Seaport Therapeutics, Inc. Common Stock TD Cowen Novel Mechanisms in Neuropsychiatry & Epilepsy Summit

Sure. Well, first, thanks for hosting us, Joe, and a warm welcome to everyone joining on the webcast. I will preface this by saying during today's conversation, we are going to be making some forward-looking statements. They're all based off of our current expectations and beliefs. So I'd encourage you to take a look at our SEC filings for any additional details. So happy to talk through upcoming milestones, which we have quite a few of, but maybe just to start by taking a step back and framing the opportunity ahead of us. More than 1 billion people are living with mental illness right now. That includes over 300 million each with depression and anxiety. And as you can imagine, this touches almost every family.

Existing psychiatric medicines have helped millions of people and are among the most widely prescribed and commercially successful drugs of all time, but they have limitations, and there remains a clear unmet need for new therapies. Seaport is a neuropsychiatry company that exists to turn the tide on mental health and deliver new therapies for patients with a validated platform, a proven team, and a pipeline that's based on clinically validated mechanisms. Our most advanced program, GlyphAllo, has shown initial proof of concept and is now advancing in a phase IIb trial in major depressive disorder, which has the potential to be registration enabling. Our second program, GlyphAgo, also recently demonstrated clinical proof of concept, and we're preparing to initiate two phase II trials in generalized anxiety disorder beginning later this year. And our third candidate, Glyph2BLSD, is currently in preclinical development.

This program really builds on the recent momentum in the psychedelic space and aims to harness similar pharmacology, but without causing a trip, which is exciting. All of these programs are built off of mechanisms that have already shown human efficacy, but they were held back by some sort of a limitation that our Glyph platform can now address. Glyph can overcome issues such as poor oral bioavailability, high PK variability, and other side effects. And the great thing is every time we Glyph a molecule, we generate a new chemical entity with novel composition of matter IP. We've got a seasoned leadership team with a track record of bringing new psychiatric medicines to patients and driving successful business outcomes.

You're probably aware that our CEO, Daphne Zohar, and our Board Chair, Steven Paul, founded and led Karuna, and the approach that we're taking at Seaport is quite similar to Karuna. For instance, at Karuna, the team knew that xanomeline was an effective antipsychotic, but it was sitting on a shelf due to GI tolerability issues. They were able to address that with the invention of KarXT, which is now called COBENFY. At Seaport, we're taking a similar approach of identifying new drugs with proven efficacy, addressing the limitations that held them back, in our case, with the Glyph platform, and then designing and executing studies with an experienced team.

At the end of the second quarter of this year, we had approximately $427 million on the balance sheet. We expect that to provide runway into 2029 and through some really exciting clinical catalysts for us. First, top-line data from our phase IIb BUOY-1 trial of GlyphAllo in MDD. We expect that in the first half of 2027. Next, top-line data from our phase IIa trial of GlyphAgo. That's in early 2028. Finally, top-line data from our phase IIb trial of GlyphAgo by year end 2028. We're really pleased with our progress to date, and we're excited about the road ahead.

Sure, Joe. Glyph is a prodrug platform. It's a prodrug technology, which essentially cloaks a molecule, a drug, so that the body recognizes it as if it were a dietary fat. What this does is allow it to be transferred through the lymphatic system, which bypasses the liver on its way into systemic circulation. This side road essentially allows us to avoid the liver, and because you avoid the liver and less drug gets metabolized, more drug is actually able to reach the brain. Also by avoiding the liver, this bypass overcomes issues like liver-related hepatotoxicity and also PK issues, low oral bioavailability, variable PK. For example, allowing us to reach therapeutic exposures, but with lower doses, or turning a drug that is only available as an intravenous drug into something that can be dosed orally.

As Lauren mentioned, every time we Glyph a molecule, it's a new molecule, and we've generated an initial proof of concept clinically with our two lead programs, GlyphAllo and GlyphAgo.

Yeah. For those who are not familiar, maybe a word on allopregnanolone and GlyphAllo, then glad to talk about that phase IIa. GlyphAllo, as you alluded to, Joe, is actually based on an approved drug. Allopregnanolone is actually an endogenous molecule, like we all make it in our brains right now. But it's actually an approved drug as an antidepressant, was approved as a rapidly acting therapeutic with anxiolytic and sleep-promoting effect. But allopregnanolone itself has very low oral bioavailability. Over 95% of it doesn't make it past the liver into systemic circulation and into the brain. What that means is, even though allopregnanolone was approved for the treatment of a form of depression, postpartum depression, it was approved as a 60-hour continuous intravenous infusion.

Now, we've shown now in the clinic that GlyphAllo, our Glyph prodrug of allopregnanolone, is able to overcome these bioavailability limitations of allopregnanolone and deliver systemic exposures that are therapeutically relevant, but with once daily oral dosing. For example, in preclinical studies, we had shown about a ninefold increase in relative bioavailability compared to unmodified allopregnanolone. In phase I, GlyphAllo was not only achieving the PK profile that we're looking for, but generally well-tolerated. The pharmacology is retained. That is, for example, the most common adverse event we observed was somnolence, which is actually consistent with the pharmacology of allopregnanolone, which is a GABA positive allosteric modulator. So we've shown now that we can overcome these limitations of allopregnanolone, and in addition, we demonstrated the pharmacology in a phase IIa randomized double-blind placebo-controlled study in a clinically validated model of anxiety called the Trier Social Stress Test.

Now, for those of you unfamiliar, this is a test where you take healthy volunteers, you put them into the clinic, randomize them, dose them, and then give them a stressful task. In this case, giving a speech, preparing and giving a speech in front of a live panel of judges who are judging the speech, and then also doing math live in front of the panel. So 2,024 minus 17 over and over again, and the judges say, "Stop, you're wrong. Start over." As you can imagine, this is stressful and actually causes salivary cortisol, the body's primary stress hormone, to spike. As expected, individuals with placebo on board showed a big spike in salivary cortisol.

But we showed that a single dose, a well-tolerated dose of GlyphAllo at the 375 milligram dose that we're actually taking now into phase IIb, achieved a statistically significant reduction versus placebo in the increase from baseline to peak in salivary cortisol. So essentially blunts that salivary cortisol response. The only neuropsychiatric drug to demonstrate a similar result on the TSST is actually alprazolam, a benzodiazepine that's better known as XANAX. But allopregnanolone is not a benzodiazepine. It's, again, an endogenous neurosteroid. So taken together, we have phase I data supporting the PK and tolerability profile, as well as phase IIa data showing that we have not only drug in body and drug in brain, but actually well-tolerated and active doses that we've now taken into an ongoing phase IIb study.