Phase 2 Results: Xanamem Shows Statistically Significant Antidepressant Effect in Difficult-to-Treat Depression

Actinogen Medical this week published Phase 2 proof-of-concept results in the British Journal of Psychiatry showing that its lead candidate, Xanamem (emestedastat), produced a statistically significant antidepressant effect in patients with difficult-to-treat major depressive disorder (MDD) and measurable cognitive impairment.

Study Design

The randomised, double-blind, placebo-controlled trial enrolled 165 participants with persistent residual MDD and cognitive deficits. Most participants continued their existing antidepressant therapy while receiving either Xanamem 10 mg once daily or placebo for a six-week dosing period, followed by four weeks of blinded observation.

Key Findings

At the primary efficacy timepoint (week 10), patients treated with Xanamem achieved a 2.7-point greater improvement on the Montgomery-Åsberg Depression Rating Scale (MADRS) versus placebo; this difference reached statistical significance. In the prespecified subgroup of patients taking a selective serotonin reuptake inhibitor (SSRI) at baseline (46% of participants), the treatment effect increased to a 4.2-point MADRS advantage versus placebo.

Investigators noted the delayed onset of the antidepressant signal, consistent with the time course expected for reversal of chronic cortisol-related effects after 11beta-HSD1 inhibition.

Safety and Cognitive Outcomes

Xanamem was reported to be safe and well tolerated with no new safety signals identified. Although both treatment arms recorded improvements in cognitive symptoms during the study, the trial detected no additional cognitive benefit from Xanamem versus placebo, and there was no observed correlation between changes in cognition and changes in depressive symptoms.

Professor Michael Berk AO, academic psychiatrist and co-author, said the data are encouraging for the 10 mg daily dose and support brain penetration and a signal of clinically meaningful antidepressant activity in a difficult-to-treat MDD cohort.

Mechanism, Development Plan and Next Steps

Xanamem is a first-in-class, once-daily oral inhibitor of the 11beta-HSD1 enzyme designed to lower cortisol levels in key brain regions without suppressing essential adrenal cortisol production. Actinogen has evaluated Xanamem in more than 500 volunteers and patients across eight clinical trials to date.

The company is advancing Xanamem primarily for Alzheimer's disease. Its pivotal XanaMIA Phase 2b/3 study is testing Xanamem in 247 patients with mild-to-moderate, biomarker-confirmed Alzheimer's disease across Australia and the United States, with topline results expected in November 2026. Actinogen said further dedicated depression trials will depend on future funding and partnership arrangements.

Dr Dana Hilt, Chief Medical Officer, noted that antidepressant activity could be a useful feature for Alzheimer's patients, who commonly experience depressive symptoms, potentially improving wellbeing and quality of life.

Overall, the Phase 2 data support further clinical evaluation of Xanamem as a novel antidepressant approach via central cortisol modulation, while highlighting the need for additional studies to confirm the cognitive and broader clinical benefits.