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DLX-001 Shown to Be Safe and Well-Tolerated Without Producing Hallucinogenic, Psychomimetic, or Dissociative Effects Based on Interim Data from Phase 1 Trial Preclinical Findings In Vivo Demonstrate DLX-001 Promotes Rapid and Durable Structural and Functional Neuroplasticity After a Single Dose Phase 2 Trial of DLX-001 Expected to Begin in mid-2024 Dr. Jeff Jonas Appointed to Scientific & Strategic Advisory Board BEDFORD, Mass.--(BUSINESS WIRE)-- Delix Therapeutics, a clinical-stage neuroscience company developing novel neuroplasticity-promoting therapeutics for psychiatric and neurological disorders, today announced interim results from the Phase 1 trial evaluating DLX-001, a novel neuroplastogen, in healthy volunteers, which were presented at the 2023 American College of Neuropsychopharmacology (ACNP) Annual Meeting in Tampa, Florida. Preclinical data characterizing the compound were also presented at the meeting. “While ketamine and serotonergic psychedelics have shown promise for treating certain neuropsychiatric disorders, they are also associated with troublesome side effects and cardiac risks,” said Aaron Koenig, MD, Chief Medical Officer of Delix Therapeutics. “We are encouraged by our preliminary Phase 1 results, which indicate that DLX-001 is safe, well-tolerated, and, as predicted by our preclinical studies, does not produce hallucinogenic, psychotomimetic, or dissociative effects in healthy volunteers. Importantly, preclinical findings confirm DLX-001’s ability to robustly promote structural and functional neuroplasticity in vivo in the prefrontal cortex, which we believe drives the underlying efficacy of this class of fast-acting agents. We look forward to the continued development of DLX-001, as we believe it has the potential to address the significant unmet medical needs of patients suffering from difficult-to-treat neuropsychiatric conditions.” A Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetic Profiles of DLX-001, a Novel Neuroplastogen Lead Author: Aaron Koenig, M.D. Session Date: Monday, December 4 Session Time: 5:00pm-7:00pm EST The Phase 1, three-part study is enrolling approximately 100 healthy volunteers with the primary objectives of assessing safety, pharmacokinetics (PK), and markers of brain activity. Part A is a randomized, double-blind, placebo-controlled single ascending dose (SAD) study of DLX-001. Part B is a standard, open-label, crossover design study to investigate the effect of food on the PK of DLX-001. Part C is a randomized, double-blind, placebo-controlled multiple ascending dose (MAD) study in which participants receive multiple oral doses of either DLX-001 or placebo over 7 days. Key Findings In the 62 healthy volunteers dosed so far, DLX-001 demonstrated a favorable safety pro was well-tolerated, with no serious adverse events reported to-date. No psychotomimetic, hallucinatory, or dissociative effects were observed, as reflected by no change over time on a robust battery of metrics including the Clinician-Administered Dissociative States Scale (CADSS), Bond & Lader Visual Analogue Scale (B&L VAS), Bowdle Visual Analogue Scale (Bowdle VAS), and Mystical Experience Questionnaire 30 (MEQ-30). DLX-001 is orally bioavailable, achieves plasma exposures within the predicted therapeutic range, and achieves measurable levels within the CSF. The maximum tolerated dose for DLX-001 has not yet been reached; additional cohorts are in progress. In addition to these interim clinical data, Delix presented preclinical data characterizing DLX-001’s neuroplastic and therapeutic effects, including comparative data marking the beneficial efficacy of DLX-001 against ketamine, psilocybin, and DMT and differentiating it from these compounds on hallucinogenic liability. Preclinical Pharmacology of DLX-001, a Novel Non-Hallucinogenic Neuroplastogen With the Potential for Treating Neuropsychiatric Diseases Lead Author: Kurt Rasmussen, Ph.D. Session Date: Tuesday, December 5 Session Time: 5:00pm-7:00pm EST DLX-001 was examined in a series of in vitro, ex vivo, and in vivo assays relevant to neuroplasticity and major depressive disorder. Key Findings In pharmacokinetic (PK) studies, DLX-001 was shown to be orally bioavailable and brain penetrant. In a phenotypic screen of neurite outgrowth in neuronal cell cultures, DLX-001 produced significant increases in both neurite length and complexity. In vivo, DLX-001 demonstrated significant effects on promoting both structural and functional neuroplasticity on par with the 1st generation compounds ketamine and psilocybin after a single dose DLX-001 exhibited both rapid, within 24-hours, and enduring, up to 7 days, antidepressant-like activity after a single dose in behavioral assays In studies relevant to cardiotoxicity and hallucinations, no signal was identified for DLX-001. Importantly, DLX-001 met or exceeded the efficacy and duration of effect of first-generation psychoplastogens, including DMT, psilocybin, and ketamine. “Delix is excited to share these data from DLX-001, the first novel neuroplastogen to enter clinical testing. These data reinforce the potential of our broader neuroplastogen platform to develop therapies that can repair damaged neurons,” said Delix CEO Mark Rus. “We are particularly impressed with DLX-001’s ability to cross the blood-brain barrier and achieve therapeutic exposures, which is a common challenge in CNS drug development, but not produce hallucinogenic effects.” Delix is also announcing today the appointment of Jeff Jonas, M.D., to the company's Strategic & Scientific Advisory Board. Dr. Jonas brings decades of experience in R&D leadership and cutting-edge CNS drug discovery and development across brands that have successfully helped millions of patients, such as Lexapro, Vyvanse, Zulresso, Zurzuvae and Namenda. In addition, across roles such as CEO of Sage Therapeutics, and Board Member of Karuna Therapeutics, Jeff's significant company building and advisory experience has generated considerable shareholder and stakeholder value, particularly when developing novel scientific approaches to CNS. "The Delix team and I are thrilled that Jeff has joined us as a Scientific and Strategic Advisor," said Delix CEO Mark Rus. "Jeff's proven track record and experience will be invaluable to Delix in the future. He and his teams have significantly advanced the CNS treatment landscape throughout his career. I look forward to leveraging his considerable experiences as we progress our novel neuroplastogen platform and build Delix into a leading neuroscience company." "The therapies being developed by Delix and their overall approach to repairing neuronal atrophy have the potential to shift the treatment paradigm for several neuropsychiatric conditions," said Dr. Jonas. "I look forward to working with Delix's talented management and scientific team as they advance a pipeline of non-hallucinatory neuroplasticity-promoting therapeutics to better treat patients struggling with difficult-to-treat disorders.” About Jeffrey Jonas Jeffrey Jonas, M.D., has more than 25 years of experience in drug development and discovery across multiple therapeutic areas in the pharmaceutical and healthcare industries. Dr. Jonas has served as CEO and Chief Innovation Officer of Sage Therapeutics, where he led the development of industry-leading CNS treatments and development pipelines. Before Sage, he was President of the Regenerative Medicine Division at Shire Pharmaceuticals. Earlier on his career, Dr. Jonas served as Executive Vice President of ISIS Pharmaceuticals and held senior positions at Forest Laboratories, Inc. and Upjohn Laboratories. He received his M.D. from Harvard Medical School and a B.A. from Amherst College. About DLX-001 DLX-001 is a novel, non-hallucinogenic, and non-dissociative isotryptamine neuroplastogen currently undergoing initial human testing to treat those diagnosed with major depressive disorder (MDD) and other associated neuropsychiatric conditions. Preclinical data suggests that in efficacious doses, DLX-001 increased dendritic spine density in rat brain layer-V PFC pyramidal neurons and had rapid and enduring antidepressant-like effects after a single dose. Recent phase 1 data found DLX-001 to be safe and well tolerated, with no serious adverse events reported. In addition, researchers did not observe significant abnormalities among crucial safety indicators, including vital signs, electrocardiogram (ECG) readings, and laboratory analysis. About Neuroplastogens Neuroplastogens are a novel class of potentially disease-modifying therapeutics for psychiatric and neurological conditions. These compounds promote rapid and sustained neuroplasticity in select neural circuits resulting in fast-acting therapeutic effects. Neuroplastogens are novel chemical entities inspired by compounds that are proving to be beneficial across a range of therapeutic areas including mood, anxiety, cognitive, and neurodegenerative disorders in addition to other synaptopathies. Generated from our phenotypic drug discovery engine, Delix’s seeks to bring to market a pipeline of neuroplastogens that will be the faster, stronger, and more effective therapies of the future. About Delix Therapeutics Delix Therapeutics is a clinical-stage neuroscience company focused on harnessing the power of novel neuroplasticity-promoting therapeutics to better treat patients struggling with difficult-to-treat neuropsychiatric and neurological disorders. The company's compounds are easily manufactured small molecules capable of rapidly inducing structural and functional neural changes in targeted areas of the brain. Through its novel Neuroplastogen Platform, Delix is pioneering a new class of fast-acting outpatient pharmacotherapies and rapidly advancing through preclinical and clinical development to bring patients FDA-approved, take-home medicines that will serve several unmet needs and enhance the psychiatric treatment paradigm for patients and providers.

The Food and Drug Administration on Friday granted approval to a new kind of antidepressant, clearing an oral medicine developed by partners Sage Therapeutics and Biogen for postpartum depression.But, in a decision that will restrict how widely its used and the amount of revenue it generates, the agency rejected the companies attempt to also win approval for major depressive disorder, or MDD.According to Biogen, the FDA found the companies clinical trial evidence insufficient proof that the medicine, known scientifically as zuranolone, is effective for MDD and asked for further testing.Both Sage and Biogen have identified zuranolone, which will be sold under the brand name Zurzuvae, as a key product for their near-term growth, with an approval in MDD a core part of their calculus. Thats because, while estimates vary, health authorities believe tens of millions of people in the U.S. experience MDD, making it one of the most common mental disorders.Yet, mixed results from studies in MDD appear to have driven the FDAs decision to approve zuranolone only for postpartum depression, or PPD. An estimated 500,000 women experience postpartum symptoms in the U.S. each year, per an estimated cited by the companies.We believe that Zurzuvae will be an important option to treat PPD and we will thoroughly review the feedback from the FDA on the use of zuranolone in MDD to determine next steps, Biogen CEO Chris Viehbacher said in a statement.For the past three decades, doctors often prescribed so-called SSRI drugs like Prozac, Lexapro and Zoloft to treat depression. But those medications dont work for everyone, and they can cause a variety of side effects, from weight gain and impaired cognitive function to aggression and suicidal thoughts.Zuranolone acts differently than SSRIs; it amplifies proteins that regulate a kind of chemical messenger found in the central nervous system. Clinical trials have shown the drug doesnt have the more worrisome side effects seen with other antidepressants.It also appears to provide rapid relief, though in MDD its degree of benefit remains unclear. A large study of zuranolone in that indication failed in 2019. And since then, further late-stage testing has raised questions about how substantial and long-lasting its effects are.Sage and Biogen have maintained their drug has the ability to quickly rebalance dysregulated neuronal networks to help reset brain function.The FDA based its approval decision in PPD on two clinical trials. One, named SKYLARK, found zuranolone to be significantly better than a placebo when tested in postpartum patients, as measured by a widely used scale that evaluates symptoms of depression. These improvements were seen as early as three days into treatment and sustained throughout 45 days of follow-up.Other antidepressants can take weeks to show an effect.Postpartum depression is a serious and potentially life-threatening condition in which women experience sadness, guilt, worthlessness even, in severe cases, thoughts of harming themselves or their child, said Tiffany Farchione, director of the psychiatry division in the FDAs main drug review office, in a statement.Having access to an oral medication will be a beneficial option for many of these women coping with extreme, and sometimes life-threatening, feelings, Farchione added.Against MDD, results with zuranolone werent as clear-cut. The failed trial, for example, showed zuranolone to be better than a placebo in the initial days following treatment. But its effects appeared to wane, and by day 15 the difference between the drug and control groups had narrowed enough that the study missed its primary goal.Sage redrew development plans for zuranolone shortly after that setback, announcing in March 2020 how it would conduct three additional late-stage trials in MDD, with the hope of generating enough positive data to support an FDA approval application. A month later, the company said it would lay off a little over half of its workforce to help reduce costs.Later that year, though, Sage agreed to sell some of the rights to zuranolone and a separate, experimental drug for tremors to Biogen. In exchange, Biogen gave its new partner an upfront cash payment and equity investment that, together, were worth $1.5 billion.Data from those three additional studies, dubbed WATERFALL, SHORELINE and CORAL, were released between mid-2021 and early 2022. Each had a slightly different design; SHORELINE followed participants for a year after treatment, while CORAL administered zuranolone along with a standard-of-care antidepressant. All tested a higher dose of zuranolone than the failed trial, and all hit their main goals.The studies werent completely positive, however. Zuranolone didnt meet some of their secondary aims, and the drugs effects still seemed to diminish over time.Barry Greene, Sages CEO, said in a statement that the company was highly disappointed in the FDAs rejection of the drug for MDD.For postpartum use, Zurzuvae will carry a boxed warning advising doctors to instruct their patients not to drive a motor vehicle or engage in other complex tasks due to the drugs depressant effects.The companies dont expect to make the drug commercially available until the fourth quarter of this year, as the Drug Enforcement Administration has to first classify it as a controlled substance.Sage already sells a drug, Zulresso, for postpartum depression. However, its given as a continuous intravenous infusion over 60 hours, and carries an FDA warning for excessive sleepiness and sudden loss of consciousness. Sales have been minimal since its 2019 approval.Ahead of the FDAs approval decision, analysts at Jefferies forecast annual sales of zuranolone would reach more than $1 billion a year, provided the drug secured an MDD indication. They modeled peak sales from PDD somewhere in the range of $300 million to $500 million. '