Good afternoon and welcome to the Trevi Therapeutics Q4 and Year-End 2022 Earnings Conference Call. [Operator Instructions] Please note this event is being recorded.

Various remarks that management makes during this conference call about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995.

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of the company's most recent annual report on Form 10-K which the company filed with the SEC this afternoon.

In addition, any forward-looking 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 our fourth quarter and year-end earnings call and business update. Joining me today on this call are Lisa Delfini, Trevi's Chief Financial Officer; and Dr. David Clark, Trevi's Chief Medical Officer. Lisa and I have some prepared remarks, then the 3 of us will be available for questions.

2022 was a transformational year for Trevi with regard to validating the broad utility of the mechanism of our drug, Haduvio. With our trials in IPF cough and prurigo nodularis both reading out positive, it left us in a strong position to decide how best to grow the company for our stakeholders.

Based on the strength of the cough data and IPF as well as the lack of competition in that space, we feel we can carve out a strong and unique position in therapy for IPF.

We also believe that because of the differentiated central and peripheral mechanism of our drug, we have the potential to provide therapy across a range of chronic cough indications regardless of what the underlying disease is.

So with those decisions made and strong capital raising in 2022, we are now buckled in and focused on executing against our plans for the next stage of development. Let me now provide an update on each of our programs, starting with our lead program in chronic cough and IPF.

IPF is a serious end-of-life disease and chronic cough is a major cause of morbidity, significantly impacting the patient's quality of life. It is estimated that up to 85% of IPF patients are suffering from chronic coughing.

As we prepare for our next trials in this indication, there are many learnings we can take from the development work occurring in refractory chronic cough.

However, there are also unique aspects of the IPF patient population related not only to a potential effect on the underlying disease but safety in this frail patient population that we also need to keep in mind. We are planning to conduct 2 studies in parallel during this next phase of development in our IPF chronic cough program.

The first is a Phase IIb dose-ranging trial that will study 3 doses. The doses we are planning to study are 27, 54 and 108 milligrams BID. Based on the data from the Phase II CANAL study, we have dropped the highest dose as it appears the efficacy occurred very early in that trial and at the lower doses.

Because of the severity of illness in these patients, it will be important to understand the minimally effective dose. We are planning for approximately 50 subjects per arm for a total end in the study of 200 and dosing for approximately 6 weeks.

We are planning on conducting this study in multiple countries to be able to complete enrollment in a timely manner. We will give better guidance on enrollment time lines once we initiate the study. In parallel, we are planning for a Phase Ib respiratory physiology study.

As you may know, all opioids have a class label black box warning regarding respiratory depression. This is not something we have seen in our safety data across our various studies to date. But because of the lung impairment in IPF patients, we feel this is an important question to study early.

We plan to run an inpatient study in IPF patients with levels of varying disease severity and increasing doses of Haduvio to determine if we see a clinically significant impact on respiratory depression. These 2 studies will help define the optimal dose or doses and the patient population in our pivotal program.

We have submitted the respiratory physiology protocol to the FDA and are awaiting their feedback. We are also preparing for submissions in the U.K. and Europe to support these trials. There is a new regulatory process in the EU called CTIS which became mandatory as of January 31, 2023.

Under the new process, the health authority and the ethics committees perform their reviews in parallel. As a result, there's more information required upfront to make the submission.

In theory, this new process will streamline the review process, although there is little data to show how the implementation is going and companies expect there will be growing pains. So we will keep you informed of our expected time lines but I wanted to make you aware there is a new process in play which makes time lines difficult to estimate.

In parallel, our clinical operations team is preparing for these studies so that we can initiate once we have regulatory agreement on the protocol and an open IND.

We expect to initiate both of these IPF studies in the second half of 2023 and we will provide guidance on the overall final design as well as the estimated timing for the trial once we begin the studies. In addition to the preparations in IPF cough, we are also developing a protocol for a Phase II refractory chronic cough study.

That study will look a lot like the CANAL trial and will seek to establish proof-of-concept in refractory chronic cough. There have been a lot of trials in this condition, with only one mechanism which has been successful, the P2X3s. P2X3s work peripherally in the lung.

However, we believe there is still a significant opportunity for a mechanism that works both centrally in the brain and peripherally in the lungs and has the potential to provide strong and consistent efficacy in a broader set of RCC patients.

Our cough data generated to date has continued to garner a lot of attention globally and has been presented at various respiratory meetings by KOLs in pulmonology. During the fourth quarter, Dr. Philip Molyneaux presented data at the British Thoracic Society meeting.

We have also finalized a manuscript on the trial results and we'll be submitting it for publication shortly. On March 29, there will be another presentation at the Annual German Pulmonology meeting. On Monday, May 22 in Washington, D.C., additional results from CANAL will be presented at the American Thoracic Society meeting.

And on June 9 through 10 in Reston, Virginia at the American Cough Conference, there will be a presentation on our central and peripheral mechanism of action and why it is unique and could be important broadly in cough. I think it is important to note that almost all of our conference submissions have been chosen for oral presentations.

I think this speaks to the medical community's interest in our program and the importance of the unmet medical need we are trying to address.

The other program where we have ongoing work is for the treatment of prurigo nodularis, or PN which is a serious and debilitating disease characterized by papules and nodules on the skin as well as incessant and severe itching. In June of last year, we also reported positive data in the Phase IIb/III PRISM trial in PN.

The trial achieved statistical significance on the primary and all key secondary endpoints. During the first quarter of 2023, we completed the 1-year open-label extension study that was associated with PRISM.

We should receive the data from that study in the second quarter and we'll prepare for an end of Phase II meeting with the FDA which we expect to have this year. Finally, we also commenced a human abuse liability study in the fourth quarter of last year. The objective of this study is to compare the abuse potential of oral nalbuphine to butorphanol.

The injectable version of nalbuphine is currently unscheduled in the U.S. by the Drug Enforcement Agency, or DEA. Butorphanol is a Schedule IV drug. This study is a randomized, double-blind, active and placebo-controlled 5-way crossover design. The study is conducted in 2 parts, with the first part characterizing various butorphanol doses.

One butorphanol dose will be selected to be studied in the second part of the protocol to determine the abuse potential of oral nalbuphine relative to the selected dose of butorphanol. The company is currently completing Part 1 of the study and expects top line data from the complete trial by the end of 2023.

It is a busy time at Trevi working to initiate or conduct 4 separate studies and completing the open-label extension in PN. This is a critical part of the process to get right and David and his team are making good progress against each of these. We will announce the start of each study with more details as we initiate each one.

As I look back on 2022, I am extremely proud of the execution by our team and the positive trial results in both of our lead indications.

The trial data and subsequent financings have positioned us well to continue the development of Haduvio in not only IPF chronic cough but also other serious chronic cough conditions such as RCC and cough in interstitial lung diseases.

For PN, we are in discussions with potential partners to advance that program into the next stage of clinical development. The end of Phase II meeting with the FDA will help determine next steps for this program. I will now turn it over to Lisa to review our financial results, then we will open it up for questions..

Thank you, Jennifer and good afternoon, everyone. The full financial results for the 3- and 12-months ended December 31, 2022 can be found in our press release issued ahead of this call and our 10-K which was filed with the SEC today after the market closed. I'll start with fourth quarter 2022 results.

For the fourth quarter of 2022, we reported a net loss of $5.5 million compared to a net loss of $8.5 million for the same quarter in 2021. This is a net loss per share for the quarter of $0.06 as compared to a net loss per share of $0.28 for the same quarter of 2021.

R&D expenses were $4.3 million during the fourth quarter of 2022 compared to $6.2 million in the same quarter of 2021.

The decrease was primarily due to decreased clinical trial costs, reflecting the completion of both the blinded portion of the PRISM and CANAL trials prior to the fourth quarter of 2022, partially offset by an increase in costs related to the human abuse liability study which we initiated in the fourth quarter of 2022.

G&A expenses were $2.3 million during the fourth quarter of 2022 compared to $2.1 million in the same period of 2021. The increase was primarily due to higher legal fees associated with intellectual property filings and other professional fees.

Other income net was $1.1 million in the fourth quarter of 2022 compared to other expense net of $300,000 in the same period of 2021.

The change was primarily due to an increase in interest income in 2022 as a result of investing the funds from our capital raises completed during 2022, coupled with higher interest rates than were available in the fourth quarter of 2021. Now turning to the full year results.

For the year ended December 31, 2022, we reported a net loss of $29.2 million compared to a net loss of $33.9 million for 2021. Our net loss was lower in 2022 as a result of decreased R&D expenses which were $19.8 million during the full year 2022 compared to $23 million in 2021.

This was offset by increased G&A expenses which were $10.1 million for the full year 2022 compared to $9.5 million in 2021. Other income net was $0.7 million in 2022 compared to other expense net of $1.5 million in the same period of 2021.

The drivers of these changes were largely the same as the drivers I just discussed related to the fourth quarter changes. A few comments on cash and cash runway. During the fourth quarter of 2022, we received $3.1 million in gross proceeds from the underwriters' option for the greenshoe related to our September offering.

These funds, together with the funds we raised earlier in the year, enabled us to end the year with cash, cash equivalents and marketable securities of $120.5 million. This gives us cash runway into 2026 which includes completing the trials that Jennifer laid out today and paying off our term loan in accordance with its terms.

Finally, I want to take a moment to address recent events related to SVB. As many of you know, last Friday, the FDIC closed SVB and appointed the FDIC as receiver. We bank with SVB.

However, the substantial majority of our cash, cash equivalents and investments were held in custody accounts in our name at another large financial institution, so we had very limited exposure. On Monday, the FDIC announced that all SVB deposits are protected. So this has now become largely an operational matter which we are managing through.

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

[Operator Instructions] Our first question comes from Leland Gershell with Oppenheimer..

I want to ask, Jennifer -- both my questions are really dosing-related questions.

As you approach the abuse liability study, will you be looking to harmonize the doses of nalbuphine that you can test with the dose-ranging study that you're starting up as well? Or will you look at maybe higher doses to see if there is any untoward activity that occurs? And similarly for the trial in RCC, if you're able to share at this point, how might the doses in the RCC study look versus the doses you've looked at so far and the doses that are being tested in the IPF IIb?.

Thank you, Leland, for the question. David, I'll take the first one on the house since I lived through that. And then why don't you take the RCC dose since you're working on that protocol, as we speak. So Leland, the process and the how, we actually already ran through that to identify the dose for nalbuphine.

We did that a year or 2 ago, where you essentially try to find a maximum tolerated dose. And so we sort of pushed up and really, there's a limit in the guidance that says once you get to 3x your effective dose in the market, you can stop which is what we were able to get to. We have not found an MTD on nalbuphine. So the exact dose is, I think, 480.

David might correct me a little bit. But that dose will be compared to the work being done on butorphanol which is also basically 3x what's in the marketplace. So the doses will get nailed down and it will be sort of 3x what you see in our clinical trials.

Okay? And then, David, do you want to talk about RCC and how you're thinking about dosing?.

Yes, yes. And by the way, you're quite right that the top dose in -- used in the HAL study is 486, as you say, Jennifer. So yes, we will be bringing the doses together. For the RCC study which as Jennifer explained, the design will be very similar to the CANAL, this 2-way crossover design in approximately 60 subjects.

The top dose we would plan to study there would be 108 milligrams due to the good signal that was seen at the lower and the intermediate doses in the CANAL study in the IPF chronic cough population. So -- and in the Phase IIb chronic cough IPF study also, that's a dose-ranging study, as you know.

27, 54 and 108 would be the 3 selected doses versus placebos for that. So yes, we are planning to run these doses together in the 2 programs..

Our next question comes from Thomas Smith with SVB Securities..

This is Nat Charoensook on for Thomas Smith. First question is like what are the gating factors to initiate a Phase IIb dose-ranging study in chronic cough with IPF which is now expected in the second half of '23? And I have a follow-up..

I didn't catch the first part of that, like what are the gating factors to getting the Phase IIb going? Is that what you asked?.

Yes..

Okay.

I mean, basically -- David, why don't you talk about the Phase IIb and sort of how we get from here to starting up since you're sort of managing that daily?.

Yes. Yes, I mean as Jennifer said in the introduction, the -- we'll give precise guidance on the conduct phase for that study once we've finalized our planning. But studies of this sort of size that we're talking about, 200 subjects, you would usually aim for about a 12-month recruitment phase. We can give that as general guidance.

The real gating factor has been a slight delay in the study start for that study, primarily driven by global supply chain issues with packaging materials, as it would happen. So we have packaging materials that were substantially coming in later than we would have planned. And that's probably the largest driver of the study start to change.

And then the other piece that Jennifer alluded to in terms of study trial conduct, the precision on what our estimate would be for how long the study will conduct, the other major factor there is this new EU CTIS process that you will have heard of. So there's a new global EU clinical trial submission process.

It's no longer optional, it's mandatory this year. And the expectation is that will slow down a lot of the EU's -- that process will be anything up to 3-plus months slower for starting EU countries because of this new process. So those are the 2 biggest factors..

Got it, that's very helpful. And maybe another one, like so you guide the full data from the open-label extension operation in second quarter '23.

So what do you plan to report? And what are your expectations on the data?.

Yes, we get this question a lot. And we haven't sorted that out yet. I think we want to see the data, sort of what does it show, what's there. We will definitely report it at a medical meeting. It's got a lot of interest by the dermatology community, for sure.

How we handle it sort of from an IR perspective, if you will, we still need to sort out the best way to do that. So I'm going to defer that once we see the data and sort out the messaging from it. We'll figure out the best way to do that..

Got it. And last one, if I may.

So what is your expectation on the R&D and SG&A expenses in '23 compared to 2022?.

I think R&D expenses will increase in 2023 as we conduct all of these studies that were -- that Jennifer referred to, as opposed to 2022..

And G&A, please, might as well..

I think G&A will also increase slightly..

[Operator Instructions] Our next question comes from Sean Kim with Jones Trading..

So I guess one question on the Phase Ib respiratory physiology study.

Can you give a little more color on what dosing levels you're intending to try out for the trial? And also, how that might inform the potential Phase III programs and other trials in the pipeline?.

Yes, David, go ahead..

Yes. So most likely, we will go to the 162 dose that was included at the highest dose that was titrated to in the CANAL study. So that is likely to be -- will titrate in a similar manner to the CANAL study.

And sorry, what was the other component of your question?.

And how to inform, David, that Phase III program and what doses we use..

So these 2 studies really are critical coming together. So for Phase III, what we need to know is how broad a population of the IPF patients and their comorbidities. Co-morbidities including comorbidities such as disordered sleep breathing, such as sleep apnea.

And we include -- so the respiratory physiology study will really answer that question for us because, as we have explained in the introductory comments, that study will include subjects with increased severity and with these comorbidities that were not included in Phase II to allow us to make that call for Phase III..

Okay. And just one quick follow-up question on the Phase IIb dose ranging study.

So now that the trial is set to initiate in second half '23, what would be the expectations for the top line readout in terms of timing?.

Yes, Sean, I'm going to defer sort of giving hard guidance on that until we actually initiate it. I mean, David told you in sort of his last answer that we're planning for roughly a 12-month recruiting process. It's going to be a 6-month dosing -- or 6-week dosing, I'm sorry. So it's not a long trial.

But I thought I want to wait until we actually get it initiated and then we'll give some better time line guidance. But that allows you to kind of do the math in your head and think about where you think it could come in. Thank you for your report this week. I appreciate it..

Our next question comes from Sir Mamtani with B. Riley Securities..

I appreciate the level of detail. So about the CANAL abstract being accepted at PDS, if you could comment on that. But also -- my understanding is that there's the PAciFy trials as well as expected from Dr. Molyneaux both for morphine, post the test in IPF.

Do you have any thoughts on your expectation for that on any relevant safety efficacy data points that could be relevant to Haduvio? And then I have a follow-up..

Yes, sounds good, Mayank. So our poster, I know exactly what it's about. I know they've been tugging and pulling on all different looks at the data. So David, I don't know. Do you know exactly what's being covered there? Might be the anti-fibrotic data but I'm not sure. Go ahead..

Yes. There will be additional analyses, including some additional end points that haven't been disclosed before. That's right presented there..

Yes. And I think, Mayank, you were asking about the Philip Molyneaux trial in the U.K. around morphine.

Is that what you were asking me about and how I think that's relevant to our program?.

That's correct. And I think there will be some data at APS around that also..

Yes. No, that's great. I think from our perspective, we're excited about that study because I think it just builds more critical evidence around the mechanism here in this whole opioid pathway. Morphine has its own set of issues, certainly around respiratory depression and also just the whole scheduling, Schedule II.

But from our perspective, we think it just continues to build critical scientific evidence around the pathway; so I think it should work. They use low doses of morphine now. And as I've heard from several KOLs, it's really the only thing that works in cough. It's part of what drew us to the space.

But we felt that, first of all, we work on 2 receptors and we felt that because of more of the safety profile and abuse addiction profile around our drug, that we could be a much better chronic option. So I'm excited to see it. I would expect that it should work. And I don't feel threatened by it because of all the things I just mentioned to you.

And they're going to have a hard time patenting that. So likely people may use it off label but there's other challenges with prescribing morphine in today's environment..

Got it.

And then about the 2 studies, Phase IIb IPF and RCC, could you just comment on the different placebo responses you're factoring in? And obviously, based on your learning from CANAL but also some of the dry run going on P2X3 development programs?.

Yes. And again, when we lay these studies out, we can get into that a little better. I would say in the IPF which is probably a little more advanced here, we -- there's a sort of accepted rate around 25%. We saw slightly lower, roughly 23% in our study. But when you look across the trials that have been done, that's a pretty good estimate.

I think in RCC, we're working with sort of the experts here in the space who have all the data. David, I don't know if you know the powering assumptions we're using on placebo. You've been working on that protocol..

Absolutely. And I just agree totally with what you said on the IPF. For the IPF, including recent studies, they've been below 30% for placebo response consistently. The RCC, the key there is that it's a 2-way crossover design like CANAL. Now in RCC studies like that, including recent RCC studies, the placebo response has been around about 20%.

So it's not -- it's quite a different placebo response than has been seen in the longer-duration parallel group studies in RCC..

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

We would like to thank everybody for participating in today's call and hope to talk with some of you at the Needham Investor Conference being held April 17 through April 20 virtually. Thank you..

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