jennifer L. Good: Our goal is to have oral now be a feeney R remain unscheduled as the parental farm has been all these years, we continue to expect top line data from this study in the second half of this year as well.

Jennifer L. Good: Finally, our IND for IPF cough was cleared by the FDA, and we expect to initiate our respiratory physiology study in the third quarter of 2024. We anticipate this study being conducted in the U.S. and in the U.K. The goal of this study is to systematically measure the impact of nalbufeniar on respiratory depression at varying levels of disease severity and IPF to determine our phase 3 patient population. To date, we have excluded sleep disordered breathing patients in our studies, and we want to better characterize the safety of this group as we move forward.

Jennifer L. Good: Finally, I N D for IPF cough was cleared by the FDA and we expect to initiate our respiratory physiology study in the third quarter of 2024, we anticipate this study being conducted in the U S and in the U K. The goal of this study is to systematically measure the impact of now you're Feeney R on respiratory.

Jennifer L. Good: Depression in varying levels of disease severity in IPF to determine our phase III patient population today, we have excluded sleep disordered breathing patients in our studies and we want to better characterize the safety in this group as we move forward.

Jennifer L. Good: 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 Hadoovio across chronic cough conditions. We are excited to begin completing these studies in the second half of this year and reporting the data. On a final note, our management team will be attending several medical conferences over the next few months, including the American Thoracic Society meeting in San Diego in a couple weeks, the London Cough Conference in July, and the European Respiratory Society meeting in Austria in September.

Jennifer L. Good: As you can see it is a busy time clinically for travel and we believe the data from these trials will be important to inform the development passport for who do B O. A cross chronic cost conditions. We are excited to begin completing these studies in the second half of this year and reporting the data.

Jennifer L. Good: On a final note our management team will be attending several medical conferences over the next few months, including the American Thoracic Society meeting in San Diego in a couple of weeks the London Cross conference in July and the European Respiratory Society meeting in Austria September. Please let US know if you plan to attend as we would love to meet with you.

Jennifer L. Good: Please let us know if you plan to attend, as we would love to meet with you. I will now turn it over to Lisa to review our financial results, then we will open it up for any questions.

Jennifer L. Good: I will now turn it over to Lisa to review our financial results. Then we will open it up for any questions.

Lisa Delfini: Thank you, Jennifer, and good afternoon, everyone. The full financial results for the three months ended March 31, 2024, can be found in our press release issued ahead of this call and our 10-Q, which was filed with the SEC today after the market closed. The first quarter of 2024 was a quiet quarter for finance, as the rest of the company was operationally focused on the enrollment and execution of our four trials that Jennifer discussed today.

Lisa: Thank you Jennifer and good afternoon, everyone.

Lisa Delfini: For the first quarter of 2024, we reported a net loss of $10.9 million compared to a net loss of $6.4 million for the same quarter of 2023. R&D expenses were $8.8 million during the first quarter of 2024, compared to $5 million in the same quarter of 2023, primarily due to increased clinical development expenses for our Phase 2b CORAL trial, our Phase 2a RIVER trial, and our HAP trial. These increases were partially offset by decreased clinical development expenses for our Phase 2b-3 PRISM trial.

Lisa Delfini: The full financial results for the three months ended March 31, 2024 can be found in our press release issued ahead of this call and our 10-Q, which was filed with the SEC today after the market closed.

Operator: G&A expenses were $3.1 million during the first quarter of 2024, compared to $2.6 million in the same period of 2023, primarily due to increases in information technology and finance staffing and activities, as well as professional fees. Other income net was $1 million in the first quarter of 2024, compared to $1.2 million in the same period of 2023. As of March 31, 2024, our cash, cash equivalents, and marketable securities totaled $72.8 million, compared to $83 million as of December 31, 2023.

Operator: The first quarter of 2024 was a quiet quarter for finance as the rest of the company is operationally focused on the enrollment and execution of our four trials that Jennifer discussed today.

Operator: For the first quarter of 2024, we reported a net loss of $10 9 million compared to a net loss of $6 4 million for the same quarter in 2023.

Operator: R&D expenses were $8 8 million during the first quarter of 2024 compared to 5 million in the same quarter of 'twenty three primarily due to increased clinical development expenses for our phase two b coral trial, our phase Iia River trial, and our Hap trial. These increases were partially offset by decreased clinical development expenses for our phase <unk>.

Operator: Slash III prism trial.

Operator: G&A expenses were $3 1 million during the first quarter of 'twenty 'twenty four compared to $2 6 million in the same period of 2023, primarily due to increases in information technology, and finance staffing and activities as well as professional fees.

Operator: Other income net was $1 million in the first quarter of 2024 compared to $1 2 million in the same period of 2023.

Operator: As of March 31, 2024, our cash cash equivalents in marketable securities totaled $72 8 million compared to 83 million as of December 31, 2023, we.

Operator: We used about $10.9 million in cash in Q1-24, offset by about $700,000 of interest received. This is within the range of our expected cash burn for the year of $9-12 million per quarter. Our cash runway guidance remains unchanged, and we have cash, cash equivalents, and marketable securities into 2026. This concludes our prepared remarks, and I will now turn the call back over to the operator for Q&A.

Operator: We used about $10 9 million in cash in Q1, 'twenty four offset by about 700000 of interest received this is within the range of our expected cash burn for the year of nine to 12 million per quarter.

Operator: Our cash runway guidance remains unchanged and we have cash cash equivalents in marketable securities into 'twenty 'twenty six.

Operator: This concludes our prepared remarks, and I will now turn the call call back over to the operator for Q&A.

Operator: Thank you. 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 are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then 2. The first question comes from Leland Gershell from Oppenheimer, please go ahead.

Speaker Change: Thank you we will now begin the question and answer session to ask a question you May Press Star then you're one star then one on your Touchtone phone if youre using a speakerphone. Please pick up your handset before pressing the keys.

Operator: To withdraw your question. Please press Star then two.

Leland James Gershell: The first question comes from Leland <unk> from Oppenheimer. Please go ahead.

Jennifer L. Good: Good afternoon. Thanks for taking our questions. Just two from us. First, in terms of the upcoming ATS meeting, we look forward to, and I believe we'll be hearing a cough bout analysis from Canal by Dr. Jackie Smith from the UK. As we look forward to those data, could you, maybe Jennifer, kind of discuss what the formal definition of a cough bout would be, at least in this setting, and to what extent do cough bouts impact patients with IPF?

Leland James Gershell: Hey, good afternoon, thanks for taking our questions.

Jennifer L. Good: Two from us.

Jennifer L. Good: In terms of the upcoming Ats meeting, we look forward to I believe we'll be hearing.

Jennifer L. Good: Our cost out analysis from to Mel.

Jennifer L. Good: Dr. Jackie Smith from the UK.

Jennifer L. Good: As we look forward to those data if you could maybe Jennifer.

Jennifer L. Good: What the formal definition of other cost out.

Jennifer L. Good: At least in this setting in and to what extent do cost outs impact patients.

Jennifer L. Good: With IPO and then a second question please.

Jennifer L. Good: Yeah, sounds good. I'll kind of tie it up, and I'm going to let David give you the specifics because he was deep into the paper. The reality is this whole concept of cough bouts, it reminds me a lot of itchiness and that, you know, when we talk about the average cough, that's sort of averaged over time. But there's a belief that when people have these severe bouts, that's what's doing a lot of the damage. So people are starting to get interested in looking at what that looks like. Unfortunately, there's no agreement in the field as to how you define a cough bout.

Jennifer: Yeah. It sounds good I'll kind of tee, it up and I'm going to let David give you the specifics because he was deep into the paper. The reality is this whole concept of carve outs of reminds me a lot of edge in that you know when we talk about average comp that sort of averaged over time, but there's a belief that when people have these severe bouts, that's what's doing a lot of the damage.

Jennifer L. Good: So people are starting to get it to get interested in looking at what that looks like Unfortunately, there is no agreement in the field as to how you define a cop out so that is sort of part of the debate and there's two very leading kols, who have taken our data and done the analysis. So a doctor Smith will present that and I'll, let David speak exactly just sort of her methodology.

David J. Clark: So that is sort of part of the debate. And there are two very leading KOLs who have taken our data and done the analysis. So Dr. Smith will present that, and I'll let David speak exactly about her methodology at this meeting. And then, I think, in the fall, one of the other KOLs is going to present it sort of using a different methodology. But David, can you explain sort of Jackie's methodology and how that will be presented? Absolutely.

David J. Clark: At this meeting and then I think in the fall one of the other Kols is gonna presented sort of using a different methodology, but David can you explain sort of jackie's methodology and how that'll be presented.

David J. Clark: Absolutely I can. So the methodology that Dr. Smith prefers is a cough bout is defined by two coughs, a minimum of two coughs, and then you have to have an off period. And the off period is so that a bout is if you have a cough, and typically, the off period is a two-second duration. So if you have a cough within two seconds, that bout is ongoing. Now, in an exploratory way, she likes to look at cough bouts for periods of one second up to 10 seconds.

David: Absolutely I can so.

David J. Clark: The methodology the Doctor squeeze prefers is.

David J. Clark: Iot is defined by two cops.

David J. Clark: A minimum of two calls and then you have to have an off period and the off period days so that.

David J. Clark: <unk>.

David J. Clark: Do you have a cough and typically the off periods are two seconds duration. So do you have a cough within two seconds that bank is ongoing now in an exploratory way she likes to look at trough.

David J. Clark: Off periods of one seconds up to 10 seconds, what you'll see in the paper is looking at the definition of this call. So that's of course within the duration that varies between one and 10 seconds.

David J. Clark: So what you'll see in the paper is looking at the definition of this cough bout. So that's a cough within this duration that varies between one and 10 seconds. And and that, sort of cough bout definition, as Jennifer Good said. There's not complete consensus in the field, but the methodology that Dr. Smith uses is probably amongst the commoner of cough bout definitions. And then we have, as we say, this other methodology will be presented later in the year.

David J. Clark: And and that.

David J. Clark: Sort of talk about definition.

David J. Clark: Jennifer Good said does not complete consensus in the field, but the methodology. The Doctor Smith uses is probably amongst the common and real estate cost large destinations and then rehab.

David J. Clark: We have this other methodologies will be presented later in the year.

Jennifer L. Good: Thank you, David. I know you're looking at a few different doses there, and it's obviously encouraging to hear recent support for the lack of scheduling for nalbufine from the FDA. If we were to see significant liking at, I guess, any of those dose levels, would that be an... incremental concern that we could see some form of DEA scheduling? What would the kind of sensitivity be if you had that, you know, in any sort of way that you could quantify for us the risk of scheduling based on that?

Speaker Change: Great. Thank you. Thank you David.

Jennifer L. Good: And then just wanted to ask with.

Jennifer L. Good: With respect to the hub.

Jennifer L. Good: I know youre looking at a few different doses, there and it's obviously encouraging to hear.

Jennifer L. Good: Support for lack of scheduling for so now you're seeing from the FDA.

Jennifer L. Good: If we were to see significant liking.

Jennifer L. Good: I guess any of those dose levels would that be.

Jennifer L. Good: Incremental concern that we could see some form of scheduling what would be kind of a sensitivity if you have that.

Jennifer L. Good: And any sort of way that you can.

Jennifer L. Good: Quantify for us for the risk of scheduling based on the absolute.

Jennifer L. Good: Yeah, so the scheduling decision will be made. It'll be a review decision, you know, first by the division that gets deferred to the DEA. They do look at sort of the gestalt, if you will, of the eight-factor plan. So the mechanism of the drug, what they know about it from epidemiology, what you saw in your own clinical trials, just there's sort of a whole big picture they look at.

Speaker Change: Yeah. So the scheduling decision will be made and it'll be a review decision you know first by the division that gets deferred to the DEA. They do look at sort of the Gestalt. If you will of the eight factor plan. So the mechanism of the drug what they know about it from epidemiology. What you saw on your own clinical trials, just theres sort of a whole big picture they look at.

Jennifer L. Good: Now, the HAP is not, the preclinical data is also quite important, which has all been done, and that's all clean. The HAP, though, is not insignificant. I think it's not that you can't see anything in your data.

Jennifer L. Good: Now they have is not answered with a preclinical data is also quite important much has all been done and that's all clean they have though is not insignificant I think if it's not that you can't see anything in your data, it's all going to be.

Jennifer L. Good: It's all gonna be, you know, in theory, you're gonna be a little more likable than placebo. I think if you're significantly more likable than butorphanol, it opens up the conversation. I think it'll just depend. We'll have to look at that data sort of in context with everything else. I will tell you, though, when I sat through the original discussions of what the FDA focuses on, it's not that you can't have any signs of this.

Jennifer L. Good: In theory, you're going to be a little more likeable than placebo I think if you're significantly more likeable them be tour for now it opens up the conversation I think it'll just depend well have to look at that data sort of in context of everything else I will tell you, though when I sat through the original discussions of what the F. D. A focuses on its not.

Jennifer L. Good: You can't have sort of any signs that that's what they really get worried about is a dose response to like ability. So if you have some like ability at call your low dose and that doubles and triples with sort of your high dose, that's where you get into issues because they obviously worried people take you know kind of your tablets and that's a problem. So it's a hard quest.

Jennifer L. Good: What they really get worried about is a dose response to likability. So if you have some likability at your low dose, and that doubles and then triples with sort of your high dose, that's where you get into issues because they obviously worry people take, you know, 10 of your tablets and that's a problem. So it's a hard question to answer, Leland, and internally, we've been grappling with it. I think when we have the data, we'll put it out as clearly as we can and have an expert join the call so that people can, you know, interrogate the data themselves and ask the questions.

Jennifer L. Good: And to answer Leland and internally, we've been grappling with I think when we have the data we'll put it out as clear as we can and have an expert joining the call. So that people can interrogate.

Jennifer L. Good: Interrogate the data themselves and ask the questions.

Jennifer L. Good: Fair enough. Thank you for the incremental colors. Yeah.

Speaker Change: Fair enough. Thank you for the incremental color.

Jennifer L. Good: Yes, thank you, and we'll see you at ATS.

Speaker Change: Yes, Thank you and we'll see at a T S.

Jennifer L. Good: Okay.

Operator: The next question comes from Jack Padovano from Stiefel. Please go ahead.

Jennifer L. Good: The next question comes from Jack Padovano from Stifel. Please go ahead.

Operator: Hi, this is Jack on behalf of Annabel. Thanks for taking our questions.

Jack Padovano: Hi, This is Jack on for Annabel, Thanks for taking our questions.

Jennifer L. Good: So when you arrive at this sample size re-estimation for IPF, what might the chances be that the study has already hit statistical significance at that point? And if that occurs, would you just continue as planned until final readout, or could you potentially halt the trial early in that case? And then kind of to follow up on that, just recalling the magnitude of effect that we've seen in IPF already, if those kinds of effects persist in upcoming trials, are there any opportunities for you to move straight from POC into Phase III?

Jack Padovano: So when you arrive at this sample size re estimation for IPF.

Jennifer L. Good: What might the chance to see that the study has already hit statistical significance at that point and if that occurs would you just continue as planned until final readout or could you potentially all the trial early in that case.

Jennifer L. Good: And then kind of a follow up on that just for calling the magnitude of effect that we've seen in the IPF already.

Jennifer L. Good: Those kinds of effects persistent upcoming trials are are there any opportunities for you to move straight from POC into phase III.

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

Jennifer L. Good: So David I'll, let you answer both of those.

David J. Clark: Yes. So, with the SSRE we are utilizing, it is not acceptable with regulators, particularly the FDA, to use success criteria such as you've outlined. So, you've got 80 subjects completed the primary time point, and you've separated several doses from placebo. The FDA will not allow you to build that sort of success criteria into this sort of standard SRE. So, there's the answer to the first question. It really just... In a closed loop system, you say, is your variance in your effect size sufficient for your assumptions going in? So your sample size cannot fall below 160. And what was your second question? I'm sorry.

David: Yes, so with DSA, sorry, we are utilizing that.

David J. Clark: It is not acceptable with regulators, particularly the FDA to use the success criteria such as you've outlined so you've got 80 subjects completed the primary time point.

David J. Clark: You've separated with several doses from placebo.

David J. Clark: David.

David J. Clark: We will not allow you to build that sort of success criteria into this sort of a standard or sorry. So that's the answer to the first question it really just.

David J. Clark: In a closed loop system.

David J. Clark: If you're a variance in your fixed size sufficient for your assumptions going in so your sample size cannot fall below 160, <unk> and what was your second question I'm sorry.

Jennifer L. Good: The second question, I can jump in, David, and then you can add color. He wanted to know if the magnitude of effect is strong, can we go straight from POC to pivotals? And I think, you know, in IPF, we're doing a phase 2B to select doses, and the intent is to roll into our pivotal program. I think with RIVR, the phase 2A, the internal consensus is, and David, this is where you can add some color, is that we are planning for a phase 2B that is structured to look like a pivotal.

Speaker Change: That's the second question I can jump in and David and then you can add color you wanted to know if the magnitude of effect is strong can we go straight from POC to pivot all of US and I think you know in IPF, we're doing a phase two b to select dose and the intent is to roll into our pivotal program I think with river the phase Iia.

Jennifer L. Good: The internal consensus says and David This is where you can add some color is we are planning for a phase two b that is structured to look like a pen at all so we still are probably going to need to do some dose ranging work to make sure. We're clear on that patient group, but we will try to structure. It to look like a pivotal study and then depending on the data can hopefully have discussions but David.

Jennifer L. Good: So, we still are probably going to need to do some dose ranging work to make sure we're clear in that patient group, but we will try to structure it to look like a pivotal study, and then, depending on the data, we can hopefully have discussions. But, David, any color you want to add to that? No, I think that addresses it very well. Thanks, Jennifer.

David: Any color you want to add on that.

David: No I think that addresses that very well thanks Jennifer.

Speaker Change: Great. Thank you.

Speaker Change: Thank you Jack.

Operator: The next question comes from Tom Smith from Lering Partners. Please go ahead.

Jennifer L. Good: The next question comes from Tom Smith from Leerink Partners. Please go ahead.

Operator: Hi, this is Nathanael Charoensook going for Thomas Smith. We have a couple of questions on the reverse study. So first, what's the rationale for choosing a 21-day duration while the other late-stage trials look at endpoints at 12 or 24 weeks?

Operator: Hi, This is natural answer Tom Smith, we have couple of questions on the reverse study. So first what's the rationale for shifting 21 day duration, while the other late stage trials and points at 12 or 24 weeks.

Nathanael Charoensook: And I have a follow up.

Jennifer L. Good: Yeah, I mean, the rationale is all Phase IIa. I mean, for the compounds you currently see in development, they all ran this Phase IIa crossover design as a proof of concept, sort of to show that your drug is working. It takes away some variability. As you exit the proof of concept phase, that's when you get into the longer trials.

Nathanael Charoensook: Yeah, I mean, the rationale is all phase two ways I mean for the compounds you currently see in development. They all ran this phase to a crossover design as a proof of concept to show that your drug is working it takes away some variability as you exit the proof of concept, that's when you get into the longer trials.

Jennifer L. Good: Got it. And what's your expectation of the data expected in SIGGRAPH-24? Do you anticipate to see different levels of efficacy in patients with moderate versus severe cough frequency as you look at whether to change in cough frequency rather than absolute changes?

Speaker Change: Got it and what's your expectation on the data are expected in second half 'twenty four do you anticipate your feet at different levels of efficacy in patients with moderate to severe cough frequency as we look at where the change in competency rather than the absolute changes.

David J. Clark: Yeah, David, would you like to talk a little bit about the sort of hypothesis around the study and what we're trying to show with the different cough levels and things?

Jennifer L. Good: And David do you want to talk a little bit about sort of the hypothesis around the study and what we're trying to show with the different cost levels and things.

David J. Clark: I'd be happy to do that, Jennifer. So, the information we have so far, and it is, as you know, it's only from the canal study in the IPF chronic cough population, is that baseline cough frequency did not influence the efficacy signal. It was as robust in the subjects independent of that cough frequency. So, that's the only information we have going into this. And as you know, there has been difficulty with peripheral-based mechanisms of action getting the signal in that moderate population. But our information going into the study is that based on the IPF chronic cough, we didn't see any evidence of a difference, a change based on baseline cough frequency.

David: Be happy to do that Jennifer so the information we have so far and it is as you know it's Tony from the Canal study in IPF chronic cough population is that.

David J. Clark: Baseline cough.

David J. Clark: Currency did not influence the efficacy signal is robust and the subjects in the.

David J. Clark: Pendant.

David J. Clark: Call frequency. So that's the only information we have going into this.

David J. Clark: And as you are aware has been difficulty with.

David J. Clark: Peripheral based.

David J. Clark: Mechanisms of action getting the signal in that moderate population, but our information going into the study is that.

David J. Clark: Based on the IPF chronic cough.

David J. Clark: Didn't see any evidence of the difference.

David J. Clark: A change based on baseline cough frequency.

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

Jennifer: Got it and do you plan to include efficacy end points that can capture for example, KOF cluster copper T cells appear to burden patients with RCC.

Operator: I'm sorry, can you repeat that question? Is that the one you meant?

Speaker Change: I'm sorry.

Jennifer: Question is.

Jennifer L. Good: Is that the cough clustering you're asking about, and are we capturing some of that data? Mm-hmm, yeah. Yeah, and David, I think we have the ability to go back and do that analysis, correct? We do. Actually, we have that for you.

Jennifer: Is that the cop clustering, you're asking about and are we capturing some of that data.

Speaker Change: Uh-huh, yes.

Speaker Change: Yeah, and David I think we have an ability to go back and do that analysis correct.

David J. Clark: We do. Actually, we have that pre-specified as an analysis, which we will be conducting because, as we have mentioned before, we think the primary endpoint for cough programs will stay the same as it is right now, using 24-hour cough frequency. But there's clinical relevance to these cough bouts by these different definitions, so we really want to study them in all of our studies moving forward, so we understand what sort of effects we're having there, in addition to what we believe will be the registration endpoint.

Speaker Change: We do actually we have that pre specified as announcements, which we will be conducting.

David J. Clark: Because as we have mentioned before we believe.

David J. Clark: We think the the primary endpoint for co programs. We believe will stay the same as it is right now with using 24 hour cough frequency.

David J. Clark: But there's clinical relevance to these cost bags by these different definitions. So we really want to study them in all of our studies moving forward. So we understand what sort of effects were having there. In addition to what we believe will be the registration endpoint.

Speaker Change: Got it thank you so much.

Speaker Change: Thank you.

Operator: As a reminder, if you have a question, please press star 1. The next question comes from Mayank Mamtani from B. Reilly Securities. Please go ahead.

Speaker Change: As a reminder, if you have a question please press star one.

Mayank Mamtani: The next question comes from Mike Mom Tani from B Riley Securities. Please go ahead.

Operator: Good afternoon, team. Thanks for taking our questions and congratulations on the progress. So this may be on the SSRE for the Cornell trial. If you could just maybe clarify the statistical assumptions for placebo as well as the, I guess, the top dose you're looking to show separation against. This may be how many patients, what sort of effect size and p-value. And also, are there any baseline characteristics that could be different between Cornell and canal that we should be aware of? And then I'll have a quick follow up.

Mayank Mamtani: Good afternoon, and thanks for taking my question and congrats on the progress so just maybe on the.

Operator: For the Carnival trial, if you could just maybe clarify the statistical assumptions for.

Operator: Placebo as well as the.

Operator: I guess those dock doors Youre looking do show separation against.

Operator: This may be how many patients what sort of effect size in P value and also are there any baseline characteristics.

Operator: It could be different between corner then can now.

Operator: We should be aware of and then I have a quick follow up.

David J. Clark: David, do you want to take that?

Operator: David do you want to take that.

David J. Clark: I'm happy to do that, Jennifer. So, in terms of the inclusion criteria, we did not change them. So, the way we are selecting the IPF chronic cough population is the same as we utilized in canal. I mean, the main difference, as you know, is that it's a global program.

David: Happy to do that Jennifer so in terms of the inclusion criteria, we did not change them. So the way we are selecting the IPF chronic cough chronic.

David J. Clark: Chronic cough population is the same as we utilized in canal I mean, the main difference as you know this is a global program. So that there is the potential for some differences there we will see in the study.

David J. Clark: So, there is the potential for some differences there, as we will see in the study. So, the assumptions we made for the SSRE, the N of 160, so that's 40 per group, that is based on an effect size of active drug above placebo on top of the placebo effect. So, the separation on top of the placebo effect is 36 percent. We've got more than 80 percent power going into the study with an N of 160, 40 per group.

David J. Clark: So the assumptions we've made for the <unk> sorry, the end of 160. So Thats 40 per group that is based on kind of fixed size of active drug above placebo on top of the placebo effect. So the separation on top of placebo effect of 36%, we've got more than 80% power going into the study.

David J. Clark:

David J. Clark: With the end of $160 40 per group.

David J. Clark: The top end of the sample size that we are allowed to go to, we set it at 160; we can go up to 400. And that's if we either have a variance which is not, is higher than we expected, or the effect size is smaller. So, for example, if the effect size is increased to the top sample size of 400, that's 100 per group, if that is necessary, that would allow us to detect a clinically relevant effect size of 25 percent on top of placebo. So, that's how we framed the SSRE characteristics.

David J. Clark: The top end of the sample size that we are allowed to go to we said at 160 <unk>. We can go up to 400 that we either have a variance which is not as high as we expected. Although the effect size is smaller. So for example, if the effect size.

David J. Clark: The increasing it to the top sample size.

David J. Clark: 400, <unk> 100 per group if that isn't.

David J. Clark: Necessary, but it would allow us to detect a clinically relevant effect size of 25% on top of placebo. So that so we framed yes.

David J. Clark: Sorry characteristics.

David J. Clark: Super helpful and then on the <unk>.

Jennifer L. Good: Super helpful. And then on the phase two reverse study, moderate versus severe cohorts, are they equally split in terms of enrollment? And would you be looking to present data in the second half, you know, in both of those cohorts, or would you do a sort of a total pooled analysis? And then lastly, what's the forum for this half study presentation? Obviously, great to see the 75% enrollment achieved, but it does have a relatively short follow-up. So just curious if that would be a press release or an event, a KOL event, if you could clarify that. Thanks for the input.

David J. Clark: Phase two study.

Jennifer L. Good: Moderate versus to the cohorts.

Jennifer L. Good: Equally split in terms of enrollment and would you be looking to present data and taken out.

Jennifer L. Good: And in both of those cohorts or are you sort of go reported analysis and then lastly, what's the ballroom for the Hajj study presentation, obviously, great to see the 75% enrollment achieved but it does have a relatively short follow up. So just curious is that would be a press release.

Speaker Change: Hey, Glenn.

Jennifer L. Good: And if you could clarify that thanks for the input English.

Jennifer L. Good: Yeah, thank you, Mayank. So, so far, so good on the enrollment in RIVR. We're seeing sort of equal numbers in both moderate and severe. Obviously, we won't finish the study till we get everybody in. We will, we will, we do plan to report that out as part of our top-line data, so that won't come later. That'll be part of our top-line data reported out. As far as the Forum for Human Abuse Potential is concerned, we're sort of working through that, but I think what we're working towards is a press release and then also doing a call with probably an expert or two on the phone who work in this area regularly.

Speaker Change: Yeah. Thank you my and so so far so good on the enrollment and river, we're seeing sort of equal numbers in both moderate and severe obviously, we won't finish the study until we get everybody in and we.

Jennifer L. Good: We will we will we do plan to report that out as part of our topline data. So that won't come later that'll be part of our topline data report it out.

Jennifer L. Good: As far as the forum for human abuse potential we're sort of working through that but I think what we're working towards is a press release and then also doing a call with probably an expert or two on the phone that works in this area regularly so well present the data on that brand. But then also open up the call to folks like you to be able to ask whatever.

Jennifer L. Good: So, we'll present the data on our end, but then also open up the call to folks like you to be able to ask whatever questions you'd like around the data. I mean, hopefully, it's clear and sort of not a lot to discuss, but that's also encouraging and allows you guys the opportunity to sort of confirm that yourself. So, that's the current plan that we are working on.

Jennifer L. Good: Question do you like around the data.

Jennifer L. Good: I mean, hopefully, it's clear and sort of not a lot to discuss but that's also encouraging and allows you guys the opportunity to sort of confirm that yourself. So that's the current plan that we are working against.

Jennifer L. Good: I understand. Looking forward to it. Thank you.

Speaker Change: Understood looking forward to that.

Speaker Change: Thank you.

Jennifer L. Good: Yeah.

Operator: 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. Thank you.

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

Jennifer L. Good: Thank you. We are expecting a data-rich year with regard to our clinical trials for Hadoopio. We see an exciting road ahead for Trevi, and we are locked down on executing good-quality trials on time. We will be participating in several investor conferences over the next couple of months, as listed in our press release, and look forward to seeing many of you there. Thank you for joining today's call, and we are available after the call for any follow-up questions you may have.

Jennifer L. Good: Thank you we are expecting a data rich year with regards to our clinical trials for <unk>, we see an exciting road ahead for travel and we're locked down on executing good quality trials on time, we will be participating in several investor conferences over the next couple of months as listed in our press release and look forward to seeing many of you there.

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

Operator: Thank you for joining today's call and we are available after the call for any follow up questions you may have.

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

Operator: Okay.