Actinogen Medical’s Xanamem Shows Antidepressant Promise in Tough Depression Trial

Xanamem Shows Antidepressant Effect in Challenging Patient Group

Actinogen Medical (ASX:ACW) has published results from its phase 2 proof-of-concept trial of Xanamem (emestedastat) in major depressive disorder (MDD) with cognitive impairment in the British Journal of Psychiatry. The trial enrolled 165 participants characterised as having difficult-to-treat depression, many of whom were already on other antidepressants such as SSRIs.

The headline finding was a statistically significant antidepressant effect, with the greatest improvement in Montgomery-Asberg Depression Rating Scale (MADRS) scores emerging at week 10; two months after the six-week treatment period ended. This delayed onset aligns with Xanamem’s mechanism targeting chronic cortisol-related effects, which take time to reverse. The antidepressant benefit was 2.7 MADRS points overall and more pronounced (4.2 points) in patients on background SSRI medication.

No Cognitive Benefit Despite Trial Design Focus

Despite the trial’s unique design to simultaneously assess cognitive impairment and depression, the study found no evidence that Xanamem improved cognition beyond placebo. Interestingly, cognitive improvements observed did not correlate with improvements in depressive symptoms, challenging assumptions that these domains improve in tandem. This nuance highlights the complexity of treating MDD with cognitive impairment.

Xanamem was well tolerated with a favourable safety profile, consistent with previous trials. The drug’s novel approach inhibits the brain enzyme 11β-HSD1 to reduce cortisol synthesis locally without affecting systemic cortisol, a pathway implicated in both depression and Alzheimer’s disease.

Implications for Alzheimer’s and Future Development

Professor Michael Berk, co-author and academic psychiatrist, emphasised the significance of these findings for Xanamem’s broader clinical development. The antidepressant signal in a difficult-to-treat population supports further investigation, although future trials will depend on funding and partnership arrangements. The company is concurrently running the pivotal XanaMIA Phase 2b/3 Alzheimer’s disease trial, with topline results due November 2026, assessing Xanamem’s ability to slow disease progression and improve psychiatric symptoms.

Dr Dana Hilt, Actinogen’s Chief Medical Officer, noted that depressive symptoms are common in Alzheimer’s patients, so Xanamem’s antidepressant activity could enhance quality of life in this population. The ongoing Alzheimer’s trial includes psychiatric symptom evaluation, potentially broadening the drug’s therapeutic profile.

Positioning Xanamem in a Competitive Landscape

The trial’s positive antidepressant results add a new dimension to Xanamem’s profile amid a crowded neuropsychiatric therapeutics market. By targeting cortisol dysregulation; a mechanism distinct from traditional antidepressants; Xanamem could address unmet needs in treatment-resistant depression and cognitive impairment. However, the modest effect size and lack of cognitive benefit underscore the challenges ahead.

With the pivotal Alzheimer’s trial and open-label extension underway, Actinogen’s next major catalyst will come in November 2026. The company’s ability to secure partnerships and funding will be critical to advancing Xanamem’s development, especially given the need for larger confirmatory trials in depression.