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
XanamemTM is an inhibitor of 11β-hydroxysteroid dehydrogenase, 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 (see Dec 2011 news series). 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., 2016). 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; Corticrine in November 2014 was acquired by the Australian biotech company Actinogen Medical.
In 2013, a Phase 1 study conducted in 48 healthy volunteers in Scotland evaluated safety, as well as blood exposure and pharmacokinetic parameters, of UE 2343 administered as oral capsules.
In 2015, a second Phase 1 trial in 40 healthy volunteers conducted in Western Australia evaluated 10, 20, or 35 mg of UE 2343 given twice daily for nine days in a crossover design. Outcome measures were safety and tolerability, plus a more 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 done as part of a protocol amendment. In September 2015, Actinogen Medical announced that lumbar punctures performed after treatment day 5 had shown Xanamem to cross the blood-brain barrier "in concentrations that are predicted to very effectively inhibit the 11beta-HSD1 enzyme in the brain" (see company press release).
In March 2016, Actinogen listed a Phase 2 trial in what is to be 200 people with a clinical diagnosis of mild Alzheimer's disease. To ascertain the diagnosis, participants must have an MRI scan consistent with AD, and have declined over the past six months prior to screening. No amyloid-based biomarker is required for this trial. The study compares a 12-week course of the 35 mg twice-daily dose to placebo for its effect on change in the AD Composite Score. ADCOMs is a new measure for mild AD that combines data from the Alzheimer's Disease Assessment Scales-Cognitive subscale version 14 (ADAS-Cog v14), the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SOB), and the Mini-Mental Status Examination (MMSE). Secondary outcomes include Rey Auditory Verbal Learning Test (RAVLT), the (CDR-SOB), the Mini-Mental Status Examination (MMSE), the Neuropsychiatric Inventory (NPI), and the Neuropsychological Test Batteries- Executive Domain. In addition, the trial features 18 voluntary outcomes spanning markers of safety, metabolic function, pharmacodynamic changes in hormones relates to cortisol, drug exposure in the blood and CSF, and CSF Aβ and tau levels. As of November 2016, this trial had not yet begun recruiting.
For all trials of Xanamem, see clinicaltrials.gov.
- Pietrzak RH, Laws SM, Lim YY, Bender SJ, Porter T, Doecke J, Ames D, Fowler C, Masters CL, Milicic L, Rainey-Smith S, Villemagne VL, Rowe CC, Martins RN, Maruff P. Plasma Cortisol, Brain Amyloid-β, and Cognitive Decline in Preclinical Alzheimer’s Disease: A 6-Year Prospective Cohort Study. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging , Volume 0 , Issue 0 ,
- Martocchia A, Curto M, Toussan L, Stefanelli M, Falaschi P. Pharmacological strategies against glucocorticoid-mediated brain damage during chronic disorders. Recent Pat CNS Drug Discov. 2011 Sep 1;6(3):196-204. PubMed.
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