Good afternoon, and welcome to the Trevi Therapeutics First Quarter 2021 Earnings Conference Call. At this time, all participants will be in listen-only mode. [Operator Instructions] After today’s presentation, there will be an opportunity to ask questions. [Operator Instructions] Please note, this event maybe recorded.

Various remarks that management makes during this 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 views change. Participating on today's call from Trevi Therapeutics are Jennifer Good, President and CEO; and Bill Forbes, Chief Development Officer.

I would now like to turn the conference over to Jennifer. Please go ahead..

Thank you. Good afternoon, everyone, and welcome to our first quarter 2021 earnings call and business update. Joining me today on this call is Dr. Bill Forbes, Trevi’s Chief Development Officer, who will be available to answer questions after my prepared remarks.

Our last earnings call was only six weeks ago, so I will focus on giving an update on our clinical development progress and reporting our earnings for the first quarter.

Our most advanced program in clinical development is pruritus in 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. There are currently no approved therapies for this indication.

Prurigo nodularis is a chronic disease, and because of the repeated scratching, the papules and nodules can spread and continue to worsen. We estimate the global prevalence of PN is approximately 730,000 patients, with 300,000 patients in the U.S. and 430,000 in the rest of the world.

Although, there are biologics also in development for PN, we are the only non-biologic oral candidate in late phase development, which we believe potentially positions us with an important competitive advantage for the serious unmet need. We are currently conducting a Phase 2b/3 trial in this condition, which we call our PRISM trial.

The PRISM trial is recruiting in both the U.S. and Europe. And today, we have more than 60 sites activated. The primary endpoint in the study is a responder analysis based on the reduction in itch intensity as measured by the Worst Itch Numerical Rating Scale after 12 weeks of blinded fixed dosing.

We currently have randomized approximately 255 of the planned 360 subjects into the trial or greater than 70% of enrollment. We are encouraged by the feedback from the site and continue to have a very high percentage greater than 95% of eligible subjects that complete week 14 and rollover into the open-label extension portion of this trial.

This will provide not only long-term safety data, but also important efficacy data around skin healing and quality of life for these subjects.

We believe that by treating the symptomatic endpoint of reducing itch, that an effective therapy has the potential to disrupt the itch scratch cycle, leading to skin healing and resulting in disease modifications over time.

Regarding enrollment, we have a good group of sites and continue to identify and implement strategies that support the sites to continue to find and recruit new subjects.

We continue to push for completing enrollment in the third quarter of this year, but we have broadened our guidance to the second half of the year, knowing that enrollment during the summer months of July and August may slow a bit, especially in light of easing COVID restrictions and the desire for people to travel again.

We will announce when enrollment is complete and I hope by our next earnings call, there will be a short runway left on enrollment for the study. In addition to executing on the clinical trial, the development team is preparing for next steps to move forward in this indication.

We are excited to announce that we recently received Fast Track designation from the FDA for this proposed indication. The Fast Track designation is intended to facilitate development and expedite the review of drugs to treat serious and life-threatening conditions so that an approved product can reach the market expeditiously.

Turning now to our second clinical program for chronic cough in idiopathic pulmonary fibrosis or IPF. IPF is a progressive and severe condition in which there is scarring of the lung tissues.

One of the leading debilitating symptoms of this disease is chronic coughing, which affects approximately 70% to 85% of these patients and for which there are no approved therapies. In the U.S., we estimate that there are approximately 130,000 patients with IPF and an equal amount in Europe.

Worldwide, it is estimated, there are in excess of 1 million patients that suffer from IPF. Due to the high five-year mortality associated with IPF, prescribers and patients are not only looking to slow the progression of the disease, but also improve their quality of life. There are currently no approved therapies for this serious condition.

We are conducting a Phase 2 double-blind crossover study with a 14-day washout period between each three week treatment arm. The primary endpoint assessment is the mean percent change in daytime cough frequency from baseline. The daytime cough frequency is measured by a digital cough monitor between the treatment and placebo arms.

This trial is currently being conducted in the UK and given that this patient group is considered high risk, if they contract COVID-19 due to their lung impairment, this trial has been more significantly impacted by COVID-19 restrictions than our PN study.

We are happy to see the lifting of the shelter-in-place restrictions for these patients in the UK, which were issued in early December. Due to their condition, IPF patients were prioritized for COVID vaccinations. And we estimate that most of these patients are now fully vaccinated.

We have been working closely with our centers to determine timelines for reopening of clinical research for this trial. We are seeing clinics begin to reopen and staff returning for research. Many of the staff and investigators had been prioritized to treating COVID-19 patients over the past year.

Today, we have several sites that have received approval to reopen their clinical research, encouraging to note some of those sites have already started screening for our trial, and we expect to see enrollment resume this quarter.

We will continue to work closely with all of our remaining qualified sites in the UK to get the study fully up and enrolling. As a reminder, this study is designed to enroll approximately 60 subjects with a goal of getting 44 completers. So if we can get some momentum in enrollment, we are optimistic we can get the study finished.

Just a quick update on Germany. As you may recall, Trevi was pursuing potential regulatory and ethics board approvals to add study sites in Germany. We did make good progress on that effort. However, we have decided not to pursue opening new clinical sites in Germany due to the estimated timeline and cost to add these additional sites.

Instead in light of the easing of pandemic restrictions in the United Kingdom, we are focusing our efforts on the completion of enrollment in the UK. With that summary on the current status of both trials, I will now review our financial results for the first quarter of 2021.

As a reminder, the full financial results for the first quarter of 2021 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 first quarter of 2021, we reported a net loss of $8.4 million compared to a net loss of $8.5 million for the same quarter of 2020.

R&D expenses were $5.6 million during the first quarter of 2021 compared to $6 million in the same period of 2020. The decrease was primarily due to decreased purchases of clinical trial supplies, which is largely based on timing and the completion of our Phase 1b clinical trial in patients with chronic liver disease that we conducted a year ago.

These decreases were partially offset by an increase in activity and enrollment in our ongoing PRISM trial, as well as an increase in personnel related expenses consulting and professional fees. G&A expenses were $2.5 million during the first quarter of 2021 compared to $2.6 million in the same period of 2020.

The decrease was primarily due to a decrease in stock-based compensation expense. We have remained at a relatively consistent runway with respect to our overhead costs. As of March 31, 2021, our cash and cash equivalents totaled $41.6 million compared to $45 million at December 31, 2020.

Our current cash position is expected to be sufficient to fund operations into the second quarter of 2022.

Beyond the anticipated top line results from the PRISM trial and although we need to see another quarter or two of enrollment before we can understand the enrollment timelines for cough coming out of the COVID-19 restrictions, we believe it can also carry us to the full enrollment of the cough trial. That is all I have for our prepared remarks.

Now I'll turn the call back over to the operator for Q&A..

Thank you. We will now begin the question-and-answer session. [Operator Instructions] Today’s first question comes from Annabel Samimy with Stifel. Please go ahead..

Hi. Thanks for the quick update. I actually wanted to ask a bigger picture question about the opioid approach. It's not quite the same mechanism, but I think the oral kappa opioid receptor was validating and shows activity in two predict population. So clearly there's something to at least in the kappa approach.

And I realized that yours is a little bit different with the dual mechanism. But I guess what we have evidence of now is the fact that behavior of these two predict populations are really very difficult to peg.

And even in an AD population, where the itch is very consistent, I think it's still very difficult to understand the behaviors of different itch population.

So what is it that you can draw from some of these studies and what can you do to, I guess, manage what could be a very variable population, even in PN where itch is endemic to the problem? So maybe you can just speak a little bit broadly about that..

Yes. Go ahead, Bill..

Yes. Thanks, Jennifer. Thanks Annabel for the question. Let me kind of step through because obviously we've given this a lot of thought. I think the kappa and as that you may talking about is actually an opioid peptide.

As you know, with our nalbuphine oral formulation, our molecule is very well behaved from an absorption distribution metabolism and excretion perspective. Our formulation scales within our dosing range in a linear fashion, and it prolongs the half-life from the parenteral formulation has been on the market for decades to this oral formulation.

It increases it from two to nine hours. So we know that nalbuphine has a well-characterized safety profile. It's got decades of use as a parenteral. We have over 800 patients in controlled clinical trials using the oral formulation.

So I think in many respects, as we look at this from a safety and efficacy perspective, our small molecule is very well behaved. As we take a look at the different populations, I mean, one of the things that we've done a very good job at using this formulation and using this product is that we're able to show dose response.

And I think our uremic pruritus data is key for that. We know that this drug is from based upon that 373 patients study looks safe and it's very effective and its effectiveness increases with dose in a statistically significant manner. So I think that when we start to compare different kappa agonists, and in our case, we're dual mechanism.

So you're right, we're not talking about the exact same mechanism here, but we do believe that there continues to be results that show that that part of the mechanism is successful in treating pruritus.

What we believe is that our drug working not only peripherally, but centrally will have a much – potentially a better effect because we believe that the itch pathway has been implicated from opioid receptors that exist on the skin into the peripheral neurons, into the spinal cord all the way up to the brain.

So the ability for us to penetrate all those areas and to be effective, we feel good about our opportunities here. So I think as it relates to showing significant benefit in these different populations, they are difficult to treat, which is why we like our mechanism much better than some of the competition and maybe with that, I'll pause.

And if you have any questions..

Just one more on the population of PN – the actual PN population, do they have variable itch in such a way that sometimes it could be – it could temper, it could have a placebo response, it could, anything in the population that we should be concerned about..

I think the way that we've recruited this particular study, I mean, one of the things that we've done, the difficulties in recruiting these patients is that we're looking for a homogenous patient population where they score at baseline seven or greater on the WI-NRS and that scale goes from zero to 10, so it's an 11 point scale.

And they can't have any scores that are less than six. So they're actually very – they seem to be scoring very consistently at baseline. Of course, once they get into the study, then we anticipate that the drug will have a treatment effect, but I think for the most part, what we're looking at here is a fairly stable and consistent population.

It's not to say that there isn't a placebo response. The placebo response in the PN studies can be around 20%..

Yeah, Bill I would just add I think to Annabel, I think the question you're asking is there things about PN that we worry about? I mean, I can tell you what I thought about over time is, obviously there's a lot of underlying triggers of itch, the atopic derm, uremic pruritus, sometimes they don't know. And so the different sort of variabilities.

And I know FDA is going to be interested to see that. I do think since our drug works, both as Bill mentioned centrally and peripherally, that is helpful there, but it'll be interesting.

In our Phase 2 data we didn't see any differences, depending on what the trigger was, but that's always, obviously on my mind, even though they all have PN and they think they will survive, we force as homogenous of a population as we can, there are underlying diseases that triggered PN in the first place..

Okay, great. Thanks for the color..

And our next question today comes from Gary Nachman with BMO Capital Markets. Please go ahead..

Hi, good afternoon. So from last quarter to this quarter, you went from about two-thirds enrolled to 70% enrolled over a few months.

So definitely some progress there, but you hit a little bit of a wall in terms of pace of accelerating enrollment, you mentioned timeline for the data, could be a little pushed out more because of the summer slowdown, but I'm curious what you've been seeing in the last few months..

Bill you want to comment on it?.

Yeah..

Yeah, go ahead..

I mean, as, you point out, and as Jennifer mentioned earlier, I mean, obviously we moved our guidance from Q3 to second half. And so one of the things that we're kind of seeing is a little bit of rubber banding on enrollment by month-by-month.

So it makes us, I mean, I think the thing that gives us confidence is that when we talk to our study staff – to the study staff and the investigators, we're finding that they're very positive about the ability to keep things moving at a good pace.

But we wanted to try to give the best guidance we can, and obviously we'll continue to update guidance as we go along here. But I mean, I feel good that the centers are completely engaged. I mean, we're talking to them on a very regular basis, daily basis and we get responses from them.

They are pushing as hard as they but as we get into this is, as Jennifer mentioned is as we see the summer months coming up, we anticipate that there may be some difficulties with people trying to take vacation on the study staff side and also on the patient enrollment side so..

Yeah, and I would add Gary, our last update was as you know, only six weeks ago. So sometimes it's just where you cut these things and we do sort of round. So yes, it does go up and down, but we've been generally I would say averaging around this 15, sometimes it's 12, sometimes it's 20, but it seems to consistently kind of come around that number..

But to answer your question, I think a little more directly, I kind of look at the last couple of months. The last couple of months of enrollment seem to kind of keep pace with some of the best months from previous – from the previous year or so.

So in a way we feel good about the activity in the last couple of months, but looking forward, we obviously know that we have to continue to increase enrollment as this goes through a difficult time of the summer months..

Yeah. So just on that last point, Bill, one or a lot of these PN patients presenting at these sites where do you need to sort of spur that, I don't know, enthusiasm or awareness in the community, so what initiatives do you have to maybe accelerate, especially as we get into the summer.

And then I think you mentioned, Jennifer that you're at 60 sites any chance you could add to that, or it sounds like you feel very good with the current sites, but do you feel like you need maybe a bigger number of sites out there?.

Go ahead, Bill..

Yeah, no, I think, let me talk about the number of sites. I mean, we look at this constantly and we've still got a couple of sites that are coming on board here.

So it's not that we're not adding sites, but we've had a lot of great activity, particularly in the U.S., Germany and Poland, they've done a lot of the heavy lifting on this study and we see activity picking up in our other countries, France and Austria.

So I think from a site perspective, we feel like the horses that we have right now can take us through this last leg of enrollment. As far as the initiatives that we do, we do what you'd expect us to do. We do a lot of advertising. We're constantly refining that and we learn what works and what doesn't work.

We have sites that are extremely successful with it, and we have sites that we're still working with to try to find a better way to do advertising and recruit them. But as far as at the site level, the initiatives that we've done, we started to roll those out in February and March. And they're taking hold now.

So I think in many respects, we're – hopefully we're going to get the fruition of all of that and try to drive this home. But trust me, every day we wake up, this is what we ask. And it's what our investigators and coordinators and study staff are hunting. So we're driving as hard as we can..

Okay. and then just last quick one on IPF.

It's nice to see that that's opening up a little bit and you're getting some progress there, but how many sites have resumed screening and also here, how many do you still have to reopen if you just going to be focusing on the UK? And is there any other sort of backstop if the UK isn't enough, if Germany doesn't make sense where you reconsider Germany at some point? It seems like you're pretty confident you could get it done in the UK, but just wanted to confirm that.

Thanks..

Yes. And I think this was obviously a strategic management call, as we kind of look at the timelines for opening up centers in Germany. How long that would take to complete that process and how much time the German investigators might have to enroll. So we're looking to actually pivot away from Germany and what we'll look at is, adding sites in the UK.

And I would say right now about a third of the sites are seem to be engaged in screening at this point in time with the rest of them coming online. I think June is going to be a very good month for us to understand exactly who's all in. And we have calls set up with the investigators and the study staff to go through how to get this.

And I think the fact that we're screening now hopefully will result in some randomizations here in the not too distant future, but that's how screening goes, sometimes not everybody gets through.

But we feel good that the centers are engaging, they're ready to come back to work, pivot away from the COVID, as you know these are pulmonary centers in the UK, so they got pulled into that end of the COVID treatment nightmare.

And so, as they come back and do their day job here doing research, we're looking forward to getting some good activity out of this in the June, July timeframe..

Okay, great. Thanks for the additional color..

Thanks Gary..

And our next question comes from Serge Belanger with Needham & Company. Please go ahead..

Hi, good afternoon. Just a couple of questions for me. Maybe I missed this into your prepared comments.

But any updates on patients rolling over into the extension study, and are you seeing kind of similar trends of discontinuations? And then anything we can glean from the recent Cara study readout? I know it's a different itching occasion, but it is a similar endpoint, so anything about the placebo effect that we saw that could be useful as we look to the PRISM trial readout? Thanks..

I'm going to make a couple of comments and then you should add your color. Serge, I'm happy to reread you my script in a private setting, saying clean out everything. But we did – we are greater than 95% still.

We've had very good success with people that make their way through the study stay on and not only roll over, but go all the way to the end, get a year of treatment, as you know these patients don't have sort of other alternatives. As far as discontinuations and Bill can add more color there.

I would say it's in line with where we thought, I think we've continued to manage that down. And Bill, you may want to comment a little bit on that in relation to the SSRE. But I would say on the Cara studies, because I studied them too Serge with that.

Their placebo effects actually have been in the same range that we've typically seen in these studies. I think they were what, 19%, 20%. So I think that's helpful. I mean, my feeling on Cara my own bias, I believe in the opioid mechanism, I think kappa agonist work.

I think as Bill alluded to in his comments, I think the challenge, Cara has outside of its injectable formulation is just do they really have that oral formulation down. And I think they've struggled to show that in a way that's sort of convincing. So I thought a lot of it was validating, I think atopic derm is a tricky indication.

There is a lot of multifactorial stuff going on there with inflammation and itch and everything else. But – so those are my thoughts. Bill, you should chime in with your thinking as well..

Yes. I guess from that, I think she pretty much covered anything, I would probably add color on. But I think, if you take a look at their study, obviously they had an interim review and they actually ended up picking a dose, so they had three active doses versus placebo. That's not what we did here, we had a sample size re-estimation.

To my comments before, because the formulation in the molecule are well-behaved, we knew what our dose was going into the study. And so we didn't have to worry about picking a dose amongst different doses.

We just – all we had to do is make sure that we had promised in conditional power and then to end up with what the final end should be for the study. So we ended up with a power of 360 total patients, 180 per treatment group. I think Cara ended up with about 120 patients per group between the two doses, placebo and the active dose that they chose.

So, I mean, as we kind of look at those results, different indication as you pointed out before Serge. And so there is – we have to always be cautious about that. They do end up enrolling patients that have a seven or greater on the edge gauge scale. So we are enrolling the same number seven or greater on our WI-NRS.

But I think in many respects, we feel good about the position we're in. We feel like we're powered up and we feel like we've got our dose..

Great. Thank you..

I’m not showing any further questions. So this concludes our question-and-answer session. I’d like to turn the conference back over to Jennifer Good for closing remarks..

Thank you. We'd like to thank everybody for participating in today's call. I'd also like to thank the Trevi team, our study investigators and all other subjects who continue to participate in our clinical trials. I hope everybody has a nice summer. Thank you..

Thank you, ma'am. This conference is now included. We thank you all for attending today's presentation. You may now disconnect your lines, and have a wonderful day..