Definium Therapeutics Announces Positive Topline Results from Phase 3 Emerge Study of DT120 Orally Disintegrating Tablet (ODT) in Major Depressive Disorder
Definium Therapeutics, Inc. a late-stage clinical biopharmaceutical company developing a new generation of therapeutics intended to address underlying causes of psychiatric and neurological disorders, today announced positive topline results from Emerge, its first randomized, double-blind, placebo-controlled Phase 3 study evaluating a single dose of DT120 (lysergide) ODT 100 µg in adults with major depressive disorder (MDD).
Emerge met its primary endpoint, demonstrating a statistically significantand clinically meaningful improvement from baseline compared with placebo, as measured by the change in MADRS total score at week 6. The Least Squares (LS) mean change from baseline in MADRS total score at Week 6 in participants who received DT120 ODT 100 µg was -13.3 compared with -5.2 for patients who received placebo, a LS mean difference of -8.1 points (p<0.0001). Beyond the primary endpoint, the effect was rapid with a placebo-adjusted LS mean reduction in MADRS total score at Week 1 of -14.2 (p<0.0001) and durable with a placebo-adjusted LS mean reduction in MADRS total score of -7.3 at Week 12 (p<0.0001).
The Emerge topline results represent unprecedented and highly differentiated efficacy, demonstrating that a single dose of DT120 ODT can deliver rapid, robust, and durable relief in MDD,” said Rob Barrow, Chief Executive Officer of Definium Therapeutics. “As the first of our Phase 3 studies to report results, Emerge marks a major milestone in our development program and strengthens our confidence in DT120 as a potential best-in-class treatment for mental health disorders. These findings could support a fundamentally new approach to treating MDD for patients and providers who continue to face the limitations of existing treatment options. We are deeply grateful to the patients and investigators who participated in this trial. Grounded in decades of scientific research, these results bring us one step closer to potentially delivering a transformative new treatment option as we advance toward FDA submission.
DT120 ODT was generally well tolerated with 99% of treatment-emergent adverse events mild to moderate in severity, transient, and predominantly occurring on the day of dosing. No new safety signals were identified, including no increase in suicidal ideation or behavior, and discontinuation rates were low and comparable between treatment groups. On the day of dosing, participants were assessed hourly from hours 5 to 8 on a structured end of session checklist (EoSC). The average time to meeting EoSC criteria was 5.8 hours for participants receiving DT120 ODT in Part A, with a median of 5.1 hours and 100% of participants meeting the EoSC criteria by hour 8.
Many patients with MDD aren’t helped by existing treatments, often experiencing partial responses, frequent medication changes, and long-term side effects,” said John Sonnenberg, Ph.D., Emerge principal investigator, clinical psychologist, founder of Uptown Research Institute, and faculty member at Northwestern University Feinberg School of Medicine. “The Emerge topline results demonstrate that a single dose of DT120 ODT can produce a meaningful and durable benefit for people with depression. Importantly, these results stand apart from existing treatments, representing a potentially new paradigm for the management of major depression.
About Emerge
Emerge is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of a single 100 µg dose of DT120 ODT versus placebo in participants with major depressive disorder (MDD). The study consists of a 12-week double-blind phase (Part A) followed by a 40-week open-label extension phase (Part B) during which participants may be eligible to receive DT120 ODT based on symptom severity.
The study enrolled 149 participants aged 18 to 74 years across 20 sites with a DSM-5-confirmed diagnosis of MDD, a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of at least 26, and a Clinical Global Impression–Severity (CGI-S) score of at least 4 at screening and baseline.
The primary endpoint is change from baseline in the MADRS total score at Week 6. Key secondary endpoints are change from baseline in CGI-S score at Week 6, Week 12 and Day 2 and change from baseline in MADRS total score at Week 12 and Week 1.
Emerge is one of two pivotal Phase 3 studies in MDD. Ascend, the second Phase 3 study in MDD, is aligned with Emerge, but includes a low dose arm and is also conducted in two parts: Part A, a 12-week, randomized, double-blind, placebo-controlled, parallel-group period; and Part B, a 40-week extension period during which participants will be eligible for open-label treatment with DT120 ODT based on symptom severity. Participants will be randomized 2:1:2 to receive DT120 ODT 100 µg, DT120 ODT 50 µg, or placebo. The 50 µg arm is intended to confound participants’ ability to accurately assess the dose condition to which they have been randomized. This approach continues to build on the Company’s Phase 2b study of DT120 in generalized anxiety disorder (GAD), which the Company believes demonstrated that DT120’s clinical activity is not attributable to functional unblinding and aligns with FDA guidance on the use of complementary designs across the Company’s DT120 clinical development program. The primary endpoint of Ascend is change from baseline in MADRS total score at Week 6 between DT120 ODT 100 µg and placebo.
About Major Depressive Disorder (MDD)
Major Depressive Disorder (MDD) is the second-most common mental health disorder in the U.S., with over 21 million adults experiencing a major depressive episode (MDE) each year.1,2 This disorder, a leading cause of disability worldwide,3 brings persistent feelings of worthlessness, fatigue, and recurrent thoughts of death4 while increasing long-term mortality risk by 40%.5 MDD also carries a $326 billion annual economic burden in the U.S., driven by healthcare costs and lost productivity.6 The MDD treatment paradigm is characterized by critical unmet needs, including fewer than one-third of patients reaching remission with first-line treatments,7 onset of clinical activity that takes weeks to months,8,9 poor tolerability,10,11 and frequent switching, augmentation, and discontinuation of pharmacotherapy.12
About DT120 (lysergide) Orally Disintegrating Tablet (ODT)
DT120 ODT is an ergoline derivative belonging to the group of classic serotonergic psychedelics, which acts as a partial agonist at serotonin-2A (5-HT2A) receptors. DT120 ODT is Definium’s proprietary and pharmaceutically optimized formulation of LSD. DT120 ODT is an advanced formulation incorporating Catalent’s Zydis® ODT fast-dissolve technology, designed to deliver several unique advantages, including faster absorption and onset of transient cognitive, perceptual, and affective changes, improved bioavailability, and a lower incidence of gastrointestinal side effects. Definium is developing DT120 ODT, the tartrate salt form of lysergide, for generalized anxiety disorder (GAD), major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and is exploring its potential applications in other serious brain health disorders. DT120 has received Breakthrough Therapy designation from the FDA for GAD. Definium maintains a strong foundation to protect and extend the long-term value of the DT120 ODT franchise through a multi-layered intellectual property strategy spanning composition, formulation, and methods-of-use patents.
About Lysergide (LSD)
Lysergide (LSD) is one of the most extensively studied psychopharmaceuticals in history, with over 1,000 published reports.13 First synthesized in 1938 by Swiss chemist Albert Hofmann in his search for active principles from ergot fungus, its profound psychological effects were discovered in 1943, which transformed psychiatric research.13 LSD, a definitional classic psychedelic, temporarily alters perception, cognition, and emotion, is physiologically safe, non-addictive, and isn’t associated with withdrawal.13 While its precise mechanism of action in the treatment of psychiatric illness is unknown, its acute perceptual, cognitive, and affective effects are mediated by agonism of the serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor, and mechanistic hypotheses suggest that it causes sustained increases in neuroplasticity in a variety of brain regions.14,15
About Definium Therapeutics
The mission of Definium Therapeutics is to forge a new era of psychiatry by applying scientific rigor to psychedelics, with the goal of developing accessible treatments that unlock healing at scale. Guided by a recognition that patients deserve more than better, Definium is relentlessly advancing a new generation of therapeutics intended to address underlying causes of psychiatric and neurological disorders. By turning evidence into impact, Definium aims to change the trajectory of today’s mental health care crisis and enable a healthier future. Headquartered in New York, Definium Therapeutics trades on Nasdaq under the symbol DFTX.
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