Anavex Life Sciences Corp., a clinical-stage biopharmaceutical company developing drug candidates to treat Alzheimer's and other central nervous system (CNS) diseases, pain and various types of cancer, has unveiled new promising preclinical data for both ANAVEX 2-73 and ANAVEX 3-71 (formerly AF710B) in two separate presentations at the 12th International Conference on Alzheimer's and Parkinson's Diseases and Related Neurological Disorders in Nice, France.
In the first presentation Tangui Maurice, PhD, a member of the Anavex Scientific Advisory Board, demonstrated for the first time the essential role of sigma-1 receptor (S1R) through S1R KO (knock out) on survival and memory in the presence of amyloid. In the transgenic amyloid expressing mouse model Tg2576, where the sigma-1 receptor (S1R) expression is impaired through S1R KO (knock out), at 12 months the survival was reduced by 50% compared to the non-S1R KO Tg2576 model. Apparently the genetic inactivation of the S1R gene worsens amyloid toxicity and has a detrimental impact on survival and also memory impairment. Amyloid is believed to play a key role in the development of the symptoms of Alzheimer's disease (AD). On the other hand, activation of the S1R through treatment with the S1R agonist ANAVEX 2-73 in the Tg2576 model alleviates amyloid toxicity and resulting learning deficits both after one month and two months daily oral treatment, respectively. In addition expression of ROS (reactive oxidative species) as well as plasticity related IEG and transcription factors in the mouse hippocampus were clearly negatively impacted through the S1R KO, however, were significantly improved through ANAVEX 2-73. This confirms that targeting the S1R, a key factor in brain plasticity, may demonstrate neuroprotection in Alzheimer's disease. ANAVEX 2-73 is currently undergoing a Phase 2a trial in Alzheimer's patients.
In the second presentation Abraham Fisher, PhD, a member of the Anavex Scientific Advisory Board, demonstrated for the first time data showing that ANAVEX 3-71 rescued mushroom synaptic or spine loss in hippocampal neurons of wild type and two mouse models of AD. The effects of ANAVEX 3-71 appear specific since a pure M1 muscarinic agonist was less potent or not effective in the tested neuronal cultures, respectively.
Further evidence was provided that ANAVEX 3-71 reduced soluble and insoluble Abeta1-40, Abeta1-42 and Abeta plaques in the 3xTg-AD animal model as well as decreased BACE1 expression.
It was further demonstrated that ANAVEX 3-71 also decreased tau phospho-epitopes AT100, AT8 AT180, AT270, PHF-1 and decreased kinases inducing tau-hyperphosphorylation (p25/Cdk5 & GSK3beta) and mitigated cognitive impairments in the 3xTg-AD animal model. Cdk5 activator protein p25 preferentially binds and activates GSK3beta. Increased Cdk5/p25 expression has been demonstrated in the brains of patients with Alzheimer's and Parkinson's diseases and several other CNS diseases. Hence, ANAVEX 3-71 may restore synaptic homeostasis, by decreasing p25 and inhibiting GSK3beta & Cdk5.
It was further shown that ANAVEX 3-71 decreased the number of 6E10 positive Abeta1-42, activated astrocytes (GFAP) and microglia (Iba-1). The decrease in these inflammatory cell markers is likely a consequence of reduced Abeta in the brain, although any beneficial direct effect of the drug on inflammation might be possible.
It is believed that the effects of ANAVEX 3-71 are mediated by a concomitant activation of the M1 muscarinic receptor (M1R) and the S1R via an induced hypothetical heteromerization between M1R & S1R.
"With the newly presented data we are very encouraged to have ANAVEX 2-73 currently in the clinic and are looking forward to provide an update on the progress of the trial next quarter. The new drug ANAVEX 3-71 indicates extensive therapeutic advantages in Alzheimer's and other protein-aggregation-related diseases given its ability to enhance neuroprotection and cognition via sigma-1 receptor activation and M1 muscarinic allosteric modulation," said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex. "We look forward to advancing ANAVEX 3-71 further into the clinic after the required GLP manufacturing and toxicology studies."
ANAVEX 2-73 is currently undergoing a Phase 2a trial in Alzheimer's patients after completing a Phase 1 study with a clean data profile. In earlier preclinical studies, ANAVEX 2-73 showed potential to halt and/or reverse Alzheimer's disease. Additionally, positive preclinical data reveals the potential for ANAVEX 2-73 as a platform drug to treat additional CNS disorders, including epilepsy.
ANAVEX 3-71, previously AF710B, is a unique and promising preclinical drug candidate with a novel mechanism of action shown to enhance neuroprotection and cognition in Alzheimer's disease. It is a CNS-penetrable mono-therapy that bridges treatment of both cognitive impairments with disease modifications. ANAVEX 3-71 is highly effective in very small doses against the major Alzheimer's hallmarks in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies, and also has beneficial effects on inflammation and mitochondrial dysfunctions.
Both Drs. Maurice and Fisher are members of the Anavex Scientific Advisory Board.