Targeting Brain Cortisol: Xanamem Shows Promise in Depression and Alzheimer Disease

A novel approach to modulating brain cortisol levels is showing clinical potential in both major depressive disorder (MDD) and Alzheimer disease, according to Dana Hilt, MD, PhD, Chief Medical Officer at Actinogen Medical. Hilt shared details of the company’s recent clinical findings in an interview with Psychiatric Times ahead of his presentation at the 2025 American Psychiatric Association Annual Meeting in Los Angeles.¹

Xanamem (emestedastat), Actinogen’s lead investigational drug, is a selective inhibitor of 11β-HSD1 (hydroxysteroid dehydrogenase type 1), an enzyme that facilitates cortisol synthesis in the brain.² “This drug inhibits the synthesis of cortisol in the brain, [but] does not affect the level of cortisol systemically,” Hilt explained. This selective targeting allows the body’s systemic stress response to remain intact while addressing the elevated brain cortisol implicated in neuropsychiatric conditions.

“There’s a large literature suggesting that elevation in brain cortisol can be detrimental to patients with a variety of neuropsychiatric conditions, including Alzheimer disease and major depressive disorder,” Hilt told Psychiatric Times.

In a recent trial, Actinogen investigated Xanamem in patients with residual depression who after at least 6 weeks of treatment with an antidepressant medication, Hilt explained. Most patients remained on background SSRI or SNRI therapy during the trial.

Participants, who had Hamilton Depression Rating Scale (HAM-D) scores of 17 or higher as well as demonstrated cognitive impairment, were randomized to placebo or 10 mg of Xanamem daily for 6 weeks, followed by a 4-week blinded observation period. “At the end of 10 weeks, there was a statistically significant separation with the treated patients doing better as compared to the placebo,” Hilt told Psychiatric Times. Improvements were also seen in global impression scores, both from the patients and the clinicians perspectives.

“The result, coupled with the initial result that we had in the first Alzheimer disease trial, suggests that modulating and decreasing brain cortisol in patients can have beneficial effects,” he added.

The study included about 180 patients, and the results are currently being prepared for publication, Hilt said in the interview.

Because the results of the studies are promising, Actinogen are looking ahead to additional studies, with one already underway for Alzheimer disease. The current data was presented in a poster at the APA annual meeting in Los Angeles, California.

Dr Hilt discusses the future of psychiatric treatment for depression and other illness in part 2 of this series.

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References

1.Hilt D, Berk M. Xanamem a selective 11β HSD1 inhibitor has positive effects on depression in a phase 2 trial of moderate major depressive disorder. Presented at the 2025 American Psychiatric Association Annual Meeting; May 17-21, 2025; Los Angeles, California.

2. Actinogen. Cognitive Impairment in Major Depressive Disorder. Accessed May 16, 2025. https://actinogen.com.au/major-depressive-disorder/