Definium’s DT120 Succeeds in Phase 3 Trial for Major Depression

Definium Therapeutics reported positive topline results from Emerge, the first of two pivotal Phase 3 studies (NCT06941844) evaluating DT120 (lysergide) orally disintegrating tablet (ODT) in adults with major depressive disorder (MDD). The study met its primary endpoint and all key secondary endpoints, demonstrating rapid and sustained antidepressant effects following a single 100 µg dose.

At Week 6, DT120 reduced Montgomery-Åsberg Depression Rating Scale (MADRS) scores by 13.3 points compared with 5.2 points for placebo, resulting in an 8.1-point placebo-adjusted benefit (p<0.0001). The treatment effect emerged rapidly, with a 14.2-point placebo-adjusted reduction in MADRS scores at Week 1 (p<0.0001), and remained durable through Week 12 with a 7.3-point placebo-adjusted benefit (p<0.0001).

DT120 Targets Serotonin Pathways Implicated in Depression

DT120 is Definium’s proprietary formulation of lysergide (LSD), a classic serotonergic psychedelic that acts as a partial agonist of the serotonin 5-HT2A receptor. The orally disintegrating tablet incorporates Catalent’s Zydis technology, which supports rapid absorption and improved bioavailability.

Major depressive disorder affects more than 21 million adults annually in the United States and remains a leading cause of disability worldwide. Despite available treatment options, many patients fail to achieve remission, experience delayed symptom improvement, or discontinue therapy because of tolerability challenges.

Phase 3 Study Met Primary and All Key Secondary Endpoints

The randomized, double-blind, placebo-controlled Emerge study enrolled 149 adults aged 18 to 74 years across 20 clinical sites. Participants had DSM-5-confirmed MDD, baseline MADRS scores of at least 26, and Clinical Global Impression-Severity (CGI-S) scores of at least 4.

In addition to the primary endpoint, DT120 demonstrated significant improvements across multiple efficacy measures:

• Week 1 MADRS improvement: placebo-adjusted reduction of 14.2 points (p<0.0001)
• Week 12 MADRS improvement: placebo-adjusted reduction of 7.3 points (p<0.0001)
• Week 6 response rate (≥50% symptom reduction): 35% vs 7% with placebo (p<0.001)
• Week 6 remission rate (MADRS ≤12): 24% vs 3% with placebo (p<0.01)
• Significant improvements in CGI-S scores at Day 2, Week 6, and Week 12

Adverse events were nearly all mild to moderate, transient, and occurred primarily on the day of dosing, with no serious adverse events, suicidality signals, or new safety concerns reported.

Clinical Implications

Rob Barrow, Chief Executive Officer of Definium Therapeutics, said the Phase 3 Emerge results support DT120’s potential as a new treatment option for major depressive disorder and advance the program toward future regulatory submission.

John Sonnenberg, Ph.D., principal investigator of the Emerge study, founder of Uptown Research Institute, and faculty member at Northwestern University Feinberg School of Medicine, said the rapid and durable antidepressant effects observed after a single dose could help address a significant unmet need for patients who do not achieve timely benefit from existing treatments.

Clinical Path Forward

Emerge is the first of two pivotal Phase 3 studies evaluating DT120 in major depressive disorder. The second pivotal study, Ascend (NCT07592689), is ongoing and includes both 100 µg and 50 µg dose arms alongside placebo. Data from Emerge and Ascend are expected to support future regulatory discussions.

Beyond MDD, DT120 is also under development for generalized anxiety disorder, post-traumatic stress disorder, and other neuropsychiatric conditions. The therapy has received FDA Breakthrough Therapy designation for generalized anxiety disorder, providing an expedited development pathway as the program advances.

What This Could Mean for Patients

If confirmed in the ongoing Phase 3 program and approved by regulators, DT120 could offer a new treatment option for people living with major depressive disorder. Unlike traditional antidepressants that often require daily dosing and may take weeks to work, a single dose of DT120 produced rapid improvements within one week and maintained benefits for up to 12 weeks in this study. This approach could be particularly meaningful for patients who need faster symptom relief or have not achieved adequate benefit from existing treatments.

Reference

Definium Therapeutics Announces Positive Topline Results from Phase 3 Emerge Study of DT120 Orally Disintegrating Tablet (ODT) in Major Depressive Disorder:: Definium Therapeutics (DFTX)