A Landmark Pivotal Study Applying Precision Medicine to Psychiatry with Denovo’s DB104 (liafensine) for Treatment-Resistant Depression Published in JAMA Psychiatry

The study represents the first successful prospective genetic biomarker-guided drug trial in psychiatry

SAN DIEGO, Sept. 11, 2025 (GLOBE NEWSWIRE) — Denovo Biopharma LLC (Denovo), a pioneer in applying precision medicine to the development of innovative therapies, today announced that results from its pivotal ENLIGHTEN trial have been published as the feature article in JAMA Psychiatry, one of the most prestigious journals in psychiatry. The study demonstrated robust efficacy of DB104 (liafensine) in treatment-resistant depression (TRD) patients carrying a novel pharmacogenomic biomarker, ANK3.

TRD is one of the most difficult psychiatric disorders to treat. Most investigational therapies for TRD are psychedelics, which are usually associated with severe adverse effects and need to be administered in qualified clinics under hours of close monitoring.

“This study represents a much-needed success in TRD with a non-psychedelic oral therapy that provides a safe, convenient, and effective treatment option for TRD, a major unmet medical need,” said Wen Luo, Ph.D., Denovo’s Chief Executive Officer. “Equally important, this achievement marks a game changer with the potential to transform how we treat psychiatric conditions and develop new therapies through a patient-specific, biomarker-driven approach.”

The biomarker‑guided, randomized, double-blind, placebo-controlled Phase 2b trial was conducted at 58 sites across the US, Canada, and China. The success of this pivotal study led to Fast Track Designation by the FDA, and Denovo needs just one more positive pivotal study before filing an NDA for liafensine in treating ANK3 positive TRD patients.

Key highlights of the published results:

• The primary endpoint was the Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from baseline (CFB) at week 6 in ANK3-positive TRD patients. Liafensine showed a 4.4-point improvement over placebo (P=0.006), a clinically meaningful and statistically significant improvement. This result replicated the 4.7-point MADRS improvement observed from biomarker-based retrospective analyses of prior studies.
• All secondary endpoints, Clinical Global Impression-Severity (CGI-S) CFB, Clinical Global Impression-Improvement (CGI-I), and Sheehan Disability Scale (SDS) CFB at week 6, also showed liafensine was statistically superior to placebo.
• Cumulative safety data for liafensine include 1,487 subjects exposed, 482 treated for at least 6 months, and 218 for at least 12 months. Adverse events reported in the ENLIGHTEN trial were similar to historical trials, and indicate liafensine is safe and well tolerated, without the highly morbid adverse effects associated with current TRD treatments.

The full publication “ANK3 as a novel genetic biomarker for liafensine for treatment-resistant depression” is available online at JAMA Psychiatry.

About Treatment-Resistant Depression

Major depressive disorder (MDD) is a common mental health disorder that impacts an estimated 280 million people worldwide. In the United States alone, approximately 21 million adults have had at least one major depressive episode. Approximately one-third of MDD patients will not respond to oral antidepressants and are considered to have treatment-resistant depression (TRD), defined as inadequate response to two medications. Despite having a significant negative impact on the lives of those affected and one of the highest economic burdens of all psychiatric disorders, TRD has limited treatment options and represents a major unmet medical need.

About DB104 (liafensine)

Liafensine is a first-in-class triple reuptake inhibitor targeting transporters for serotonin, norepinephrine, and dopamine. It was licensed from Albany Molecular Research, Inc. (now Curia) and was previously developed by Bristol Myers- Squibb (BMS) for treatment-resistant depression (TRD). BMS had conducted 14 clinical trials which proved the superior safety of liafensine, but failed to show efficacy in non-biomarker-selected TRD populations. Denovo’s ENLIGHTEN Phase 2b pivotal trial prospectively demonstrated robust efficacy and favorable safety profile of liafensine in ANK3-positive patients with TRD. See NCT01573546 on www.clinicaltrials.gov for additional information on the ENLIGHTEN trial.

About ANK3 Biomarker

The ANK3 gene, which encodes a scaffolding protein primarily expressed in the nervous system, plays an important role in neuronal signaling through modulation of cell membrane proteins and is linked to psychiatric diseases including bipolar disorder and depression. Denovo discovered a single nucleotide polymorphism (SNP) located on ANK3 gene as a pharmacogenomic biomarker which is associated with liafensine efficacy via Denovo’s unique artificial intelligence (AI) and whole genome scan-based DGM biomarker discovery platform.

About Denovo Biopharma

Denovo Biopharma LLC is a clinical-stage biopharmaceutical company that uses novel biomarker approaches to execute efficient clinical trials in targeted patient subpopulations to increase the probability of success. Denovo has seven late-stage drugs in its pipeline addressing major unmet medical needs in central nervous system diseases and oncology, most of which are first-in-class drugs with global rights. Visit www.denovobiopharma.com for additional information.

Investor Contact:

Stephen Jasper
Gilmartin Group
stephen@gilmartinir.com