HJ-006: A NON-HALLUCINOGENIC SYNAPTOGENIC COMPOUND WITH RAPID AND SUSTAINED ANTIDEPRESSANT EFFICACY

Introduction

Current antidepressants (SSRIs/SNRIs) face limitations including delayed onset (4–6 weeks) and modest efficacy (~50% response rates), while serotonergic psychedelics show rapid antidepressant potential via 5-HT2A agonism and synaptic plasticity but are hindered by hallucinogenic activity and 5-HT2B-mediated cardiotoxicity.

Objectives

To address these challenges, we characterize HJ-006, a novel synaptogenic agent, designed to promote neuroplasticity without hallucinogenic or safety liabilities, and antidepressant efficacy.

Methods

Antidepressant-like efficacy was evaluated using established in vivo models, including the forced swim test (FST), tail suspension test (TST), and sucrose preference test (SPT) in chronic unpredictable mild stress (CUMS) and corticosterone-induced depression paradigms. Neuroplasticity-related effects were assessed using neurite outgrowth and synaptogenesis assays, as well as multielectrode array (MEA) recordings in corticosteronedamaged hippocampal neurons. Safety and liability assessments included the head twitch response (HTR), conditioned place preference (CPP), and cardiovascular monitoring by nonhuman primate ECG. Pharmacokinetic properties were characterized by in vivo PK profiling.

Results

HJ-006 is an orally active, brain-penetrant, small molecule. In vitro, HJ-006 showed significant effects on neurite-outgrowth and synaptogenesis in primary cultures of rat cortical neurons. It demonstrated rapid (30 min post-single dose) FST antidepressant effects in corticosterone-induced depression and reversed CUMS-induced deficits in FST, TST, and SPT, with efficacy sustained ≥8 days, with no hallucinogenic behavior (HTR-negative). Safety profiles included no CPP rewarding effects, enhanced dendritogenesis/synaptogenesis in cortical neurons, rescued CORT-impaired hippocampal activity (30 nM, 15 min post-treatment), 5-HT2B antagonist activity (Ki=2.18 nM, IC50=272.8 nM), favorable brain penetration, CYP3A4 metabolism, no cardiovascular signals in primates, and a 40× safety margin in 14-day toxicity studies.

Conclusions

HJ-006 is a first-in-class non-hallucinogenic neuroplastogen with rapid, sustained antidepressant-like efficacy and improved safety, supporting its potential as a transformative depression treatment. W44. PATIENT REPORTED OUTCOME RESPONSE FOLLOWING TREATMENT WITH LIAFENSINE IN ANK3 BIOMARKER POSITIVE PATIENTS WITH TREATMENT RESISTANT DEPRESSION Larry Alphs*1 1Denovo Biopharma LLC Abstract

Background

Liafensine, a triple monoamine reuptake inhibitor, has demonstrated antidepressant efficacy in patients with treatment-resistant depression (TRD) who are positive for an ANK3 genetic biomarker. While clinician-reported measures are commonly used to assess treatment response, they may not fully capture patients’ lived experiences of symptom burden and functional impairment. Patient-reported outcome measures may provide complementary and clinically meaningful information regarding treatment benefit.

Methods

This post hoc analysis evaluated patient-reported outcomes from a randomized, double-blind, placebo-controlled study of liafensine (1 mg or 2 mg daily) in adults with moderate-to-severe ANK3-positive TRD. Patient-Reported Depression Functioning (PRDF) total and domain scores, assessing symptom frequency and functional impact across nine symptom groupings, were analyzed in 188 participants (liafensine, n = 124; placebo, n = 64). Changes from baseline through Days 7 and 42 were assessed using mixed-effects models for repeated measures. Effect sizes were calculated, and correlations with clinician-reported measures were examined.

Results

Compared with placebo, liafensine produced statistically significant improvements in PRDF total frequency, functional impact, and global impact scores as early as Day 7, with effects sustained through Day 42. Improvements were observed across all PRDF symptom domains, including mood, anxiety, cognition, energy, social functioning, and suicidality, despite relatively low baseline severity in some domains. Effect sizes were generally in the medium range and comparable to those observed for clinician-reported outcomes. PRDF impact scores demonstrated sustained functional improvement over time and were sensitive to treatmentrelated changes consistent with improvements on the Sheehan Disability Scale.

Conclusions

In ANK3-positive patients with treatment-resistant depression, liafensine demonstrated early, sustained, and multidimensional therapeutic benefit from the patient perspective. The PRDF sensitively captured improvements in both symptom burden and functional impact, supporting its utility as a complementary endpoint alongside clinicianreported measures in biomarker-defined clinical trials.