How Seaport is hedging against failure in Phase 2b depression study

When brexanolone won FDA approval in 2019 as the first-ever treatment specifically for postpartum depression, it felt like the opening of a new chapter in neuropsychiatry. The catch: it required a 60-hour hospital IV infusion, cost $34,000 per course, and generated all of $800,000 in its last full quarter before Sage Therapeutics quietly stopped marketing it. The FDA withdrew approval in April 2025. The drug worked. The logistics killed it.

That history hangs over Seaport Therapeutics, a clinical-stage biotech that launched in April 2024 with $325 million in committed capital and a single conviction: that allopregnanolone, the neurosteroid at the center of brexanolone, deserved a second chance at life. Not as an IV hospital treatment, but as a pill.

The company calls its oral formulation GlyphAllo. The drug is SPT-300 (formerly LYT-300), and it uses a lymphatic absorption pathway that bypasses first-pass liver metabolism — the mechanism that makes oral allopregnanolone practically useless at any tolerable dose. In a first-in-human study of 99 participants, Seaport reported that SPT-300 reached approximately nine times the allopregnanolone exposure seen with oral allopregnanolone in published literature — roughly matching what IV-infused brexanolone achieved. No treatment-related severe or serious adverse events were reported; the most common side effect was somnolence.

GlyphAllo then cleared a Phase 2a proof-of-concept trial, hitting the primary endpoint of cortisol response to the Trier Social Stress Test with a p-value of 0.0001 — a result that, in the notoriously noisy depression space, is hard to ignore. The company dosed its first patient in the Phase 2b BUOY-1 study last year, enrolling up to 360 adults with major depressive disorder, with or without anxious distress, randomized to GlyphAllo or placebo once daily for six weeks. The primary endpoint is change from baseline in HAM-D-17 score — the standard depression severity scale.

The personal stakes are real for CEO Daphne Zohar, who has family members with depression and anxiety, and left her executive role at PureTech Health — the biotech investor that founded both Seaport and Karuna Therapeutics — to run the new company. Karuna's lead program, KarXT, is a muscarinic receptor agonist that won FDA approval on September 26, 2024 and is now sold as Cobenfy through a partnership with Bristol Myers Squibb. The team at Seaport includes Karuna alumni who spent years navigating the particular frustrations of neuropsychiatric drug development.

The broader allopregnanolone problem is worth dwelling on, because it was not a biology failure. Biogen terminated its collaboration on SAGE-324 — a related oral allopregnanolone program from Sage — effective February 17, 2025. Sage's oral Zuranolone was rejected by the FDA for major depressive disorder in August 2023 and development was abandoned in October 2024. The FDA formally withdrew approval of brexanolone on April 14, 2025. Three separate programs, three different formulations, one shared problem: delivery.

The BUOY-1 study includes a pre-specified contingency plan — if the overall cohort misses its primary endpoint, Seaport will analyze the anxious distress subgroup separately. If that framing sounds like a hedge against failure, it is also just how modern depression trials work. The space has a 60-plus percent Phase 2 failure rate. Pre-specifying a subgroup analysis is not a tell of expected failure; it is a rational response to a known problem. The team also schedules patient check-ins less frequently in the early weeks, to avoid accidentally stoking a placebo response — a mistake the field has made before.

If GlyphAllo works, the addressable population is substantial. Major depressive disorder affects roughly 280 million people globally, nearly 60 percent of whom also experience anxious distress — a subgroup that responds poorly to standard SSRIs and SNRIs and has been largely left out of the recent GLP-1 psychiatry wave. An oral, once-daily allopregnanolone would be something genuinely new.

The remaining risks are real. Phase 2a cortisol reduction via stress test is not the same as demonstrating HAM-D-17 improvement over six weeks in a larger cohort. The mechanism is real; the delivery solution still has to survive a real trial. PureTech Health, the founding investor, holds 36.7 percent of Seaport on a diluted basis post-Series B, which means alignment of interest is real but so is the degree of parent-company exposure if things go sideways.

What makes Seaport worth watching is that the biology was never the problem with allopregnanolone. The problem was getting it into a patient without a hospital bed and 60 hours. If GlyphAllo solves that, the franchise does not die here — it just took a different form.