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Friday, February 22, 2019 2:19:27 PM
2/22/19 Biostock
These links date back to some of the early knowledge ascertained about 2-73 and 3-71. This might account for the reason that 2-73 was brought along first by the company, which thought it was in its best interest. Additional preclinical tests on 3-71 and 1-41, have been done since these publications were released, but given the information at the time, the company had to choose (a biotech cant do preclinical exhaustively, if several compounds give signals of success. Neither time nor money permit.) As in sports, you must start your best player in each position at the time - if Peyton Manning and Tom Brady were both on your roster, would be a tough call. And someone would always say, “Why didn’t they start the other one first?”
Anavex PR dated March 2015:
https://www.anavex.com/anavex-presents-positive-results-for-both-anavex-2-73-and-anavex-3-71-in-alzheimers-models-at-2015-adpd-conference/
Parkinson’s News Today 4/2017
https://www.google.com/amp/s/parkinsonsnewstoday.com/2017/04/13/presentations-show-anavex-therapies-reverse-cognitive-deficits-in-mice/%3famp
Bottom lines:
A2-73 is a S1r agonist (weaker than 3-71) but mixed muscarinic agonist also. This led the company to postulate that the compound could work on many CNS diseases which are due to impaired mitochondria and clearing of Amyloid Beta simultaneously.
Early indications showed strong signals of efficacy repairing the dysfunction and restoring memory and cognition. Although A2-73 showed ability to reduce Amyloid and restore functioning of cognition, memory, learning, it does not mention any ability to reduce neurofibrillary tau tangoes.
Also, this compound showed the potential to combat several CNS diseases, not just dementias where tau tangles are involved.
Focusing on 2-73
From cite 1 above (2015):
“ANAVEX 2-73 strong reversal of memory impairment in Alzheimer’s disease model”
“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.”
Note: This focus is on Amyloid only.
“Additionally, positive preclinical data reveals the potential for ANAVEX 2-73 as a platform drug to treat additional CNS disorders, including epilepsy.”
Focusing on 3-71 Same source:
“ANAVEX 3-71 strong reversal of synaptic loss in Alzheimer’s disease models”
“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.”
Again, specificity 3-71:
“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.”
However, more potent:
“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.”
And, now we learn that taupathologies are spread through lack of sleep or sleep interruption which causes loss of synapses.
Maybe, aha!
“For those who are interested in AD pathology, the new issue of Science Magazine has interesting article on the role of sleep deprivation in the development of AD. (And no, , A2-73 as a sleeping pill is not going to solve the problem).
PERHAPS, 3-71 IS?
“Tau is predominantly a cytosolic neuronal protein with important physiological roles in maintaining the cytoskeleton and regulating axonal transport. In a family of neurodegenerative diseases called tauopathies (which includes AD), pathological forms of tau species develop that are hyperphosphorylated, aggregated, and arranged into filaments that form neurofibrillary tangles ( Display footnote number: 6 ). Tau aggregates spread through neural circuits in the brain, starting in the medial temporal lobe. The presence of pathological tau strongly correlates with synaptic loss, neuronal dysfunction, and the severity of cognitive or motor symptoms ( Display footnote number: 4, 6 ), so understanding how tau neuron depolarization or stimulation of excitatory synapses in vitro ( Display footnote number: 7 ) and in vivo ( Display footnote number: 8 ). Released tau can be measured in the ISF that surrounds neurons and connects the brain vasculature to neural networks.”
From BIOchecker4’s post #182613 Science Magazine article. Much thanks and respect for contributing a potential important piece of the puzzle for our pipeline.
Again, 3-71 shows strong reversal of synaptic loss in Alzheimer’s disease models. Also, decreases tau.
Further interesting note, I did not know this:
In 2016, 3-71 was granted FDA Orphan Drug Designation for treatment of Frontotemporal Dementia.
Note: the FDA designation runs for 7 years. Anavex will need to use this advantage within the next 3-4 years.
https://www.anavex.com/u-s-fda-grants-orphan-drug-designation-to-anavex-3-71-for-the-treatment-of-frontotemporal-dementia/
Additionally, from cite 2 above Parkinson’s News 4/17:
Dr. Helene Hall, Professor at McGill:
“Anavex 3-71 also decreased the accumulation of amyloid beta protein and reversed cognitive deficits in mice with Alzheimer’s. The reversal occurred despite the mice having an advanced stage of the disease. [Bold, underline]
Same source:
Importantly, the results held after the body eliminated Anavex 3-71, a finding that appears to strengthen its therapeutic potential.” [Bold, underline]
Back to me. My commentary: It appears 3-71 is much more potent than 2-73, but is more specific to dementias which is smaller market.
Perhaps this would answer some questions as to why A2-73 was brought out earlier. (Potential size of indications) Note to BaltimoreBullet, if reading.
This research was done in 2017. Until then, we didn’t know what we didn’t know...which was Peyton Manning and which was Tom Brady, but both very good. I speculate we went with potential market size - it’s tough to beat Manning and those Nationwide commercials, for large endorsement dollars.../joke
Additionally, was VERY good news to hear that 3-71 showed reversal even in more severe cases of AD, and approached from the synaptic loss, and was able to combat tau. All this even in small doses.
Perhaps, a 2-73, 3-71 combo someday will prove as formidable as Manning/Brady roster?
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