Actinogen’s Xanamem Shows Antidepressant Benefit in Phase 2 MDD Trial

Actinogen Medical has published peer-reviewed Phase 2 data showing that Xanamem (emestedastat) improved depressive symptoms in patients with major depressive disorder and cognitive impairment. The findings support further evaluation of the investigational oral therapy while reinforcing its potential role beyond Alzheimer’s disease.

Actinogen Medical has reported the peer-reviewed publication of its Phase 2 proof-of-concept XanaCIDD trial evaluating Xanamem® (emestedastat) in patients with major depressive disorder (MDD) and cognitive impairment (CI). Published in the British Journal of Psychiatry, the study showed clinically meaningful antidepressant activity in a population with difficult-to-treat depression while confirming a favorable safety profile.

The publication strengthens evidence supporting Xanamem’s novel brain cortisol-targeting mechanism and adds to the company’s ongoing clinical development program, which also includes late-stage studies in Alzheimer’s disease.

Novel Brain Cortisol Inhibitor Targets Depression Through a Different Mechanism

Xanamem is an investigational, once-daily oral inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme responsible for generating cortisol within brain cells. Unlike conventional antidepressants, the drug reduces excess cortisol in key brain regions, including the hippocampus and frontal cortex, without affecting normal cortisol production by the adrenal glands.

Chronic elevation of brain cortisol has been linked to depression, cognitive dysfunction, and Alzheimer’s disease, making the pathway an attractive therapeutic target for multiple neuropsychiatric disorders.

Phase 2 Trial Demonstrated Significant Improvement in Depression Symptoms

The randomized, double-blind, placebo-controlled Phase 2a study (NCT05657691) enrolled 165 patients with clinically significant residual MDD and measurable cognitive impairment. Most participants continued their background antidepressant therapy during the six-week treatment period followed by four weeks of blinded follow-up.

The strongest antidepressant effect emerged at Week 10, when patients receiving Xanamem achieved a 2.7-point improvement on the Montgomery-Åsberg Depression Rating Scale (MADRS) compared with placebo (p < 0.05). Among participants receiving background selective serotonin reuptake inhibitors (SSRIs), representing approximately 46% of the study population, the treatment difference increased to 4.2 MADRS points (p < 0.05).

Investigators noted that the delayed clinical benefit was consistent with the expected timeline for reversing chronic cortisol-related effects.

Although the trial also evaluated cognitive outcomes, Xanamem did not improve cognition beyond placebo. Researchers observed unexpectedly large placebo-related improvements in cognitive measures and found no correlation between improvement in depression symptoms and cognitive performance.

The treatment was reported to be safe and well tolerated throughout the study.

Publication Supports Continued Development

Co-author Professor Michael Berk said the results demonstrate clinically meaningful antidepressant activity with the 10 mg daily dose currently being evaluated in Alzheimer’s disease. He added that the findings support the need for new therapies with novel mechanisms that can be combined safely with existing antidepressants for patients with difficult-to-treat depression.

Chief Medical Officer Dr. Dana Hilt noted that depression frequently affects patients with Alzheimer’s disease and suggested that Xanamem’s antidepressant activity could improve quality of life in that population. She also highlighted that psychiatric outcomes will be assessed in the company’s ongoing Alzheimer’s program.

Next Milestone Focuses on Alzheimer’s Disease

While additional MDD studies will depend on future funding and partnership opportunities, Actinogen’s immediate priority remains Alzheimer’s disease. The company’s pivotal XanaMIA Phase 2b/3 trial is evaluating Xanamem 10 mg in 247 patients with mild-to-moderate biomarker-confirmed Alzheimer’s disease, with topline results expected in November 2026. An ongoing open-label extension is also assessing the therapy’s longer-term safety and efficacy. Xanamem remains an investigational product and has not been approved by any regulatory authority.

Reference

Xanamem® (emestedastat) phase 2 depression proof-of-concept trial published in the British Journal of Psychiatry demonstrates meaningful anti-depressant activity in a difficult-to-treat population