Trevi Therapeutics, Inc.

Good afternoon and welcome to the Trevi Therapeutics third quarter 2024 earnings conference call. At this time, all participants will be in 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 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 call over to Jennifer Good, Trevi's President and CEO. Please go ahead.

Good afternoon, and thank you for joining us for our third 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. James Casella, Trevi's Chief Development Officer. I will give an update on our trials and upcoming data milestones, and Lisa will give a brief financial update. Then the three of us are happy to answer any questions. First, I would like to take a minute and introduce you to Jim Casella, who has recently joined our leadership team as our Chief Development Officer. As some of you may know, Jim has been on our Board of Directors for the past four years and has been a valuable advisor to me in that role. Jim has a deep background in neuroscience drug development, with over 35 years working specifically on CNS therapies. Prior to joining Trevi, Jim served as CDO for Concert Pharmaceuticals, which was acquired by Sun Pharma in 2023, where he led the development activities, resulting in the successful U.S. FDA approval of the autoimmune JAK inhibitor Lexalvi. Prior to joining Concert, Jim was EVP Research and Development and CSO at Alexa Pharmaceuticals, from 2004 to 2015, where he was responsible for the US and European approval of the CNS drug, Adesuv. Jim received a PhD in Physiological Psychology from Dartmouth College and completed a post-doctoral fellowship in the Department of Psychiatry at the Yale School of Medicine. Jim brings a wealth of development experience to Trevi, including phase three and recent regulatory approval experience, which will be invaluable as we advance into late stage development. He joins Trevi at an exciting time as we read out important studies over the upcoming months and prepare for phase three pivotal trials and NDA submission. So welcome, Jim. This has been a very productive quarter at Trevi as we continue to execute against our clinical development plans for both patients with chronic cough and idiopathic pulmonary fibrosis, or IPF, as well as patients with refractory chronic cough, or RCC. We have a number of upcoming data readouts, and we hope to build on the strong efficacy we saw in our Phase 2A trial in patients with IPF chronic cough. As we have advanced the clinical development in our two programs, there have been continued failures with competitors' products in both disease modification trials and IPF, as well as drugs being studied in RCC, reminding us of the continued need for new therapies for patients suffering from these serious conditions. I will run through an update on our upcoming clinical data readouts, which I believe are seminal in value creation for the company. I will discuss them in order of timing. First up, the human abuse potential, or HAP study. I have discussed this extensively with investors and analysts, so I'm sure you all feel you know more about HAP studies than you ever cared to. So let me summarize the key points on HAP as we prepare for data. As a reminder, injectable nalbufine, which is indicated for severe pain, has been around for decades and has remained unscheduled by the DEA. The DEA looks at scheduling of molecules regularly and schedules drugs based on the chemical entity, not the delivery mechanism. As recently as 2023, the date of their last review, the DEA has kept nalbufine unscheduled. Importantly, I wanted to summarize for you their reasonings and their recent opinion. First is nalbufine's unique mechanism of action. Nalbufine is a kappa agonist and mu antagonist, or CAMA, which is in the class of mixed agonist-antagonist drugs. All drugs that are either a kappa agonist or a mu antagonist are unscheduled, and these were designed to mitigate abuse potential. Second, nalbufine is less attractive to abusers due to its potent antagonistic effects at mu, which precipitate drug withdrawal. Third, even though nalbufine is currently available, the DEA cites that nalbufine is rarely encountered by law enforcement personnel or submitted to forensic labs for analysis. So there's a lot of history with nalbufine as a molecule, and it is not new to the DEA. So why are we doing the HAP study at all? There is FDA guidance from 2017 that requires HAP studies for all CNS active drugs. So we are bringing the package up to current day standards. Finally, this study will be reviewed by the Controlled Substance Staff, CSS, a group in FDA as part of the eight-factor plan. The eight-factor plan has several categories of which only one is the half. So we will wait to see the final data, but we believe there are a lot of reasons why nalbufine will remain unscheduled if approved in chronic cough. Okay, moving on to our clinical indications. Next up for data will be the sample size re-estimation in our IPF cough trial. First, I want to note that new treatment options for IPF patients have been scarce since the antifibrotics were approved 10 years ago, and neither of the two approved antifibrotics have shown significant reduction in chronic cost. Second, other than our Phase II data, there have not been any successful trials in IPF cost, despite being one of the primary complaints by these patients. And third, we believe cough may be a risk factor that plays a role in the progression of the underlying disease. 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. So, we continue to believe our program is important to these patients, their loved ones, and doctors. Our IPF chronic cough trial, CORAL, is a Phase IIb parallel-arm dose-ranging study that will investigate three active doses of Heduvia and placebo. The study is a six-week trial in approximately 160 patients. The next milestone in CORAL is to conduct the sample size re-estimation, SSRE analysis, when 50% of the patients complete the study. 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 will be informed of one of the following three outcomes. One, continue on with the planned 160 patients, which will reconfirm the original powering assumptions. Two, the drug is working within the pre-specified 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 pre-specified range and the company should consider stopping or futility. We will announce the results of this analysis when we have the information, which we expect in December of this year. We continue to expect top line data for the full study in the first half of 2025, subject to the outcome of the SSRE. From my perspective, the SSRE is a key de-risking event for the ultimate success of this trial, if the answer back is anything but futility. The statistical range in this study, both the original N as well as the upper limit of the range, is aligned to a clinically meaningful placebo-adjusted change, so it is just a matter of figuring out the right sample size in this study population. Following the SSRE and IPF cough, we expect data in the first quarter of 2025 for our Phase IIa river trial in RCC. RCC is a debilitating disease that affects approximately two to three million U.S. adults and is defined as a persistent cough lasting greater than eight weeks, despite treatment for an underlying condition or where no underlying condition exists. With a 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 mechanisms. Although there have been many failures in RCC drug development, we believe our unique central and peripheral mechanism could change that outcome. The many drugs that have failed have all been peripheral only agents. The types of cough we are studying are linked through hypersensitivity in the brain, and this is why we believe our mechanism may be important in this condition. Our RCC trial is a phase 2a crossover design that has been conducted in several cough trials across the industry and was designed to enroll approximately 60 patients. These patients were randomized to now bufini R or placebo with patients stratified by cough count. Those with 10 to 19 coughs per hour, moderate cough, and those with greater than or equal to 20 coughs per hour, high cough. The primary analysis will be conducted on the total population, but we will have the ability to understand if our drug shows a signal in these moderate coffers where other programs have been unsuccessful. This trial is now fully enrolled with the last patient out at the beginning of 2025. We are excited to complete this study and report the data for this significant chronic cost condition in Q1 of 2025. As you can see, we made a lot of progress over the last few months on completing enrollment and dosing, and are eager to see the data from each of these trials. To summarize, we expect half data in December of this year, followed by Coral Phase IIb SSRE by year end as well. Then looking into 2025, we expect River Phase IIa top line data in Q1 2025, then the top line data from the full Coral Phase IIb study in first half 2025. assuming no increase in the sample size. This is an exciting time at Trevi, with strong news flow in the upcoming months, all representing important value inflection points. I will now turn it over to Lisa to review our financial results.

Thank you, Jennifer, and good afternoon, everyone. The full financial results for the three months ended September 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 third quarter of 2024, we reported a net loss of $13.2 million compared to a net loss of $7.7 million for the same quarter in 2023. R&D expenses were $11.2 million during the third quarter of 2024 compared to $6.3 million in the same quarter of 2023. The increase in R&D spend reflects the significant clinical development activity Jennifer just discussed, including continued enrollment in our CORAL trial in chronic cough and IPS, the final full quarter of enrollment in the RIVER trial in RCC, and the final full quarter of dosing in the HAP trial. G&A expenses were $2.9 million during the third quarter of 2024 compared to $2.7 million in the same period of 2023, primarily due to an increase in stock-based compensation expense and importantly demonstrating the control of overhead expenses, which we continue to be mindful of. As of September 30, 2024, our cash, cash equivalents, and marketable securities totaled $65.5 million compared to $83 million as of December 31, 2023. Our current expectation is that our cash burn for 2024, excluding proceeds from share issuances and interest and investment income, will be between $41 and $43 million, in line with our previous guidance. We now project cash runway into the second half of 2026, more than a year past all current projected data readouts. This concludes our prepared remarks. I will now turn the call back over to the operator for Q&A.