$AVXL A Day in the Struggle…Against the World

Please, read first this posting from Charles Hugh Smith of Of Two Minds Blog  Blog Post.

If you have no doubts that the whole system with Big Pharma and FDA is in its current form the paragon of  honest capitalism, let me tell you that when you win these kinds of money certain things happen to  your brain reward center, it is just like being on cocaine.  Have you ever seen sharks congregating and getting into feeding frenzy – now there you go!

I remember when during Clinton times there was discussion ( disingenuous ) of the CEO compensation and finally a system was born where the named was connected to the price of the stock through mechanism of stock options.  The price can be manipulated by stock buybacks and accounting manuevers on paper. Then add the dose of lower capital gain taxes to spice up the lives of the corporate deciders. So was created system rewarding people for not honest work in capitalism risk-reward machine but flight on the edges of the envelope of law, accounting and credibility to bag windfall compensation as long as it lasts.  I guess the system never was the former ever but now there is no question of its moral hazard. I bet that that participants are aware that this opportunity can never happen twice.  Ethics of capitalism be damned!

The corner offices in Big Pharma have lived through all those manipulations and used them to the hilt. Now, they are exploring the final frontier that is rising the prices beyond the reasonable on the premiss that next compensation package must be ever greater.  The participants abandon all restraint and work towards its logical conclusion by exposing themselves as the ones only benefiting here. One can’t say any more that we get hell lot of a deal with these new drugs and that the costs of bringing it to market through the regulatory and funding maze is indeed staggering so that the exorbitant prices are justified.  They are in effect strip mining the system and hastening its demise.

Sorry to go off on a tangent, It is very hard to reform system where the old rewards are still left in place.  FDA is kind of very meticulous with ANAVEX 2-73.  I am very grateful to Australian Government for thinking along the lines of benefits to its people.  The change in emphasis again from Rett to Alzheimer tells us a lot.  The start of testing ANAVEX 2-73 on Parkinson’s in Europe seems to seal my conviction on the “unresolved issues with FDA”.

When I arrived in UIC in 1980 I spied the local student life with curiosity of a cat and noticed two kinds of books most prevalent on campus; Plato or Clausewitz.  The guys in liberal arts learned about possible existence of a better world whose corrupt version they were living now (Plato) but the business students learned about the “fog of war” where no plan survives for long and where dog eats dog. Will we soon see those two mindsets rioting in the streets since nowadays nobody wants to think or advance arguments for or against anything?

There is something admirable in Germans, and Dr Missling is the best German I know so for time being count your blessings. Ask me, he can keep his hair!

Your $10k Investment Since 1990 in Terms of Real Purchasing Power.

Methodology

We source real inflation from ShadowStats.com.  This measure keeps the methodology the same since 1980 and dispenses with all those great ways of obfuscation of the real thing.  Then we take series of multiplication to get the compounded rate of inflation since 1990 to target year.  Next is reading of monthly chart of SPX the dollar value of investment plus multiplication with compounded inflation and there you go.

 

image051.jpg

 

Through years.png

 

Purchasing Power since 1990.png

 

Isn’t it interesting? Is there purchasing power heaven?

 

$AVXL Inflammation as Cause of Ultimate Destruction in Alzheimer, and ANAVEX 2-73 as Close as it Gets to Cure at The Source of AD.

I have a rather preordained idea what inflammation is all about, and this comes from the multiple descriptions of suspected etiologies and connections with chronic diseases for which there is great, mostly unmet, need.  Being a creature of habit and digging only to the depth of buzzwords I will quote Wikipedia on inflammation:

Inflammation (from Latin: inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants,[1] and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.

The take away here is that inflammation is a response to irritants or harmful stimuli as well as infection.  In itself it should be precursor of healing but might be connected to harm as in chronic inflammation.  In some sense it is a general immune reaction aimed at making it hard to survive (by creating toxic environment?) by foreign organisms but if not wound down quickly enough leads to destruction of tissues.  Circumstantial evidence is piling up at an alarming rate. See Reference 1.

To just review the neuroinflammation as the process of destruction one would look for trigger for the “toxic environment” cascading into the telltale of Alzheimer disease as it is defined right now and reasons for not wounding down its apparent toxicity.

Reference 1: 

A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease

Joseph Park1,2,3,4,5, Isaac Wetzel1,2,3,4, Ian Marriott2,3, Didier Dréau2,3, Carla D’Avanzo5, Doo Yeon Kim 5*, Rudolph E. Tanzi 5* and Hansang Cho 1,2,3,4*

This paper describes devising model of Alzheimer disease including the inflammation process entailing destruction of the neurons by the CNS innate immune system.  The question of the trigger is not solved.  In previous models Aβ and Tau were alone the trigger in creating functional model of the disease.  These substances are toxic in themselves to mice brains and can bring about primary level effect by their toxicity alone.  For example in murine models plain injection of Aβ and Tau into brains sufficed to bring about Alzheimer like symptoms.  What the model does is to add inflammation by solicitation of astrocytes and microglia to the resultant outright destruction of neurons by them. In this respect the increased  complexity of the model lies in the addition of inflammation to it.

The process where inflammation is triggered by deposits of plaque and tau seems to be just a link in much longer cascade with yet unknown incipient physiological change in the brain of Alzheimer sufferers.

I just pulled from publication on ANAVEX 2-73 information on Tg2576 model performance ( male-female difference) and looked for description of the model on ALZFORUM website.  The model timeline indicates that changes in hippocampus and cognitive deficits predate in the model onset of detectable plaque and Tau deposits.  Some very basic process might be at play here, and it seems to be caused by the Swedish Mutation making mouse brain to produce plaque as the only known biomarker of Alzheimer. All up the stream effects, those creating deposits of plaque are unknown at this moment. Had this statement been false set of more efficacious therapeutic targets would have been selected long time ago.

The buzzword of “cellular stress” has been used by Dr Missling to describe the context in which one has to look at ANAVEX 2-73 and the evolutionary utility of SIGMAR1.  I am more prone to call it “an improved quality control” at the point of heightened protein synthesis at the site of endoplasmic reticulum where 50% of all protein are synthesized in cell.  The conditions to put the synthesis into higher gear might either be connected to embryonic state or innate immune response, or yet to increased plasticity of the brain which in lay terms is creating new neural connection hence more protein building material needed. The innate immune response can be inferred from reading of lists of certain reaction to infection by the innate immune system on its Wikipedia page. Could the ultimate trigger be genetic or epigenetic, slowly accumulated over time is not ascertained yet.

If the cascade resulting in Alzheimer disease, or rather syndrome (set of symptoms), starts with some problems with “cell stress” in basic processes like synthesis of protein (at the region exhibiting most plasticity in brain – hippocampus) (plasticity = synthesis of proteins?) and leads to Aβ and Tau deposits then straight into soliciting action of the innate immune system cells and triggering inflammatory response resulting in massive loss of  neurons at the later stages of the disease can be just stopped at the source of the cascade when dosed soon enough then shouldn’t we talk about cure?

Is the evidence mounting for a source of Alzheimer’s cure or is it not the case?  It seems that if given early enough ANAVEX 2-73 can stop or even reverse progress of the disease.  That much could be indicated from results of Phase 2a after 2 years.  The four patients who up to 2 years into trial consistently beat the disease progression can prove with time that this can be classified as such, yet for time being this is only a signal of efficacy, not statistically significant outcome. If one makes connection between this event and high initial MMSE score for those patients (just the onset of the disease) one can be inclined to believe that indeed ANAVEX 2-73 stops Alzheimer at the source before the plaque and Tau deposits formed sufficiently large to make the inflammation progress to wholesale destruction of neurons. Beyond that point there is no return.

I can’t write any more on this subject, kind of exhausted my thinking at this moment but I would gladly promote my Beer Fund.

 

 

Beer Fund

$1.00 is about one bottle so .....please contribute..

$1.00

$AVXL Something about Dropout Rate Phase 2a ANAVEX 2-73

I guess I am getting deep into weeds, I haven’t been smoking for decades if you wonder whether I had smoked something before writing this, but I got this idea to compare the dropout rate between Reference 1 and actual 2 years dropouts from Phase 2a.  Let me present a picture which shall say thousand words to you (because I can’t):

Dropout of Phase 2a File B .png

Let’s sketch the background first.  The green line is the normalized to 32 patients the number of patients still in the study, expected per Reference 1.  One can notice that the first year the retaining rate is .9375, all other years it is between .58 to .7, and the average of .66 excluding first year  If the average rate would hold sway from the beginning the black line would determine the retained patients count in the study.  Notice that it ends with the same participants at the six years mark.

At the mark of first year in ANAVEX 2-73 Phase 2a trial the 32 participants dwindled to 26 and at the time of KEM analysis (2 year mark) to 21.  This gives about .80 retaining rate over two periods, steady and consistent.  If we keep the rate of retention the same over additional periods we end up at the mark of 6 years with 9 patients versus 2 for Reference 1.

Seemingly, the difference between .66 and .80 retaining rate is rather small yet over few periods it accumulates.  Would that be another reason to break out in festivities over ANAVEX 2-73 superiority or just another exercise in massaging data which will be soon tested?

Extrapolating data is fun but real life might be rather “non-linear”.  The curve per Reference 1 suggests acceleration of  dropouts from one year on.  The dropout rate for ANAVEX 2-73 seems to be uncannily steady, albeit we have only two data points versus six to make such inference.  Nevertheless, many phenomena in natural sciences follow steady exponential decay.

If I read myself correctly I suggest that the dropout rate of Reference 1 might be skewed at the beginning study and then at the end basically outcome is converging to the same given by exponential decay curve.  How nice, it is to deconstruct your own personal intentions!  In the same vein ANAVEX 2-73 might not show this bias (at year one) and then again might have its own (further on) that is the therapeutics effect of ANAVEX 2-73 as it stabilizes dropout rates even at smaller than those in HIgh Concentration Cohort doses.

Next thing: Positions of constellations and planet and ANAVEX 2-73!

P.S.

I cannot recall which sex of 3xTg murine model mice performed better and also could not find anything on my computer so I turned to IR.  I hope I get the data for further speculation on the subject of neuroinflammation.

The Winning Combination for ANAVEX 2-73 and is it all about inflammation?

Sorry, I hasn’t been in condition to write anything but I think I am back at least for some time. Beside, I have tendency to miss certain things and home on others with the grace of single-minded heat seeking missile as I have explained myself before with all my problems.  I have just finished reading the transcripts from the Q2 2018 Conference Call.   There was a part which gave me the impression that my approach with slicing and dicing the ANAVEX 2-73 data was corroborated.  Namely, mention of the combination of  SIGMAR1 variant, COMT variant, above 20 MMSE and High Concentration of ANAVEX 2-73.  They were never put explicitly together in one paragraph and this is the killer application for Alzheimer suffers, at least at this moment.  In the High Concentration Cohort about 50% were responders, and other 50% declined faster rate than average so the only conclusion can be reached about this group is that there was something innate what made them decline faster.  Actually, we don’t know much about this group at all save that the five patients did not behave like average set of patients. But do we have a reason to expect it?  So my previous reasoning might be faulty. It leads nowhere.

The reasoning for SIGMAR1 seems straightforward as it is first object to be affected in a cascade triggered by ANAVEX 2-73.  COMT variants have something to do, at least as cognition is involved, with trade-off between attention and ability to perform under stress.  In some references there are hints of connections between mental stress and inflammation of CNS.

Beyond the existence of the plaque theory the most encompassing is the inflammation theory.  All other therapy targets look at isolated links in the chains of cause and effect, at least that is what it seems to me (lol).

Returning to inflammation, I looked at description of murine model of Alzheimer used by AVXL. it is called 3xTg. Its description can be found on ALZFORUM. Reference

3xTg Murine Model of AD.png

It seems to me that the cognitive impairment starts at 4 months but the Aβ plaque appears at 6 months earliest.  Would that genetic model engender inflammation which would later lead to Alzheimer?

I had received  communication from AVXL IR on the mouse model with plots for two opposing sexes of mice.  If I correctly remember the therapeutic effect was more pronounced in female mice.  ANAVEX 2-73 “cured” 3xTg mouse from the cognitive impairment placed on them by the model.  It seems that women are more prone to suffer from autoimmune diseases than men (immune reaction – inflammation to one’s own body).  Reference1   What differentiate men’s and women’s immune systems is the pregnancy where women’s bodies have to “accommodate” in their system a “foreign body”.   The paper I am going to reference here points to chronic neuroimflammation,  taking place in CNS with certain genetic markers, which leads to all those the bells and whistles of fully fledged Alzheimer disease.  Possibilities here are endless (exaggeration), but is the action of ANAVEX 2-73 alleviating the damage done by chronic inflammation or it abates inflammation itself? It could do both at the same time.   Reference2

In Reference3 when considering the natural agonist for SIGMAR1 progesterone was named as the most likely.  This hormone is related to preparation for pregnancy.

 

I can’t do detailed analysis on both grounds; I know only buzzwords and mentally I lack of the attention needed to do detailed study.

 

 

 

 

 

 

 

 

$AVXL The mystery of SIGMAR1 that it is…

Reference:

PMC6048940

Sigma Receptors and Cancer

Boy! Was I wrong!  The SIGMAR1 receptor molecule had already a 3D model! Let us not dwell on my ignorance, because there is much to see here and not much contributing to my pride as a sort of pundit (lol).

Indeed, I have puzzled and at the same time not given much weight to the fact that some drugs acting on SIGMAR1 had anything to do with cancer.  After reading the reference the connection became clearer.  As an investor (at one or other time) with some Stem Cell and Cancer companies (slowly gathering knowledge on buzzword level) I view the cellular environment in embryonic developement and cancer runaway growth as similar on the grounds of greatly increased rate of synthesis of proteins in Endoplasmic Reticulum where most of SIGMAR1 receptors are expressed (1/2 of all protein synthesized).

Here, I have to pose to remark that my ideas are amateurish.  I think that looking at SIGMAR1 as just stress response mechanism deep down might be incomplete.  At lower level SIGMAR1 might be a way for cells to “improve quality” of protein synthesis at moments the cell needs to secret or produce large quantity thereof, when under “normal” conditions this is not warranted.

The 3D molecular model of SIGMAR1 does not determine a very specific configuration of ligand to turn it either way.  The reference talked about a varied class of compounds possibly with different affinity and effect working with the receptor.  No wonder that so many SIGMAR1 drugs failed. Serendipity required here for drugs success.

I think many of us heard about the old mice rejuvenating after transfusion of blood from young (still growing) mice.  The researchers in Stem Cells have tried and succeeded to isolate compounds which reactivate the “youth environment” in more mature cells.  Who knows maybe SIGMAR1& 2  might be involved here.

That is so much I remember at first reading of this reference.  Since due to my problems with memory I suggest you read on your own. It would be great to start discussing this thread with people who can see more than just few basic aspects of cancer connection and SIGMAR1 & 2.  Discussion always sharpens senses and every person notices different aspects of reality which others omit.

And Now, Something Completely Different…..UBI

 

Universal Basic Income: Bankers Way For Everybody Else…

Since 1971, when the dollar has been denied backing of gold, the quantity of dollars has miraculously multiplied by over 21 times.  On these free-flowing rivers of printed money, savings not needed any more,  immense sea of credit has been created floating an economy where there is no need to produce anything material, just the promise of future profits is enough to become wealthy.  The wealth of the top asset owners rises ever higher on waves in the sea of credit but its waves are not lifting all boats equally.  The pedestrian Main Street living off the material world has been hurt and now clamours for its own wave on the sea of credit.  here comes, the tsunami on the sea of credit: Universal Basic Income!

The plan was semi-rational at the beginning : as long as the goings are good let pour more rivers into the sea.  Soon the sea claimed the land on which grew the reasons for Main Street wealth in developed countries.  With each season passing, ever-increasing in size and scope storms hit the land and wash away Main Streets assets to the sea.  Now, the generation who grew up not seeing anything else but the sea swelling wants to claim some of its fruits.

The bankers are truly seafaring people, they live by it and die by it.  The sea is the element most prone to turn against those who live off it.  UBI tsunami might strip the land barren of any wealth left to Main Street and when it returns to the sea it might sink  almost all these seafarers.  Water, water everywhere and nothing to drink!

When in the olden days seafarers lunched an expedition where the maps color was still white they carried with them gold and silver because beyond the seas people always accepted them, at least it has been this for five thousand years.

Just don’t, It isn’t worth it!

Only $3 Bills Accepted

$3.00