Terran Biosciences

Seaport will use the $225m funding to advance its pipeline of experimental drugs for neuropsychiatric disorders. Credit: eamesBot via Shutterstock. PureTech-founded Seaport Therapeutics has raised $225m in a Series B financing round to support the development of new prodrug treatments for psychiatric disorders. Seaport plans to use the new funds to push forward its pipeline of experimental drugs, including its most advanced candidate, SPT-300, which is being advanced into a Phase IIb trial for major depressive disorder. SPT-300 is an oral prodrug of brexanolone, a neurosteroid compound with known anti-depressant effects. Topline results from Seaport’s SPT-300 Phase IIa proof-of-concept trial were reported in November 2023, where the study met its primary endpoint of salivary cortisol response. The financing was led by General Atlantic, with backing from several other major investors such as T Rowe Price, Foresite Capital, and Goldman Sachs . The latest funding comes after the company’s launch in April 2024, when it secured $100m in initial funding from founding investors ARCH Venture Partners, Sofinnova Investments, Third Rock Ventures, and co-founder Puretech Health . The funding will also support Seaport’s Glyph technology platform, which helps drugs be absorbed more efficiently by using the body’s lymphatic system. This platform could improve the delivery of drugs that have a low bioavailability, or have side effects such as liver enzyme elevations or hepatoxicity, says the company. See Also: FDA approves Astellas’ VYLOY for gastric cancer treatment Intercept’s liver disease drug Ocaliva faces FDA approval delay The company has several other candidates in its pipeline, including SPT-320, an experimental prodrug of agomelatine being advanced into Phase I studies to treat generalised anxiety disorder (GAD). By leveraging Glyph, SPT-320 bypasses liver first-pass metabolism, allowing for lower dosing and reduced liver exposure. Seaport is also developing SPT-348 for mood and neuropsychiatric disorders and has several preclinical programmes under its belt. Prodrugs are medications that start as inactive or less active, and once inside the body, are converted into the active form, usually through natural processes involving enzymes. Prodrugs can be used to enhance drug delivery, minimise side effects, and improve drug solubility and oral bioavailability. In the announcement accompanying the financing, Seaport’s founder Steve Paul said: “The development of important new neuropsychiatric medicines is often halted due to poor drug-like properties or unacceptable tolerability, challenges that our Glyph platform can now uniquely address.” The potential of prodrugs was recently in the spotlight in the case of xanomeline, which initially faced tolerability challenges, but once resolved, was approved Cobenfy (formerly KarXT) for schizophrenia. Xanomeline helps reduce symptoms of schizophrenia, but it can cause unpleasant side effects that include nausea and sweating. Trospium was added to the drug to block these side effects while still allowing xanomeline to work in the brain. Now, Cobenfy is expected to earn $2.99bn in revenues by 2030, as per GlobalData analysis. GlobalData is the parent company of Pharmaceutical Technology. New York-based Terran Biosciences is taking it a step further by developing two prodrug versions of Cobenfy. Terran aims to curb issues surrounding medication adherence by optimising its dosing schedule to a more convenient once-daily oral regimen (TerXT), and a multi-month injectable (TerXT LAI).

Bristol Myers Squibbs highly anticipated schizophrenia drug KarXT is fast approaching a September deadline for the Food and Drug Administration to decide on approval. Yet competition already looms for a market thats estimated to soon be worth billions of dollars.KarXT, a so-called muscarinic agonist, may become the first new kind of schizophrenia drug in decades. Close behind it is AbbVies emraclidine, which works in a similar fashion.People with schizophrenia experience a broad range of symptoms, from hallucinations and delusions to cognitive impairments and social withdrawal. Clinical testing has shown that, like KarXT, emraclidine, which AbbVie acquired from Cerevel Therapeutics in a multibillion-dollar deal, is effective at controlling symptoms without the debilitating side effects or drawbacks of traditional antipsychotics, which cause almost three-quarters of patients to abandon treatment.But experts say once-daily dosing versus twice-daily treatment, and a potentially more gut-friendly formulation, may give emraclidine an edge over KarXT, which Bristol Myers Squibb acquired in a $14 billion acquisition of Karuna Therapeutics.Emraclidine is designed to reduce the excess dopamine signaling that causes schizophrenic symptoms, but without blocking the receptors altogether. By blocking specific M4 receptors, rather than others more broadly, the drug could help patients deal with symptoms without the side effects that come with less precise treatment.A Phase 1b study found people who received emraclidine for six weeks saw statistically significant improvements on a standardized scale of symptom severity without side effects like weight gain, restlessness and movement disorders.By selectively targeting the M4 receptor, emraclidine resulted in infrequent gastrointestinal side effects, with rates similar to placebo, Dawn Carlson, AbbVies vice president of neuroscience development, wrote in an email.AbbVie is testing the drug in two mid-stage trials that support approval, and expects to release topline data later this year.According to Carlson, the Cerevel acquisition, finalized this month, not only gave AbbVie emraclidine but several preclinical and clinical-stage drugs that fit into the pharma giants existing portfolio.There are multiple programs in Cerevels pipeline across several psychiatric and neurological conditions such as schizophrenia, Parkinsons disease and mood disorders, where there continues to be significant unmet need for patients, she wrote.Emraclidine may also have applications outside of schizophrenia for dementia-related psychosis in diseases like Alzheimer's and Parkinsons.Several other new schizophrenia drugs are advancing through testing. While many have the same dopamine or serotonin targets as traditional antipsychotics, others rely on novel approaches like KarXT and emraclidine.Neurocrine Biosciences is testing a muscarinic agonist in a Phase 2 study with Nxera Pharma. The company also has another mid-stage schizophrenia candidate called luvadaxistat. Boehringer Ingelheim is in Phase 3 with its drug iclepertin, a selective glycine transporter 1 inhibitor.Meanwhile, Terran Biosciences is looking to compete with a prodrug therapy thats meant to improve on KarXTs twice-daily dosing schedule with a once-daily pill. Its also developing a long-acting injection, dubbed TerXT LAI.Its unclear how either KarXT or emraclidine might compare to these investigational drugs. AbbVie has yet to conduct any head-to-head studies comparing emraclidine to other potential therapies.An increasingly competitive market may create hurdles for drug companies, but it could create new options for people with schizophrenia. The condition affects less than 1% of the population, but is among the top 15 leading causes of disability worldwide.There remains a significant unmet need for more therapies with different mechanisms of action in the treatment of schizophrenia, Carlson wrote. '

Pictured: A smiling brain jumps over a hurdle against a psychedelic background/Taylor Tieden for BioSpace Psychedelic drug developers got a wake-up call when the FDA’s Psychopharmacologic Drugs Advisory Committee recommended against approving Lykos’ MDMA-assisted therapy to treat post-traumatic stress disorder. Now, companies in this space are scrutinizing their own protocols to ensure they don’t make the same mistakes. “It’s really a shot over the bow,” Joe Tucker, CEO of Enveric Biosciences, a neuropsychiatric drug developer, told BioSpace. “The FDA gave guidance specifically on clinical trials involving psychedelic drugs one year ago. When I read it, I remember thinking, ‘The FDA is basically bending over backwards . . . to help.' To me, that says the FDA really wants companies in this sector to be successful.” This desire, however, pales in the face of unsatisfying clinical safety and efficacy. And, based on its recommendation, it’s clear the advisory committee insists on conducting and evaluating clinical trials “the right way,” Tucker said. Dan Karlin, chief medical officer of MindMed, which is developing an LSD therapeutic, agreed that the FDA seems open to psychedelic drugs in general. “Committee members didn’t necessarily seem biased against psychedelics, so much as they had real reservations around the methods MAPS [now Lykos] had employed,” Karlin told BioSpace. Focus on Trial Design At the Lykos adcomm meeting, committee members seemed to focus more on the clinical trial than the company’s midomafetamine (MDMA) drug itself. “I think the issue was a trial issue, and not a compound issue,” Pamela Tenaerts, chief scientific officer of Medable, which designs digital trial software, told BioSpace. Lykos showed post-traumatic stress disorder (PTSD) symptoms declined substantially, but Tenaerts said “it did less of a good job [with] the things surrounding that endpoint.” As examples, she cited symptoms that weren’t recorded, a case of sexual misconduct and uncertainty over endpoints “because they didn’t track the positive side effects, like the euphoria.” Additionally, “there are indications of patients being told that maybe they were contributing to making history,” which may have affected their perceptions of their experiences, she said. The adcomm pointed out several issues in the trials, to which Lykos responded. Despite working closely with the FDA under a Special Protocol Assessment, the FDA did not require data regarding cardiovascular and liver toxicity risks, and Lykos did not include such information in its filings. The lack of this physiologic safety data wasn’t a make-or-break omission, though. “The safety pro already known and MDMA is only dosed three times in therapy . . . so that kind of safety data can be recorded in post-marketing surveillance Phase IV trials,” Sam Clark, CEO of Terran Biosciences, which develops therapies for neurological and psychiatric diseases, told BioSpace. Additionally, “companies can [design] a comprehensive risk evaluation and mitigation program to mitigate safety risks.” Nonetheless, he said, that data should be collected and submitted going forward. “Future trials should include those labs.” Data regarding the potential for abuse also was absent from Lykos’ regulatory filings. Although Lykos recorded adverse events during trials, it generally didn’t record patients’ neutral or positive feelings, such as elevated moods or euphoria, according to the FDA briefing document. This “limits the assessment of abuse potential,” the FDA noted. “However, there is an extensive literature in both animals and humans and other available data . . . to inform the assessment.” Relying on that data, however, proved inadequate for the committee. Clark and Karlin both recommend recording all acute experiences with the drug, whether they’re expected or unexpected, positive, negative or neutral, to generate more thorough data and, thus, more significant information. Recording positive experiences, Clark explained, is important because that data helps address criticism around expectation bias. Functional Unblinding The Drug Enforcement Agency notes that MDMA acts as both a stimulant and a psychedelic. As Karlin explained, “MDMA is not a [classic] psychedelic. It’s an entactogen or empathogen.” Unlike psychostimulants or hallucinogenics, MDMA promotes profound introspection rather than “trips,” according to research from the University of North Carolina at Chapel Hill. The “profound alterations in mood, sensation, suggestibility and cognition” make these types of studies “nearly impossible to blind,” the FDA said in its briefing document. The agency recommended using niacin or other stimulants or low-dose MDMA, each of which Lykos rejected, arguing that those options could exacerbate anxiety or worsen PTSD symptoms, according to the same document. But, Clark pointed out, “functional unblinding is not uncommon in drugs in psychiatric trials.” Therefore, the FDA eventually agreed, despite concerns, with Lykos’ plan to use an inactive placebo with psychotherapy as a control. The Role of Psychotherapy Alterations in mood, etc., pose a bigger issue than merely unblinding a study. Their occurrence means that such guided therapies are conducted alongside psychotherapy, which makes it difficult to determine whether results were caused by the drug or the psychotherapy, the FDA briefing document noted. “No one has suggested that MDMA, in the absence of psychotherapy, would be an effective treatment,” Karlin underscored. “Psychotherapy research is hard to standardize. It’s hard to know how to do an appropriate control condition.” Lykos, he said, was “in a tough spot . . . because now you have two different interventions that are not well controlled and not really well-understood.” Dose escalation studies can help differentiate between the effects of the drug and those of psychotherapy. “There could potentially be a dose-dependent response,” Clark said, which may resolve the issue of functional unblinding. If drug-assisted psychotherapy is a part of a trial, companies should also clarify what “psychotherapy” means in that context. “In Lykos’ situation,” Tucker said, “it seemed there was a lot of variability in what psychotherapy meant, how it was administered and how it was monitored.” Neuroplasticity Over Hallucination The original thinking around psychedelics was that, as a patient, “You took a drug, had a hallucination, and psychotherapy helped you process it. That solved your trauma, and you were cured,” Tucker told BioSpace. In the past five years, however, scientists have proposed an alternative mechanism called neuroplasticity. “In people with depression or anxiety, the prefrontal cortex has lost some of its ability to calm the amygdala,” Tucker said. By enhancing the brain’s neuroplasticity, existing neurons make more connections with other neurons, he explained. This “strengthens the signaling from the prefrontal cortex (which governs logical thinking) to the amygdala (which governs emotions).” Under that theory, the hallucination is a side-effect, and the benefit is the increased neuroplasticity. For biopharma, this makes psychiatric therapies more appealing, Tucker said. Enveric, as well as AbbVie and Gilgamesh—which announced a collaboration in May—are developing neuroplastogen molecules, which minimize the risk of hallucinations. The Risk of Bias Sponsor and investigator bias was another issue for the Lykos adcomm. To minimize this, MindMed is working with “20 different clinical research sites to minimize bias [in its trials] . . . and to ensure results aren’t overweighted by one site or another,” Karlin said. Extremely rigorous site training also helps, as does meticulous oversight to ensure adherence to protocols. MindMed and Lykos both use centralized independent raters to talk with patients about their treatments. “We use an off-site service to do the primary efficacy assessments,” Karlin said. Because they are not in the room during the sessions and are blinded to visit number, he suggests their assessments are more likely to be unbiased. Given Lykos’ experience, Clark advised companies in this space to plan their trials meticulously to minimize the risk of encountering similar objections from future adcomms. The ultimate goal, Karlin said, is “to develop the drug in such a way that people who would never in a million years today think about taking [psychedelic drugs] can have a medical and psychiatric evaluation and access an [effective] treatment." Gail Dutton is a veteran biopharmaceutical reporter, covering the industry from Washington state. You can contact her at gaildutton@gmail.com and see more of her work on Muckrack.