Seaport Therapeutics Files IPO Prospectus: Advancing Next-Generation CNS Therapies with Glyph™ Platform

On January 13, 2025, during the JPM conference, pharmaceutical giant Johnson & Johnson (J&J) announced the acquisition of Intra-Cellular, a Nasdaq-listed biopharmaceutical company, for a total valuation of $14.6 billion (approximately 106.947 billion RMB).In the first three quarters of 2024, Intra-Cellular's revenue was $482 million, with $175 million in Q3 2024 (growth +39%); full-year revenue is projected at $685 million. In the 2023 fiscal year, Intra-Cellular's revenue was $464 million. Before the acquisition announcement, Intra-Cellular’s stock price had increased by approximately 40% over the past 12 months.

More than a year ago, in December 2023, Bristol-Myers Squibb (BMS) announced the acquisition of Karuna Therapeutics, a company specializing in psychiatric and neurological drugs, for $14 billion (approximately 101.5 billion RMB).Karuna Therapeutics, creating the second-largest pharmaceutical M&A deal of 2023. This also gave the industry a sense that the once "black hole" of new drug development – the CNS disease field – seems to be showing signs of revival.

In September 2024, the U.S. FDA officially approved COBENFY (KarXT, xanomeline-trospium chloride) for oral treatment of adult schizophrenia. This isThe First in Decades to ReceiveFDANew Mechanism of Action Drugs Approved for the Treatment of Schizophrenia. This drug comes from Karuna Therapeutics, which was acquired by Bristol-Myers Squibb. According to Evaluate Pharma's forecast, the sales of KarXT will reach 3.1 billion US dollars by 2030.

A series of successes by Karuna have brought attention to the company behind it ——PureTech HealthStep into the spotlight. PureTech Health is a relatively unique biotechnology company, adoptingHub-and-spokeThe business model, under which the parent company establishes subsidiaries for individual new drug projects to manage and facilitate the flow of new drug assets, while actively seizing opportunities such as licensing out or selling the subsidiaries’ new drugs, helps create value quickly and flexibly.Creating assets that large pharmaceutical companies are interested in is undoubtedly a viable option.。Karuna Therapeutics was incubated by PureTech Health.

Related Reading:140The $1 Billion Small Molecule! What's Behind Karuna Therapeutics?

According to the disclosure, PureTech Health plc has a total investment in Karuna Therapeutics, Inc.Invested1850Million US dollars, and the cash revenue generated so far has reached11Billion US dollars, and is eligible to receive potential milestone payments of up to $400 million, in addition to other economic benefits (including milestone payments from Karuna/BMS and a 2% royalty on KarXT annual sales exceeding $2 billion). The role played by PureTech Health includes building a top-tier team of experts, inventing and patenting the technology covering KarXT, and funding and conducting early-stage human studies to mitigate risks.

Following Karuna Therapeutics, PureTech Health launched another subsidiary in 2024, also focused on the field of neuropsychiatric disorders ——Seaport Therapeutics。

In April 2024, Seaport announced the completion of a $100 million oversubscribed Series A financing round, making its official debut, with top biotech investors ARCH Venture Partners, Sofinnova Investments, and Third Rock Ventures participating to support the development of novel neuropsychiatric drugs.

Daphne Zohar, founding CEO of PureTech Health plc, will serve as the CEO of Seaport, and Dr. Steven Paul, former CEO and Chairman of Karuna Therapeutics, Inc., will serve as the Chairman of Seaport.

In October 2024, Seaport, founded just six months prior, announced the completion of a $225 million oversubscribed Series B financing round. The round was led by General Atlantic, with participation from T. Rowe Price Associates, Foresite Capital, Invus, Goldman Sachs Alternatives, CPP Investments, and other new investors. Founding investors ARCH Venture Partners, Sofinnova Investments, and Third Rock Ventures also joined the round, with co-founder PureTech contributing $14.4 million to the financing.

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After the Series B financing,PureTechHoldSeaport 36.7%Diluted EquityThis financing brings Seaport's total funding to $325 million, which will support key clinical milestones in Seaport's first-in-class and best-in-class neuro-psychiatric drug pipeline.

Under the Hub-and-spoke model, the catalyst for PureTech to independently establish Seaport was PureTech's decision to spin off projects from its internal pipeline.Has advanced to a critical turning point。

In November 2023, PureTech Health plc announced its candidate drugLYT-300(OralGlyph-Allopregnanolone, currentlySPT-300) Conducted in healthy volunteers2aPrimary Endpoint Achieved in Acute Anxiety TrialThe trial evaluated the response of salivary cortisol in subjects under the Trier Social Stress Test (TSST), a validated clinical model of anxiety in healthy volunteers. The study showed that, compared to the placebo group, the increase in stress hormone salivary cortisol from baseline to peak was statistically significantly reduced in the SPT-300 group (p=0.0001).

According to Cohen's d calculation, the treatment effect size of SPT-300 compared to placebo was 0.72. SPT-300 demonstrated a treatment effect size similar to that previously observed with alprazolam (a benzodiazepine used to treat anxiety disorders) following evaluation in the TSST procedure. Additionally, SPT-300 was well-tolerated, with all treatment-related adverse events being transient and mild to moderate in severity, consistent with the known pharmacological profile of allopregnanolone.

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SPT-300 is aOral Prodrug of AllopregnanoloneAllopregnanolone is an endogenous neurosteroid whose potential to treat a range of neurological and neuropsychiatric conditions has been recognized and clinically validated in third-party trials as a fast-acting antidepressant with anxiolytic effects.

However, the main obstacle to the past application of drugs related to endogenous neurosteroids is their lack of oral bioavailability and inability to be administered to patients over the long term, which means they can only be delivered throughLengthy and Complicated Intravenous Infusion Administration. For example, Sage Therapeutics' brexanolone was approved for the treatment of postpartum depression, but its method of administration isContinuous intravenous infusion required60Hours or moreMoreover, although medicinal chemistry approaches have been used to synthesize orally bioavailable analogs of allopregnanolone, these analogs may exhibit pharmacological differences from endogenous allopregnanolone and thus might not fully realize their therapeutic potential.

SPT-300 is designed to preserve the natural bioactive response, potency, and breadth of endogenous allopregnanolone in an oral form, with the potential to exert significant clinical antidepressant and anxiolytic effects. It is reported that the oral bioavailability of SPT-300 is higher than the oral allopregnanolone data reported by third parties.About High9Times。

And this is inseparable fromPureTechProprietaryGlyphOral Prodrug PlatformAs previously reported by PharmaCircle, this platform is a synthetic lymph-targeting chemical platform designed to leverage the natural lipid absorption and transport processes of the lymphatic system, making the development of certain oral drugs possible. The platform's design allows oral drugs to directly target the lymphatic system instead of the liver, thereby enhancing oral bioavailability, reducing dosage, minimizing first-pass hepatic toxicity, while also creating new intellectual property for compositions of matter. It is understood that PureTech initially developed this technology.Monash UniversityObtained the exclusive license for this technology and related intellectual property, and further development led to the creation of the Glyph technology platform.

Seaport is advancing SPT-300 into a potential registrational Phase 2b clinical study for the treatment ofMajor Depressive Disorder with or without Anxious Distress。

In August 2023, the U.S. Department of Defense awarded PureTech Health plc a grant of $11.4 million to advance SPT-300 for the treatment of Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). According to disclosures at the time, research for the FXTAS indication will be conducted in collaboration with the University of California, Davis.

Based on the Glyph platform, Seaport has other novel CNS candidate drugs under development.

December 2023,SPT-320(OralGlyph-Agomelatine,LYT-320）Nominated as a new therapeutic candidate powered by the Glyph platform. SPT-320 is a novel prodrug of agomelatine being developed for the treatment of anxiety and mood disorders. Seaport is advancing SPT-320 for the treatment.Generalized Anxiety Disorder (GAD）Phase 1 Clinical Study.

Anxiety disorders affect nearly 30% of adults in the United States, representing a field with significant unmet needs. First-line treatments for Generalized Anxiety Disorder (GAD) and depression include Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs). However, these medications have limitations in terms of side effects and efficacy, with major adverse events including sexual dysfunction and emotional blunting.

Agomelatine, on the other hand, works through a completely different mechanism of action and is better tolerated than standard treatment regimens. The drug is a naphthalene derivative of melatonin, with a dual mechanism of action as an agonist of melatonin receptors 1 and 2 (MT1/MT2) and an antagonist of serotonin (5-HT) receptors. It has been approved in the EU for Major Depressive Disorder (MDD) and in Australia for MDD and Generalized Anxiety Disorder (GAD). However, due toAgomelatine has high first-pass metabolism in the liver and low bioavailability (~1%), with the risk of hepatotoxicity, which requires frequent liver function monitoring, thus hindering the development of the drug.

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SPT-320 Utilizes Glyph Platform TechnologyBypassing the first-pass metabolism in the liver, which is expected to reduce liver exposure, hepatotoxicity, and the need for liver function monitoring. Multiple in vivo studies have shown that the oral bioavailability and plasma exposure of SPT-320 are higher than those of oral agomelatine.High10Times or moreComputer modeling using the FDA-authorized DILIsym platform for drug-induced liver injury assessment showed that a lower dose of SPT-320 could achieve exposure comparable to the approved therapeutic dose of agomelatine, which is expected to significantly reduce the clinical risk of hepatotoxicity.

Since agomelatine has not been approved in the United States,SPT-320Has the potential to be a first-in-class in the U.S. market, with best-in-class potential in other regions of the world.

Besides, in the Seaport pipeline,SPT-348Is a prodrug of a non-hallucinogenic neurofunctional remodeling factor, is being developed for the treatment of mood disorders and other neuropsychiatric disorders.

In the future, can Seaport replicate Karuna's success and become a CNS star company favored by major pharmaceutical companies?

Reference:

NMPA/CDE；

Moxie Pharma Data pharma.bcpmdata.com (formerly Pharma Intelligence Data);

FDA/EMA/PMDA；

Relevant companies' public disclosures (all images in the text are from the official enterprises unless otherwise stated);

https://www.jnj.com/media-center/press-releases/johnson-johnson-strengthens-neuroscience-leadership-with-acquisition-of-intra-cellular-therapies-inc;

https://news.puretechhealth.com/news-releases/news-release-details/puretechs-lyt-300-oral-allopregnanolone-achieved-primary；

https://news.puretechhealth.com/news-releases/news-release-details/puretech-launches-seaport-therapeutics-with-%24100-million-oversubscribed-series-a-and-announces-management-transitions；

https://news.puretechhealth.com/news-releases/news-release-details/puretech-founded-entity-seaport-therapeutics-closes-225-million；

https://news.puretechhealth.com/news-releases/news-release-details/puretech-year-end-update-and-outlook-2024; etc.

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