Therapeutics

XanamemTM

Overview

Name: XanamemTM
Synonyms: UE 2343
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Actinogen Medical

Background

XanamemTM 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 HSD-1 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 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" (see company press release). 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 past six months prior to screening and 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 to 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 Rey Auditory Verbal Learning Test (RAVLT), CDR-SOB, Mini-Mental Status Examination (MMSE), Neuropsychiatric Inventory (NPI), and Neuropsychological Test Batteries- Executive Domain. They 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 (press release). 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.

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 October 1, 2019, Actinogen announced completion of the trial’s 20 mg portion. Treatment was associated with a beneft in two of the six tests making up the CogState battery (see press release and slides). 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.
As of the announcement, the company had not decided whether to go ahead with the 30 mg dose.

For all trials of Xanamem, see clinicaltrials.gov.

Last Updated: 29 Nov 2019

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References

News Citations

  1. Stress and AD: Does One Beget the Other?

Therapeutics Citations

  1. ABT-384

Paper Citations

  1. . Selection and early clinical evaluation of the brain-penetrant 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor UE2343 (Xanamem™). Br J Pharmacol. 2017 Mar;174(5):396-408. Epub 2017 Jan 25 PubMed.
  2. . Plasma Cortisol, Brain Amyloid-β, and Cognitive Decline in Preclinical Alzheimer's Disease: A 6-Year Prospective Cohort Study. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Jan;2(1):45-52. Epub 2016 Sep 7 PubMed.
  3. . Pharmacological strategies against glucocorticoid-mediated brain damage during chronic disorders. Recent Pat CNS Drug Discov. 2011 Sep 1;6(3):196-204. PubMed.

External Citations

  1. company press release
  2. press release
  3. press release and slides
  4. clinicaltrials.gov
  5. Actinogen Medical

Further Reading

Papers

  1. . Cognitive and Disease-Modifying Effects of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition in Male Tg2576 Mice, a Model of Alzheimer's Disease. Endocrinology. 2015 Dec;156(12):4592-603. Epub 2015 Aug 25 PubMed.