Even when depression drugs address known and validated targets, their commercial potential can be constrained by dosing or safety limitations. Seaport Therapeutics’ drugs use a novel delivery approach to overcome those limitations. The startup launched on Tuesday, backed by $100 million in financing.
Boston-based Seaport was formed by PureTech Health, a company that creates startups, typically around a platform technology. One notable example is neuropsychiatric drugs developer Karuna Therapeutics, which grew and eventually spun out of PureTech as a publicly traded company with a lead drug taking a novel approach to schizophrenia. Bristol Myers Squibb last year struck a $14 billion deal to acquire Karuna, whose schizophrenia drug is currently under FDA review.
Former Karuna CEO Steven Paul is chair of Seaport’s board of directors. The startup’s technology platform, Glyph, leverages the lymphatic system for drug delivery. The company says its drugs are absorbed like dietary fats through the internal lymphatic system and then transported into circulation.
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Glyph research was published in 2021 in the Journal of Controlled Release and in 2022 in Frontiers in Pharmacology. The technology was initially developed at Monash University in Australia. In 2017, PureTech licensed the platform, which it continued to develop in a subsidiary named Glyph Biosciences. That company was later merged with other PureTech subsidiaries, which together produced a pipeline that includes Seaport’s two most advanced drug candidates.
Seaport’s SPT-300 is a prodrug, a substance that is pharmacologically inactive until converting into an active therapeutic inside the body. SPT-300 is an oral prodrug of allopregnanolone, a neurosteroid found in the body that regulates GABA-A receptors. Sage Therapeutics has already shown that these receptors can be successfully drugged with Zulresso, the biotech’s FDA-approved post-partum depression drug. While Zulresso is chemically identical allopregnanolone, it requires a burdensome 60-hour continuous infusion.
Sage does have an oral alternative with Zurzuvae, a small molecule that also regulates GABA-A receptors. But FDA approval of Zurzuvae last year covered only post-partum depression, and not the much larger major depressive disorder indication the company also sought. The regulator told Sage more clinical testing is needed to demonstrate effectiveness in this indication.
According to Seaport, SPT-300 (called LYT-300 during its development within PureTech) retains the activity and potency of endogenous allopregnanolone, but in an oral form that “has the potential to capture the breadth of the natural biological response.” The company added that this prodrug demonstrated proof-of-concept in a validated clinical model of anxiety in healthy volunteers. The drug is currently in mid-stage development for treating major depression with anxiety.
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“We believe offering the proven mechanism of natural allopregnanolone via the innovative orally administered approach of LYT-300 represents an advancement that could have a truly meaningful impact for patients,” PureTech CEO Daphne Zohar wrote in a letter to investors included in the company’s 2022 annual report. “LYT-300 may also unlock the class of medicines targeting GABA-A receptors, which has the potential to offer advantages over current standards of care, such as rapid onset of action, for a range of conditions including depression, anxiety, and others.”
Seaport says Glyph enables it to develop oral drugs with better side effect profiles. The technology also circumvents high first-pass metabolism, in which metabolism of a drug at a specific location in the body reduces the amount of active drug available to reach circulation. That capability is key to the Seaport program SPT-320, a prodrug of agomelatine. Agomelatine drugs have been approved as antidepressants in Europe and Australia, but not the U.S. Agomelatine is associated with a higher risk of liver injury due to high metabolism of the drug in the organ. Seaport says SPT-320 uses Glyph to bypass first-pass liver metabolism, which could in turn require lower dosing and eliminate the need to monitor liver function in patients. This Seaport program is in preclinical development for generalized anxiety disorder.
A third Seaport program, SPT-348, is a prodrug of a non-hallucinogenic neuroplastogen. This discovery-stage research could lead to a new treatment for mood and other neuropsychiatric disorders. SPT-348 leverages Glyph to improve certain properties, such as how the drug interacts with the body as well as its tolerability. Other programs in discovery and preclinical development address targets that remain undisclosed.
“Given the historically low success rates within neuropsychiatric drug development, precisely solving the previous limitations of clinically validated mechanisms improves the probability of success and enables us to significantly accelerate development,” Paul, who was also a Sage co-founder, said in a prepared statement.
Seaport’s Series A financing was co-led by Arch Venture Partners and Sofinnova Investments along with Third Rock Ventures and PureTech Health. Along with the financing, Seaport announced the appointment of Zohar as Seaport CEO and board member.
Image: Aleksei Morozov, Getty Images
