Background

Xanamem is an inhibitor of 11β-hydroxysteroid dehydrogenase type 1, an enzyme in the hypothalamic-pituitary-adrenal (HPA) axis of the body's stress response. 11β-HSD1 converts the stress hormone cortisol to its active form, which binds to glucocorticoid receptors. 

A growing body of evidence has begun linking a chronically active stress response, particularly the HPA axis, to amyloid plaque and neurofibrillary pathology deposition in mouse models of Alzheimer’s disease (Dec 2011 conference news). More recently, six-year longitudinal data of the AIBL natural history study was reported to show faster cognitive decline in amyloid-positive participants whose plasma corticol levels were elevated (Pietrzak et al., 2017). 11β-HSD1 acts peripherally and centrally, and has become a drug target (Martocchia et al., 2011).

UE 2343 was originally developed by Corticrine, a venture of the University of Edinburgh; in November 2014 Corticrine was acquired by the Australian biotech company Actinogen Medical. 

Another HSD1 inhibitor, Abbvie's ABT-384, was evaluated in Phase 2 in mild to moderate Alzheimer's disease, where it inhibited the enzyme and reduced cortisol levels in the brain, but did not improve cognition.

Findings

In 2013, a Phase 1 study conducted in 48 healthy volunteers in Scotland evaluated the safety, blood exposure, and pharmacokinetic parameters of UE 2343 administered as oral capsules.

In 2015, a second Phase 1 trial in 40 healthy volunteers in Western Australia evaluated 10, 20, or 35 mg doses given twice daily for nine days in a crossover design. Outcome measures were safety and tolerability, plus a detailed set of blood and urine pharmacokinetic measures. The trial listing includes no CSF measures in its outcomes, but mentions a blood-brain barrier measure as part of a protocol amendment. In September 2015, Actinogen Medical announced that lumbar punctures after treatment day five had shown Xanamem crossed the blood-brain barrier "in concentrations that are predicted to very effectively inhibit the 11β-HSD1 enzyme in the brain." Phase 1 results were subsequently published (Webster et al., 2017).

In March 2016, Actinogen listed a Phase 2 trial that was to enroll 200 people with a clinical diagnosis of mild Alzheimer's disease. To ascertain the diagnosis, participants had to have declined over the six months prior to screening and have an MRI scan consistent with AD, but no amyloid-based biomarker was required. The original study protocol compared a 12-week course of 35 mg twice daily with placebo for change in the ADAS-COG14 and AD Composite Score. ADCOMs is a new measure for mild AD that combines elements from the ADAS-Cog v14, Clinical Dementia Rating Scale-Sum of Boxes (CDR-SOB), and Mini-Mental Status Examination (MMSE). Secondary outcomes included the Rey Auditory Verbal Learning Test (RAVLT), CDR-SOB, Mini-Mental Status Examination (MMSE), Neuropsychiatric Inventory (NPI), and Neuropsychological Test Batteries-Executive Domain. The trial also used 14 voluntary outcomes spanning markers of safety, metabolic function, pharmacodynamic changes in blood cortisol, hormones related to cortisol, and drug exposure in the blood. Before enrollment began, the drug dose was lowered to 10 mg once daily. The trial began recruiting in March 2017, at 25 sites in Australia, the U.S., and the U.K.

In May 2019, Actinogen announced the trial had failed to meet either of the primary endpoints. Xanamem was well-tolerated, with no safety concerns. Actinogen presented no data on cortisol levels, but showed changes in cortisol-related hormones in the expected directions in the treatment group. Results were subsequently posted on clinicaltrials.gov. In October 2022, Actinogen offered a new analysis of the trial data, claiming that a subset of participants with high plasma ptau181 showed less decline in the CDR-SB after 12 weeks treatment compared to placebo (company presentation). 

January 2019 saw the start of a new, higher-dose safety study of Xanamem in 84 healthy volunteers age 50 to 75. In this single-center Phase 1 study, 30 people were to take 20 mg and 12 placebo once daily for 12 weeks. Pending results, a dose escalation committee would decide whether to start 42 additional participants on 30 mg once daily or placebo. The study monitors participants for changes in blood and liver markers, ECG, signs of peripheral neuropathy, and suicide risk. Secondary measures include changes in cognitive performance on the CogState battery and serum cortisol.

On September 30, 2019, Actinogen announced completion of the trial’s 20 mg portion. Treatment was associated with a benefit in two of the six tests making up the CogState battery (see press release). Besides statistically significant changes in working memory (p<0.01) and visual attention (p=0.05), Actinogen reported a trend toward improvement in reaction speed (p=0.09), but no effect on three other domains. Treatment resulted in a significant reduction in serum cortisol, without serious adverse events.

A target occupancy study using an 11b-HSD1-specific PET tracer indicated maximum target occupancy was achieved at the 20 mg dose, and the company decided not to proceed with the 30 mg dose (Apr 2020 conference news).

In June 2021, a Phase 1/2 short-term efficacy trial began testing 5 and 10 mg daily against placebo in 107 healthy volunteers. The primary outcome was change on a modified Cogstate battery, and safety, after six weeks of treatment. The trial, at five sites in Australia, finished in February 2022. According to a June 2023 company presentation, the combined 5 and 10 mg groups improved on an attention composite at weeks 4 and 6, but not at week 10 (slides),

In November 2022, the company began a Phase 2 study testing six weeks of 10 mg daily to improve cognition in people with major depressive disorder and cognitive impairment.

In November 2023, Actinogen Medical registered a Phase 2b trial of a 36-week course of 10 mg Xanamem or placebo in 220 people with mild to moderate Alzheimer's dementia. Three primary outcomes include a custom global cognitive test battery and safety measures. Eleven secondary outcomes include seven clinical/cognitive/psychiatric measures such as the CDR-SB and the Amsterdam Instrumental Activities of Daily Living, plus blood biomarkers and participant/care partner global impressions. To be conducted at nine sites across Australia, the trial had not yet begun recruiting as of January 3, 2024. 

For all trials of Xanamem, see clinicaltrials.gov.