Anavex 2-73 targets protein misfolding and oxidative stress by binding to a protein called sigma-1. Recent clinical trials have indicated that the treatment may slow cognitive decline in patients with mild-to-moderate Alzheimer’s disease.
What is Alzheimer’s disease?
Alzheimer’s disease is a progressive neurodegenerative disorder. As the disease progresses, nerve cells in the brain start to die. The cause of cellular death is not known, but there are theories based on the presence of tau tangles and amyloid plaques in patients’ brains.
Tau is a protein that normally helps nutrients move throughout the brain. In Alzheimer’s disease, the normal structure of tau is disrupted, and tangles of protein are formed. These tangles may interfere with the function of the protein and prevent nutrient transport in the brain, causing cell death.
Amyloid plaques are protein clumps made up of fragments of a protein called beta-amyloid. These clumps may interfere with communication between brain cells, causing cell death.
How does Anavex 2-73 work?
Anavex 2-73 is a small molecule that activates the sigma-1 receptor, which is known to modulate cellular processes relevant to neurodegeneration. Specifically, Anavex 2-73 is thought to help restore cellular balance by targeting protein misfolding (when proteins fail to fold correctly, into a normal configuration, they do not work as intended), oxidative stress (which damages cells due oxygen molecules with free radicals, or unpaired electrons), mitochondrial dysfunction, inflammation, and cellular stress.
The sigma-1 receptor is a small transmembrane protein, a stress-reducing survival protein, mainly located on the endoplasmic reticulum membrane of cells. This receptor also is present on the surface of some nerve cells and multiple other central nervous system cells and tissues. As sigma-1 receptors are present in various sites, different physiological and pathological processes may be influenced by Anavex 2-73 treatment.
The brain of a person with Alzheimer’s disease has fewer sigma-1 receptors than that of healthy people of the same age. That’s why the activation of these receptors could improve the clinical symptoms of the disease and protect against neurologic changes.
Anavex 2-73 in clinical trials
A Phase 1 clinical trial assessing the safety and pharmacokinetics (movement in the body) of Anavex 2-73 was successfully completed in healthy men in Germany. The maximum tolerated dose of the drug was determined to be 55 mg.
A Phase 2 study (NCT02244541) enrolled 32 participants with mild-to-moderate Alzheimer’s disease and consisted of two parts. Part A, a five-week study, assessed the safety, tolerability, and maximum tolerated dose of the treatment; part B, a 26-week open-label extension, investigated the continued safety and tolerability of Anavex 2-73, exploring a dose-effect relationship.
The results showed a favorable safety profile for Anavex 2-73, which was important for further studies. The most common adverse side effects were minor, such as dizziness and or headache, and most were resolved. The researchers noted that “unexpected” therapeutic responses also were seen, including improved alertness and mood, and better engagement with family and friends.
A 104-week, open-label extension study (NCT02756858), which enrolled participants with mild-to-moderate Alzheimer’s disease who had taken part in the previous trial, evaluated long-term safety of Anavex 2-73. A total of 21 patients were evaluated over three years. Patients’ cognitive function was assessed using the mini-mental state examination (MMSE) while functional changes were measured using the Alzheimer’s disease cooperative study-activities of daily living (ADCS-ADL), a test that assesses the competence of Alzheimer’s disease patients in daily living activities.
The results of the study showed a significant association between the dosage of Anavex 2-73 and cognitive and function improvements. Anavex was safe and well-tolerated throughout the study.
An ongoing Phase 2b/3 (NCT03790709) is evaluating two doses of Anavex 2-73, 30 mg or 50 capsules taken once daily, against a placebo capsule in 450 adults, ages 60 to 85, with mild-to-moderate Alzheimer’s disease. Its primary goals are measures of changes in cognitive abilities on the Alzheimer Disease Assessment Scale-Cognition scale (an 11-item measure of memory and language skills) and in daily life activities using the ADCS-ADL after 48 weeks of treatment. Treatment safety and changes in sleep are among other trial goals.
An independent trial monitoring board found acceptable safety with Anavex 2-73’s use by enrolled patients in April 2021, recommending the study continue as planned at sites in Australia, Canada, Germany, the Netherlands, and the U.K.
Patients who complete this Phase 2b/3 trial will have the opportunity to enroll in ATTENTION-AD (NCT04314934), an open-label extension study in which all will be treated with Anavex 2-73 for two years. Treatment safety with long-term use is its primary goal; changes at 96 weeks in cognitive skills and daily life activities will also be assessed.
Last updated: June 30, 2021
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