Xanamem is an investigational therapy for Alzheimer’s disease that’s being developed by Actinogen Medical. The treatment, previously known as UE2343, was originally developed by Corticrine, a subsidiary venture of the University of Edinburgh. Actinogen acquired Corticrine in 2014.

How Xanamem works

Xanamem is designed to reduce levels of the steroid hormone cortisol in the brain. It does this by blocking an enzyme called 11-beta‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1), which converts inactive cortisone to cortisol, the active hormone.

Cortisol is produced by the adrenal glands and is involved in a variety of functions such as metabolism and blood pressure. Cortisol levels fluctuate throughout the day and increase in response to stress.

A growing number of studies suggest a link between increased cortisol levels and Alzheimer’s disease.

For example, the Baltimore longitudinal study of aging found that increased cortisol levels in urine were associated with an increased risk for developing Alzheimer’s disease.

The Australian imaging, biomarker & lifestyle flagship study of aging tracked 416 older adults with normal cognitive function for six years, looking at their blood cortisol levels, cognitive ability, and levels of beta-amyloid, a protein that forms plaques in the brains of Alzheimer’s disease patients. Study participants with accumulations of beta-amyloid in their brains had a greater cognitive decline if their cortisol levels were elevated, the researchers reported.

In mice models of Alzheimer’s disease, treatment of the animals with a chemical that acts similarly to Xanamem — by inhibiting the 11β‐HSD1 enzyme — prevented cognitive decline.

Xanamem in clinical trials

The University of Edinburgh completed a Phase 1 clinical trial of Xanamem (NCT01770886) in 2013. The trial enrolled 48 healthy volunteers who took Xanamem in capsule form, or a placebo. The researchers assessed the safety of Xanamem and how it moves and is processed in the body.

A second Phase 1 trial (NCT02616445) was sponsored by Actinogen in 2015. Forty healthy volunteers were administered increasing doses of Xanamem or a placebo. The researchers monitored the safety and tolerability of the treatment, as well as how it moves and is processed in the body. Blood and urine levels of cortisol were also measured.

Both Phase 1 trials showed that Xanamem was safe and well-tolerated, and helped to inhibit the 11β-HSD1 enzyme and reduce the production of cortisol in the brain.

Subsequently, Actinogen sponsored a Phase 2 clinical trial (NCT02727699) to evaluate the safety, tolerability, and effectiveness of Xanamem in patients with mild Alzheimer’s disease. The trial, which the company is calling XanADu, enrolled 186 people at 25 sites in the U.S., Australia, and the U.K. Participants took a capsule containing 10 mg of Xanamem or a placebo once a day for 12 weeks. Scores on cognitive tests were measured.

Initial results from the XanADu trial were released in May 2019, which showed that although Xanamem treatment was safe at this dose, it did not lead to statistically significant improvements in cognitive decline compared with a placebo. The researchers at Actinogen think that higher doses and a longer treatment period could yield positive results.

Actinogen is currently recruiting 84 healthy volunteers, 50 to 75 years old, for a Phase 1 clinical trial (NCT03830762) to test the safety and tolerability of higher doses of Xanamem. The participants will be divided into two groups. Those in the first group will be further divided to either receive 20 mg doses of Xanamem or a placebo. If the results are positive, the safety and tolerability of 30 mg of Xanamem compared with a placebo will be evaluated in the second group of participants originally recruited for the trial. The estimated completion date of the study is December 2019.

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