Three Quotations From Wikipedia On Rett Syndrome And Their Implications For ANAVEX 2-73. $AVXL

I would like to present 3 quotations fro the page on Rhett Syndrome. Let’s first tackle the big picture. https://en.wikipedia.org/wiki/Rett_syndrome

It has been argued that Rett syndrome is in fact a neurodevelopmental condition as opposed to a neurodegenerative condition. One piece of evidence for this is that mice with induced Rett Syndrome show no neuronal death, and some studies have suggested that their phenotypes can be partially rescued by adding functional MECP2 gene back when they are adults. This information has also helped lead to further studies aiming to treat the disorder.[21]

The distinction here is of primary importance. Alzheimer’s or Parkinson’s are connected to death of neurons which in their final run is undeniable. Nevertheless, the development of brain is connected in some respects with program death of neurons, apoptosis, or called pruning and growth of connections, dendrites. The observation of partial rescue in case of introducing the wild form of MECP2 gene (unmutated) is congruent with this model of development of brain as you cannot retrace the brain development and its structural changes in the brain but you can rescue the function of individual neurons. What one can gather from this is that Rett is ideally suited to be treated with gene therapy at the onset from 6 months on, or even earlier if the mutation can be detected by a test. The most striking implication for ANAVEX 2-73 Blarcamesine that it works by altering the brain wide concentration of basics neurotransmitters like Glutamate and GABA. Both of these are involved in about 90% of all synaptic connections in brain. Excessive amounts of Glutamate are connected to Lou Gehrig disease (ALS), Alzheimer’s and seizures, among others. I think that both Glutamate and GABA are two neurotransmitters concentration to the easiest to measure currently without autopsy. This is the 30,000 feet view of the disease. Yet, it is very valuable since it measures the global disruption to normal function of most of the synaptic connection and its improvement alike measures homeostatic equilibrium moving in the desired direction. Nevertheless, researchers try to pin point the exact epicenter of the disruption cause by the genetic mutation in MECP2.

Researchers have concluded that “Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett syndrome, such as respiration and cognition, we hypothesize that the locus coeruleus is a critical site at which loss of MECP2 results in CNS dysfunction.” The restoration of normal locus coeruleus function may therefore be of potential therapeutic value in the treatment of Rett syndrome.[29][30]

I do not have much to comment as I can only touch on matter of concepts and this goes into deatails which make a web of links between multitude of findings, papers and molecules. I will repeat that SIGMAR1R is connected in broad sense with homeostasis, and in more deatil to synthesis and “quality control” of proteins, synaptic potential and oxidative stress. Blarcamesine can not replace the completeness of gene therapy, but can alter the broad chemistry of the patients brains. This is indeed an amazing feat for an CNS drug in genetic disease. I am tempted to venture here into the unknow sea to me. I have checked what locus coeruleus is. It is located in lower brain and tied to reaction to stress and panic itself. If it can somehow deregulate Glutamate and GABA, it would be driving brain to “overexitation”, as if in biochemical equivalent of state of panic, stress, overpowering the inhibiting mechanism on synaptic level. That might not be true (!), but to my layperson mind it makes a good description of the gist of that quatation. Is the Blarcamesine working on Glutamate or GABA “level” directly or if I can venture, on the level of locus coeruleus, or somewhere in betweeen? A 64 billion dollar question?

RTT pathology, in some aspects, overlaps the motor phenotype observed in PD patients.[39][40][41] Several neuropathological studies on postmortem brain samples argued for an SNpc alteration evidenced by neuromelanin hypopigmentation, reduction in the structure area, and even controversial, signs of apoptosis. In parallel, an hypometabolism was underlined by a reduction of several catecholamines (dopamine, noradrenaline, adrenaline) and their principal metabolic by-products.[26] Mouse models of RTT are available and the most studied are constitutively deleted Mecp2 mice developed by Adrian Bird or Rudolf Jaenisch laboratories.[42][43][44][45]

The only part I can digest here, is that the autopsies point to similar effects on neurons on cellular in Rett and Parkinson’s. In light of recent release of trial for ANAVEX 2-73 in Parkinson’s Phase2 the quatotation increases hopes for substential theurapetic effect in Rett patients.

In the above discussion I concentrated on the neurotrasmmitters and not the measures of patients progress in behavior. For care givers and parents these are a Godsent, but on my level would require thourogh understading of the symptoms. That is a domain of pratictioners in medicine and not blogers who never interacted with a stricken child or parents so I limit my entry to neutrasmitters.

George, I think you wanted me to write somthing about Rett, so here it is.

Also, thanks to Joseph f. for a donation, it is duly appreciated. All the best to you! Thank you.

One-Time
Monthly
Yearly

Make a one-time donation

Make a monthly donation

Make a yearly donation

Choose an amount

$5.00
$15.00
$100.00
$5.00
$15.00
$100.00
$5.00
$15.00
$100.00

Or enter a custom amount

$
——

Your contribution is appreciated.

Your contribution is appreciated.

Your contribution is appreciated.

15th of October 2020…comes another confirmation of blockbuster status of blarcamesine Anavex 2-73. $AVXL

Every investor and his aunty fret over the company not releasing yet the statistical data or “raw data” from PDD (Parkinson’s Disease Dementia) phase 2 Clinical trial. From what the Dr. Missling said even the cohort with 30mg dose responded and that all the targets have been achieved with statistical significance. The last two words require some explanation or rather some discussion. The threshold for statistical significance is the power of study threshold <= .05, that means there is only 5% or less chance that the results are a fluke.

I am not a statistician, but I was taught to think in terms of the smallest sample size for a large population. The number cited was 30 specimen. The PDD Phase 2 had cohorts of roughly 44 patients. I think the reason was twofold, on one hand the savings for the company on the cost of trial, usually about $10-30,000 per subject, and the other was that the there were expectation of strong signal so small cohort would not obscure the efficacy. The rather shocking truth is that $AVXL can not afford a drug with low efficacy and 1000’s of patients to justify approval. Biogen in point. $BIIB

The goal of a statistician is to detect signal, useful information in the sea of random change. That is why we have a placebo cohort to measure the noise. In medical practice outcomes are subject to variation and this creates a background noise against which one has to detect the signal in the cohorts receiving the drug. The larger the sampling population the more clearly the noise and the signal converge to their mean so there is less ambiguity in distinguishing one from another. Converging to the mean implies that with larger sample size approval is more likely even if the therapeutic signal is of lesser strength. On a very superficial level, you get a number with standard deviation, the mean and the spread around the mean. The ultimate goal is to separate the mean so much that standard deviations don’t overlap, and you have a clear signal. People cheering thousands of subjects in trial miss the point. It should rather be a sign that likely the drug is barely to make it through the trial, as it crafting the trial to the drug and not the drug to the trial.

The Phase 2a of Alzheimer’s did achieved statistical significance in few measurements, if my memory serves me well, PDD Phase2 even at this small sample size reached all targets, i.e., all measurements showed presence of a signal of the required strength for approval. Had the sample rate in AD (Alzheimer’s) Phase2a been ~44 patients per cohort the same could have been expected? Time again we, the longs, have another signal that efficacy is strong and undeniable. The periods of time between the old guard AD or PDD drugs and $AVXL drugs proves that SIGMAR1 receptor drug did open a new vistas in CNS therapeutics.

It seems that the projections in my blog were not entirely wishful thinking or extrapolations on unrealistic assumptions, but one of possible outcomes to which the reality of Blarcamesine clinical trials results seems to converge.

But as they say in the world of investing better to be stupid and lucky than wise and wrong.

I would like to thank you guys for all the views, this makes me feel great and useful. If you find this blog useful could you give me a small donation to cover the cost of at least the account with WordPress? Thank you!

Also if you can fill the poll at the end of page I would appreciate.

One-Time
Monthly
Yearly

Make a one-time donation

Make a monthly donation

Make a yearly donation

Choose an amount

$5.00
$15.00
$100.00
$5.00
$15.00
$100.00
$5.00
$15.00
$100.00

Or enter a custom amount

$
——

Your contribution is appreciated.

Your contribution is appreciated.

Your contribution is appreciated.