Good morning, everyone. Thank you for joining us. It's day three of the Goldman Sachs Healthcare Conference, and it's my pleasure to introduce Seaport Therapeutics. With us, we have Lauren White, CFO, and Michael Chen, CSO. To start here, and thank you so much for being here, given the recent IPO. Could you provide a brief overview of the Seaport story and the 12 to 18-month catalyst outlook for the company? Sure. First off, we'd love to thank you for having us here, Salveen. We're super excited to be here. Seaport is a neuropsychiatry company. We've got a clinically validated platform, and we've got a pipeline of three robust programs. Our lead program is currently in phase II-B and has the potential to be registration-enabling. Our second program, we just shared phase I key proof-of-concept data, and our third program is in preclinical development. All of our programs are based off of clinically validated mechanisms that were held back by some sort of an issue that we're able to address with our Glyph platform. Glyph is a lymphatic-targeting prodrug platform that's able to overcome limitations such as poor oral bioavailability, liver-related AEs, and other items like that. The great thing is that every time we Glyph a molecule, we create new IP along the way. We've got a seasoned leadership team with a track record of success in this space, both in developing medicines for new patients and in driving successful business outcomes. As you mentioned, we recently completed our IPO, where we raised over $260 million of gross proceeds, which provides ample capital to take us through our next set of milestones. If we take a step back, there's over one billion people living with mental illness globally. When you think about prevalence, it's similar only to hypertension and obesity. We here at Seaport are really focused on depression and anxiety. Those are areas that typically tend to be comorbid. They each impact over 300 million people globally, and it's clear we need better medicines in that space. If you look at the current landscape of medicines that are prescribed, there's millions of patients that are on them. There's huge commercial successes. They're held back by some limitations. They can take weeks to work. They have modest efficacy. They don't work for one out of three patients, and they have unfavorable side effects such as sexual dysfunction, weight gain, and sleep disturbances. We at Seaport believe we're uniquely positioned across those three parameters. You're probably familiar with the fact that our CEO, Daphne Zohar, and our Board Chair, Steve Paul, founded and led Karuna, and so we have some similarities to Karuna. Specifically, one example is Karuna knew that xanomeline worked, but it was held back and sitting on a shelf due to GI tolerability issues. The team was able to go in, fix it, and invent KarXT, now called Cobenfy. We at Seaport, as I mentioned, have similarities to that. We go after drugs that have validated efficacy but have some issue that's holding them back, we're able to apply the Glyph platform to support that as well. Looking ahead over the milestones for the next 12 months-18 months, we've got a really healthy set of cadence of milestones. First, we'll be sharing data from our phase I driving study for GlyphAllo. That'll be in the second half of 2026. Next, we've got our BUOY-1 readout of our GlyphAllo program in the first half of 2027. We've got some interesting milestones related to our second program, GlyphAgo. We've got a phase II-A readout in the early 2028, we've got our phase II-B readout in the end of 2028. We're really excited about the path forward. We've got a great set of capital from our IPO to take us through these next set of milestones. Great. At a high level, how does the Glyph platform enable a differentiated product profile, and how de-risked is it at this point? Sure. I'm happy to describe it. Glyph, as Lauren mentioned, is a lymphatic-targeting prodrug technology. The way it works is that it takes a small molecule that might otherwise be chewed up by the liver and cloaks it so that it looks like a dietary fat. When we do that, we create a new molecule with new composition of matter IP, but importantly, that molecule now goes into the body via a side road, via the lymphatic system of the gut. What this enables is to bypass the liver. That can mean for small molecules for drugs with limitations like poor oral bioavailability, highly variable PK pharmacokinetic profile, or even liver toxicity due to, again, the liver seeing a lot of drug. We're able to overcome these particular issues. This is a technology that we have now validated through multiple programs. First with our GlyphAllo program, in which we successfully demonstrated an increase in oral bioavailability, and most recently with our GlyphAgo program, where again, in the clinic, we're able to validate that the platform works, and with GlyphAgo in particular, demonstrate that we're able to bypass that first pass effect and get to an exposure that we need to get to while reducing the dose. This is really critical for not only generating the new medicines that are in our pipeline, but for also taking molecules with the limitations that we know about, addressing those limitations, and creating new potential medicines. In terms of the data that you've generated with this platform, have you been able to completely eliminate the side effect profile that you're trying to? I'll give you one great example again from the data that we announced very recently with GlyphAgo, including the multiple ascending dose data that we announced recently. This is a program in particular where the parent molecule, so to speak, agomelatine, is actually an approved drug. It's not approved in the U.S. It is approved in Europe. It's approved in Australia for the treatment of both depression and generalized anxiety disorder in Australia. It's held back by a key limitation, which is really tolerability associated with the liver. Agomelatine has dose-dependent elevations in liver enzymes, and this occurs in a small percentage of patients, but it's notable, and it must be monitored. So practically for clinicians, for patients, what this means is liver enzyme testing, blood tests, before initiating treatments at three weeks, six weeks, 12 weeks, 24 weeks, every time you increase the dose. This is not something that clinicians or patients really love. With agomelatine, we know that the liver enzyme increases are dose-dependent. They're really dependent on how much drug the liver sees. The issue is that the brain sees less than 10% of the drug that the liver sees. The liver chews up so much of the drug before it can actually reach the brain. We've now demonstrated by glyphing agomelatine with our GlyphAgo molecule that we're able to bypass the liver. For example, in phase I data, what we showed was an increase of bioavailability that can be as great as 9.6- 14.5 folds greater than agomelatine. Practically what this means is we know the exposures of agomelatine that work in the clinic. Part of our strategy is looking at clinical data and going towards that. We can reach the same exposures of agomelatine that we know are efficacious, for example, in generalized anxiety disorder, dose less drug because we don't lose so much drug to the liver before it gets to the brain. In our phase I, not only did we show that PK difference that enables that, but from a safety and tolerability perspective, GlyphAgo was generally well-tolerated. There were no serious or severe AEs, and there were no liver-related AEs, all while hitting this PK profile. I'll mention one last fact, again, to the advantages of the Glyph platform that can play out clinically. We know agomelatine actually has a drug-drug interaction. Again, not an AE, not a side effect, something that patients must be cautious about using, in this case, estrogen-containing oral contraceptives, because they can interact with agomelatine at the level of the liver, and you can see this in the PK profile. When we dose GlyphAgo, we don't see this difference in patients or in healthy volunteers, in this case, with or without oral contraceptives. That's because that drug-drug interaction is happening in the liver, and the Glyph platform allows us to bypass the liver. To your point, we're able to hit the profile, in this case, PK-wise, that we believe will translate into a reduction in liver enzyme elevations and a new molecule without the burdens that has really held back agomelatine from having a significant impact. Can we dig into that reduction in liver enzyme elevation? When you look at the parent asset that's approved, ex-U.S. what is that rate of liver elevation and in what proportion of patients? What are you seeing when you say reduction? Right. This is actually something that you're able to model because of how much clinical data there are out there with agomelatine. With agomelatine, in thousands of patients who have used this and in reports, it's been found that these liver enzyme elevations can be as high as 2%-3% of the patient population, which doesn't sound like a lot, and indeed, it's not a huge number, but it is several times greater than the placebo background rate. It is a notable increase, and it is dose-dependent. The more agomelatine a patient receives in terms of drug, the higher likelihood that they're going to have these elevations. Now, I should caveat, these are elevations that tend to be 2x-3x greater than the upper limit of normal. It's not necessarily bilirubin increases or Hy's law or things like that, but it is a notable increase. What we were able to do before we actually set out on phase I was to actually create a bar for ourselves, which is to use a program called DILIsym to help model the liver injury risk with agomelatine and how that's associated with the PK profile, how much dose of drug. Through that modeling, we were able to set a bar for ourselves of how much we need to increase the bioavailability of GlyphAgo relative to agomelatine in order to eventually show those reductions in liver enzyme elevations. That bar was 2x, twofold. When we went into phase I, we ran single ascending dose, multiple ascending dose, but importantly also a crossover, where healthy volunteers received agomelatine, the parent molecule, without Glyph, then GlyphAgo. What we saw was actually nearly 7x the increase in bioavailability. Our bar was 2x. What we saw was nearly 7x. Taking away the complication of oral contraceptives, it goes as high as 14.5x. We're clearly exceeding the threshold that we've modeled will result in a reduction of liver enzyme elevations. That's why we're excited to now launch two phase II studies with GlyphAgo, a phase II-A clinical pharmacology study, a phase II-B potentially registration-enabling placebo-controlled study, where we will look at efficacy and safety for GlyphAgo. Great. Maybe starting here with GlyphAllo- Sure. -which is a Glyph version of allopregnanolone in major depressive disorder. Can you walk us through your data to date and the clinical rationale here? I think the clinical rationale goes back to our strategy on looking at compounds that have clear clinical activity but are held back by a shortcoming. In this case, allopregnanolone is an endogenously occurring neurosteroid. We're all making it in our brains right now. It's a GABA positive allosteric modulator. It's actually an approved drug. It's been approved for the treatment of a form of depression, postpartum depression, where it's effective. It's actually found to be rapidly acting with anxiolytic and sleep-promoting activity as well. But allopregnanolone has poor oral bioavailability. That approved drug was in the form of a 60-hour intravenous infusion. Drug that works, 60-hour IV infusion. With GlyphAllo, we were able to Glyph allopregnanolone, create a new molecule with, by the way, a new composition of matter IP. In phase I, what we're able to show is that we're able to reach clinically relevant exposures of allopregnanolone, but now with GlyphAllo with once daily oral dosing. In that phase I, we're able to show not only that drug gets into the body, but also gets into the brain. Allopregnanolone, as it's released from the Glyph prodrug system, actually gets into the brain and has pharmacodynamic activity. That is things like EEG markers, eye movement markers, all consistent with allopregnanolone in the brain. Drug in the body, drug in the brain, and at well-tolerated doses. In fact, we don't see AEs that might be associated with the Glyph platform itself, but the most common AE is from allopregnanolone's pharmacology. As a GABA PAM, that means mild transient somnolence was the most common AE. We're actually dosing GlyphAllo once daily at night. On the basis of these clinical data, what we did was actually launch a phase II-A proof of pharmacology study with GlyphAllo. What we did there is use a clinically validated model of anxiety called the Trier Social Stress Test, or TSST. In this model, we take healthy volunteers in a randomized placebo-controlled trial. They receive drug and then are given a task, a stressful task, which is to prepare and then give a speech in front of a panel of judges on why they deserve a job. Then to do math live in front of this panel. Subtraction, 2,000- 17 over- and- over again. Then they're told wrong, start over, wrong, start over. As you expect, this might be stressful. Individuals who are dosed placebo will show a big spike in the stress hormone cortisol, which is the primary endpoint of that trial, which we can just swab. That big spike in salivary cortisol is potently and statistically significantly blunted in healthy volunteers randomized to GlyphAllo at a single well-tolerated dose of GlyphAllo. P equals 0.0001 in that case. The only other neuropsychiatric drug that has shown that effect is actually XANAX, alprazolam. This is consistent with the role of allopregnanolone as not only a known antidepressant, but also with that anxiolytic activity. Importantly, we know allopregnanolone as an endogenous molecule is very different than a benzodiazepine. What we have in GlyphAllo is a molecule where the parent allopregnanolone has been shown to work, antidepressant activity, anxiolytic, and sleep-promoting activity, but is held back by a key limitation that in phase I we demonstrated we were able to overcome by increasing the oral bioavailability. That 60-hour IV infusion is now once daily oral dosing of GlyphAllo. On the back of that, as Lauren mentioned, we're currently in a phase II-B potentially registration-enabling study in major depression with or without anxious distress using GlyphAllo. That's a randomized placebo-controlled study, global study, and it's one that we believe is adequately well-powered to be a potentially registration-enabling study. That's something that we'll read out in the first half of next year, 2027. Just to step back here, we're all familiar with this asset. When it went through U.S. trials for major depression, the parent compound here through Sage and Biogen. Help us understand what the challenges were with regard to outside of tolerability? But what really played out here and how you aim to overcome them, including trial design? I think it's a great way to look at what we view as the third pillar of what we're doing here at Seaport. When we're having the right molecule, but actually having the right clinical trial, both in terms of design and in execution. To your point, Sage had developed oral synthetic analog of allopregnanolone, because, of course, allopregnanolone, as we talked about, has very poor oral bioavailability. That means 60-hour IV infusion. A synthetic oral analog called zuranolone was developed and was tested in MDD. Interestingly, it has antidepressant activity. In five out of six trials, it met its primary endpoint. It's actually approved for major depression outside of the U.S., for example, in Japan. However, it was studied as a two-week course and is given as a two-week course. While it met its primary endpoint, if you look at the FDA guidance for antidepressants, agency is really looking for durable efficacy out to six weeks or greater. If you give patients drug for only two weeks, then you take them off of drug and then ask for efficacy at six weeks, that can be a different challenge. That durable efficacy was never really established in those trials, even though clearly zuranolone has antidepressant activity, and even though zuranolone is approved for MDD outside the U.S. and is approved for postpartum depression in the U.S., there is nothing in this GABA positive allosteric modulator class that's actually approved for the broader major depression indication. We can learn from these past experiences, and for our GlyphAllo program, the BUOY-1 phase II-B, one of the important things we're doing is dosing for the full six weeks. We're also taking other learnings from past neuropsychiatric programs, including the successful examples of Karuna, taking these design and execution patterns from these previous programs to inform our own development program. I'll give you one or two examples. We know the placebo response can really bite programs, we're trying to reduce that placebo response by carefully studying what contributes to that placebo response. We've put out meta-analyses, for example, showing that the frequency of clinician-administered assessments can actually predict the magnitude of the placebo response. The more you interact with patients in a site during a trial, the more likely they are to generate a placebo response. We are tuning and calibrating the number of clinical assessments to not have an excessive number of clinical assessments. It can be very tempting to put in many, many assessments to look at how wonderful your drug activity looks. The more you do that, the more you drive the placebo response. Another one is the number of active arms in a study. It can be very tempting to range across a number of doses, have three active arms, one placebo arm. Every active arm you add to a neuropsychiatric study actually increases the placebo response. Participants know they have a 75% chance of getting a potentially active compound, and that can contribute to the expectancy and the placebo response. In our BUOY-1 study, we have one-to-one randomization, drug, placebo, and that's it. It's these little tricks of the trade that we're adding to try to control the placebo response and maximize the likelihood of success. There's not one silver bullet, but it's a number of these small things that we have to do to make sure that the drug's activity can really show itself. ZURZUVAE has a black box warning for driving impairment, and I believe you're going to initiate a driving study later this year with results in the first half of next year. What do you hope to confirm or establish with this study? Yeah, we've initiated a driving study. The results, which will come out later this year, second half of this year, will really inform the overall profile of GlyphAllo in this program. To back up, we know that zuranolone as a synthetic analog of allopregnanolone has different PK characteristics. Allopregnanolone, when it's infused, for example, clears relatively rapidly. This is something we observed with GlyphAllo, the oral lymphatic-targeting prodrug of allopregnanolone, that by the time you get to six to eight hours post-dose with GlyphAllo, you have something like 15% of the Cmax of the drug remaining. It pretty rapidly drops from its peak at three to four hours to six to eight hours. We actually saw this in phase I, not only in the PK data, but in the pharmacodynamic data as well. If you look at those brain markers, the EEG markers, they peak at three to four hours, and they're back to baseline by six to eight hours. We feel this is consistent with a drug that can be dosed at bedtime. That's what we're doing in BUOY-1. We're dosing GlyphAllo once daily at bedtime. Now, in the U.S., there's a driving restriction in BUOY-1 in that patients cannot drive while taking BUOY-1. In the EU, it's actually a six-hour driving restriction. Once daily at bedtime, six hours no driving, the next morning, fine. The goal of the driving study is to add more information to the overall clinical knowledge around GlyphAllo. We feel that based on the PK properties of GlyphAllo, that the outcome of this study, the driving study, which we'll get actually ahead of the BUOY-1 study. That driving study plus BUOY-1 will be very informative towards the overall clinical picture of GlyphAllo, it's something that we believe has the potential to, over time, reduce that driving restriction as we continue to gather key data. The driving study itself is a driving simulator study. It's actually, I hate to use the word canned, but it's a little bit of a canned study. It's a very standard study with dosing of GlyphAllo at night next day driving and looking at the simulator-based driving, not an actual in-car experience. When we see this phase II-B data in the first half of next year, I believe. What is the bar for success that you're looking for here? I think in these antidepressant trials, BUOY-1 is no exception, the table stakes are a statistically significant separation between drug and placebo. The way we've designed and powered BUOY-1 is that a statistically significant result will be a clinically meaningful result. This is on top of other benefits of allopregnanolone that we believe could have an impact with GlyphAllo as well. For example, we know allopregnanolone is rapidly acting, very rapid antidepressant effect. We also know that allopregnanolone has anxiolytic activity and sleep-promoting activity, and those are facets that we'll be looking at in addition to that sort of top-line key efficacy with the Hamilton Depression Rating Scale. We'll look at the activity of GlyphAllo, but we'll also look at the side effect profile because I think one key potential differentiator is that allopregnanolone, and we believe GlyphAllo, does not have sexual dysfunction or weight gain or insomnia or some of the other baggage that has really held back standard of care like SSRIs or SNRIs in major depression. Table stakes, statistically significant separation between placebo and drug. When you think about the HAM-D delta that one would want to see, typically, whatever you see in phase II just gets more narrowed as you get to kind of that bigger phase III trial. What do you think is an appropriate delta here as you look at the approved drugs that have played out to be meaningful? Yeah, if you look historically at approved antidepressants, you can see effect sizes in the 0.3 and up range. For us, again, table stakes is just demonstration of that statistically significant difference between drug and placebo. That change between phase II and phase III, some of those design factors that we talked about may contribute to that change. We think that even though it is a potentially registration-enabling trial, historically, there have been multiple trials run to have a drug successfully approved. We believe that we'll need to do additional trials beyond BUOY-1 to confirm efficacy and safety if that's a signal that we see in BUOY-1. Really what we'd be looking at for here is data to inform those phase III programs and something that you can interact with the agency as part of an end of phase II meeting, for example. Okay. For GlyphAgo, can you outline the differences between the planned phase II-A and phase II-B studies and what you would consider a successful outcome for each of those? Yeah. Maybe I can just back up and give a little bit more background on agomelatine as well, because I know we sort of jumped straight into the very exciting top-line data that we recently put out. GlyphAgo, I think, is another great example of our strategy, where it's based on agomelatine, which as I described, is actually an approved drug. It's approved for major depressive disorder and generalized anxiety disorder. We're actually starting development of GlyphAgo in GAD, in generalized anxiety disorder, which as Lauren mentioned, is a huge unmet need. Over 300 million patients around the world affected. It's startling that despite this unmet need, in the U.S., the last approved GAD drug was about 20 years ago. It's been a dearth of innovation in GAD, despite, again, the unmet need. Agomelatine we know works in GAD. For example, there have been four placebo-controlled trials of agomelatine in patients with GAD, where agomelatine statistically significantly separates from placebo in all four trials. In addition, it does not have side effect profiles similar to SSRIs. It's actually in a different class altogether. It's a melatonin receptor agonist and serotonin 2C antagonist. A part of that, it doesn't have sexual dysfunction, doesn't have weight gain, it actually helps improve sleep. This has been something that's been shown in MDD, and we'll come back to that when we talk about our phase II-A. The profile of agomelatine is something that in meta-analyses and reviews has been described as both more efficacious and better tolerated than standard of care like SSRIs, benzodiazepines, with that one exception, with the liver enzyme elevations as the exception that has caused that label restriction and onerous liver function testing and monitoring requirement. With GlyphAgo, we're starting where the clinical data take us, which is in generalized anxiety disorder. We put out that phase I data supporting that we hit the PK profile that we believe will lead to a reduction or elimination of the restrictive labeling. What we're doing now with these positive first in human data in hand is to launch two separate studies, the phase II-A and phase II-B. I talked briefly about sleep with agomelatine. With agomelatine, the parent molecule, head to head against an SSRIs, which makes sleep worse. You can actually worsen insomnia. Agomelatine in the past has been shown to actually improve sleep. Not only the subjective experience of sleep, but actually the objective sleep architecture. When you look at EEG polysomnography of sleep, it actually improves with chronic daily treatment of agomelatine. That was shown in major depression, and that's something that we're going to be exploring in a phase II-A proof of pharmacology study with GlyphAgo. We'll be looking at patients with generalized anxiety disorder, not MDD, but in this case GAD, with sleep disturbance. We'll be looking at measures of sleep. This proof of pharmacology study will be a randomized, double-blind study of two different dose levels of GlyphAgo to look at a potentially dose-dependent effect on sleep outcomes in that population. We believe this is really important because of how central sleep symptomatology is in GAD. Many patients with GAD and MDD actually have complaints of sleep, difficulty falling asleep, staying asleep, waking up too early, et cetera. That's the phase II-A. Sometimes I joke it's the appetizer study that we'll be starting soon and will read out in the first part of 2028. Where it really differentiates the phase II-B is a potentially registration enabling, very much a placebo-controlled, randomized, double-blind, very sort of weighty study. That will be in GAD without the bells and whistles. Again, we talked. That phase II-B will be taking the same learnings. We'll be looking at sort of standard endpoints with anxiety rating scales, et cetera. That's really designed to be a primary look at safety, efficacy, tolerability with GlyphAgo. That again, could be one of potentially several registration enabling studies. Remind us what happened here with regard to the U.S. process, like why it was approved ex-U.S. but not in the United States? I think this comes down to a contribution of the liver enzyme elevations and the lack of composition of matter IP, which is actually an important point. Agomelatine currently doesn't have composition of matter IP. That and the PK challenges, the lack of oral bioavailability leading to that high first pass metabolism, and the resulting liver enzyme elevations led to some development in the U.S., but never any attempts at having it registered for either MDD or GAD. Then frankly, patent life has really been a challenge. You see that in the E.U., for example, it's only approved in MDD, where, by the way, agomelatine has also demonstrated efficacy. In Australia, it's approved for MDD and GAD. With GlyphAgo, with our Glyph prodrug of agomelatine, not only do we improve the profile by having a radically different PK due to this first pass avoiding lymphatic transport, we actually create a new molecule with new composition of matter IP. At the end of the day, what's circulating, what gets to the brain is agomelatine, which we know works, and we know the exposure that works. That's, again, back to our strategy of taking compounds with known efficacy and addressing their shortcomings. What is the overlap between GAD and MDD, how would you position these drugs in the context of that? Secondly, just speak to where else you could go with the Glyph platform outside of neuropsych. I'm glad to answer this, Lauren, if you want to chime in as well. There is substantial overlap, and this is something that can be a comorbidity between MDD and GAD, for example. It can also be the presentation of anxiety within depression. This is something we're actually exploring in BUOY-1. I noted earlier that's an all-comers trial, MDD, and that's the primary outcome we're looking at is drug versus placebo in MDD. We will have a qualitative look at what's called anxious distress within major depression. It's a specifier. It's actually a major specifier. Over 60% or more of patients with MDD will have anxious distress. Due to that, the fit pharmacologically with GlyphAllo, the data that we've demonstrated with the TSST, we believe that GlyphAllo could have an even more beneficial effect in those patients with anxious distress. There's a lot of overlap between this, and you see this with agomelatine. It's approved for both GAD and for MDD. With GlyphAllo, we're starting with MDD, but we are looking at that anxiolytic profile of allopregnanolone. With agomelatine, we're following the clinical data where it's very strong in GAD. We're starting in GAD, but we know it's approved in depression. I'll just briefly comment on the Glyph platform itself. It's not specific to the brain. In fact, we believe we can have the impact on a wide variety of molecules that are limited by first-pass metabolism or liver toxicity due to that first pass, poor oral bioavailability, et cetera. Actually, we are exploring outside of the CNS. For example, we recently received up to $15 million as an award from ARPA-H to explore metabolic disease, oncology, and I&I applications of the Glyph technology because we, as a company, Seaport, are going to be focused on neuropsych. Maybe just to complement that, we retain worldwide global rights to the Glyph platform and any programs that come out of it. Just to reiterate, the IP piece is a big play here, where every time you Glyph a molecule, you create new IP. We're really excited about where the platform can go as well. Lauren, last question here. Where does the cash runway take you two in the context of these trials that you're running? Sure. With our recent IPO, we raised gross proceeds of over $260 million. That combined with our Q1 cash on the balance sheet takes us into 2029. To reiterate, that covers the driving study that Michael touched on in the second half of 2026. That covers our key BUOY-1 trial in the first half of 2027. It includes the phase II-A and the phase II- trial of GlyphAgo in early 2028 and the end of 2028. Great. Well, with that, thank you so much. Really appreciate the time today. Thanks so much, Salveen.