Unified Alzheimer’s Theory? $AVXL is doing what no company has ever done. Blarcamesine

There is a myriad of Alzheimer’s drugs.  Each of them has a therapeutic target.  Just a molecule or a receptor.  The question is how far-reaching waves the drug makes in the patient’s physiology?  Are they localized like as in the case of Donezepil; just availability of a neurotransmitter at synapses or system-wide?

CATD 2019 for $AVXL is the moment when the company might prove that beyond the data from the trials there is a cascade of changes from cognition to plaque in brain and gut biome together altering the etiology of Alzheimer’s.

I get on a limb when I suppose that the imaging which, one of the presentations lists, is aimed at measuring the disappearance of plaque after 104 weeks of dosing, and not the thickness of the cortex.  If this would be true because the plaque is the only biomarker of the disease detectable and approved by FDA then it could be beginning of acceptance by the medical establishment that Blarcamesine is the drug that has been eluding the industry for years.

If indeed this is the case then this is Ignaz Semmelweise moment!  I hope $AVXL is not going to end up like him, but the powers that be…

This would be seminal.

The gut biome is interesting but not that seminal from the point of view of the resistance by the medical establishment as right now it is relegated to be a side story.  It is now obvious that it is the inflammation that does the most irreparable damage to brains of the patients. The question now is: Does Blarcamesine control inflammation by lowering plaque deposits or lowering system-wide inflammation? Another would be: Is the brain condition affecting biome or lowering inflammation in the gut alters biome?  Is the biome directly affected by Blarcamesine?

Read the story of Ignaz Semmelweis, since history rhymes.

 

 

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New guy on the block … Oligomannate…off the boat from China. $AVXL

So $AVXL slowly but surely prepares the ground for acceptance of Anavex 2-73 as the drug for Alzheimer’s.  Yet, as this takes more than just 18 months and our expectations that everybody and their aunt would be buying $AVXL stock are alway premature, we fear that somewhere out of the left-field a wonderdrug would kill our golden goose.  The CATD 2019 presentations by $AVXL point to campaign to prove the Anavex 2-73 be a drug acting across numbers of paradigms of Alzheimer’s disease.  The model of the disease readers of this blog should have; progresses from dislocation of homeostasis to plaque deposits and then towards inflammation wrecking the final havoc on the brain tissue.  FDA has accepted the plaque to be the only biomarker in AD. Since the etiology of AD is largely unknown as nothing is definitively established to be the canon. The plaque came as close as it can get to be the canon as the publicized clinical trials by the likes of BIIB imply and their failures to deny it.

The triad of homeostasis, plaque and inflammation is translated in a myriad of papers looking for interactions between few compounds amoung at least hundreds of others, known and unknown.  Each paper can advance this picture of triad closer to acceptance or upend it.

A Chinese company is about to market drug which is derived from Brown Alge, and they claim it is just a complex sugar.  Many species of alge excrete compounds controlling bacterial films living on their bodies.  The piece of information in the article hints at suppressing a strain of bacteria in the human gut, hence the benefit of lowered systemic inflammation is bestowed on Alzheimer’s sufferers.  I have heard of mother’s milk containing sugar undigestable by humans but a perfect food for a strain of bacteria that produces a beneficial film on the baby’s gut wall.  It might be the case that the sugar in question does not suppress but just feeds a strain of bacteria which then outbreeds others in patients’ guts.

There might be two concepts on the role of biome in your gut.  Either by bacteria produce compounds that get to bloodstream and end up in the brain, or by lowering indirectly inflammation by building a beneficial bacterial film on the intestine wall which also affects the inflammation at the brain.

In case of Oligomannate the connection between gut biome and slowing of AD disease progression is direct and proven.  Yet the mechanism of action is unknown.

How competetive is Oligomannate to Anavex2-73?  The n=818 but no information on arms is given.  The other is that the effects are seen in just 4 weeks and that benefits are better than drugs of the type of Donezepil.  Hard to say.

see article Oligomannate article.

Read the next entry, it is even better, soon.

Hey, Budy can you spare a beer?

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The thorn in the side of $AVXL investors explained. BIIB037 vs. Anavex 2-73

Again..

It is very hard to just by reading the improvement numbers from placebo to assess the drug’s performance (15% over MMSE or ADCS-ADL 40% scores).  The fundamental question is the base in the placebo performance.  I looked up some sources on the internet and as far as I remember and my old posts confirmed this placebo average MMSE scores for AD are declining -3.79/y, ADCS-ADL scores about -6.5/y.  In the graph below the performance of Anavex 2-73 was taken for the whole High Concentration Cohort so it is in this case not adjusted for the genetic markers so includes the fast decliners.  The slope of Anavex 2-73 was derived from 109 weeks results. The plot is extrapolated to 6 years.  The progress of the disease in this graph is very general and might differ from the real trials.

MMSE SCORE for BIIB037 and A2-73 as of 10-23-2019

Most trials are starting from about MMSE 20 score, which corresponds to ADCS-ADL 55.

Another graph depicted the general extrapolated decline of ADCS-ADL scores for the same drugs, with the difference that the Anavex 2-73 decline is from 148 weeks data and corrected (I need to check it, I don’t remember now) for genetic markers. Again, the starting point is the corresponding score (theoretically) to standard trial.

 

ADCS-ADL SCORE for BIIB037 and A2-73 as of 10-23-2019 copy

 

Discussion

  1. The decline for Anavex 2-73 in ADCS-ADL sores is so small that when we take into consideration the advanced age of most subjects in those trials (70-80) it means that they are more likely to die or become dependent due to other causes than AD.  The MMSE scores which certainly do not include correction for the genetic markers to a great degree corroborate this assertion.
  2. BIIB037 improves the prospects of the patients to a degree, yet I would exercise caution here.  The study has only looked into 18 months of dosing vs. Anavex 2-73 for almost 3 years, the data collected to produce the slope of ADCS-ADL scores.  Extrapolation has its limits.
  3. BIIB037 can stand on his own if this extrapolation of further benefits holds but it can not beat the results of Anavex 2-73.  The safety of the monoclonal antibodies targeting the plaque up to now was a mixed bag and some had serious side effects.  At this point, after 5 years of dosing, Anavex2-73 has not been implicated in some sort of serious side effect.  The difference between these drugs, approaches, can not be overstated.

 

I hope that this is not the last post and that it will survive the horror of Halloween.  Can you spare a beer?

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The Case of the Extruded link…Final Chapter! $TSLA $TSLAQ

Thanks to @KeefWivanef1 on Twitter and Flickr I was able to obtain a good picture of the Tesla Link.

two.png

I copied the webs inside the link and I got this model ready.  This is similar but not identical to the Tesla Link.

LINK TESLA volume 9.812 in cube.png

Everything from the picture is there i.e. webs and their relative positions with radiuses (very important).  The volume of the model is V=9.818 in3 (that is only a model scaled down).

LINK ALTERNATIVE volume 9.767 in cube.png

An alternative link has almost the same volume of material V=9.767 in3, so both models can be compared apples to apples. All other things are the same;  material, loads, constraints and the volume of material.

The results for Tesla Link were;

Final LINK TESLA TENSION 1000 lbf sf 1.685 def .00445 in 4747 psi.png

Following parameters were computed:

Min. Factor of Safety = 1.685; displacement max. = .0045″ ; stress max. = 4747 psi.

Let’s see the same for Alternative Link;

LINK Aternative 1000lbf tension 3173 psi dis .00345 in sf 2.522 v 9.767 in cube.png

Min. Factor of Safety = 2.522; displacement max. = .0034″ ; stress max = 3174 psi

From the picture where the scales of Safety Factor are the same, it is obvious that Tesla Link is less efficient in carrying the load. Both designs use the same amount of material and are readily made by extrusion. The more yellow the worse it is.  The highest stresses are at the points the there is either change cross-section or sharp corner (at all sharp corners radiuses are applied to dissipate stresses)

In the Alternative Link, there is only 66% sensitivity to load than in the Tesla Link.

Initially, I thought that my first pass at this link was deficient by not incorporating all those details revealed in the picture.  After bringing them to the model the first conclusion still holds water.

 

INTERNS WERE HERE: THE SAGA OF THE WHOMPY WHEEL IN $TSLA

Disclaimers:  this analysis is done by somebody with Bachelor’s in Mechanical Engineering and not by a structural engineer with experience in car suspension design and dynamics (but might be because of that even more damning), so take it with a grain of salt: I have been wrong before!

Let’s see a picture of real Model X rear suspension after a failure of some links.teskla drive two.png

I marked up the two broken links.  These links can only be loaded in tension and compression – pinned ends.  It seems that both have failed, most likely one was first then the other followed. I do not know much about the dynamics present in vehicular suspension, so I follow basic knowledge on linkage and mechanisms. Both failed links are not the ones carrying the most load in this mechanism. I looked at the upper longer link and found this to be designed in a very inefficient WTF way.

The link in question can only be loaded in tension or compression.  Tension is much more straight forward then compression as buckling can occur.  Let’s see my recreation of that link in 3D modeler software Fusion 360 by AutoCad.  If you do not follow basics even fancy 3D Cad software can not help.

Link Rear Suspension.png

This isn’t a copy of the original but just model of its design features approximating the real thing.  I do not know whether I am correct but what I can make out from the picture seems to recreated here. The link is extruded with its profile then “sliced” to make a link.  If the designer added these v-shaped ‘braces” to the profile to add strength or prevent buckling we don’t know.  these can be reasons, the other being that the extrusion process required it but not necessarily this way.

I did run FEA analysis for stress and deformations with very coarse mesh (large size of an element). The smaller the more accurate results.  In all subsequent analyses, all parameters were the same and only geometry changed. Link Rear suspension Temsion 1000 lbf.png

This is the link in tension. yellow parts are in greatest stress.  The red tag denotes the place of greatest stress.  Notice that the v-shaped braces are not carrying the load. The factor of safety is 1.119 (how close the link is to failure, bigger the better)

Link Rear Suspension Compresion.png

The same link in compression. The factor of safety is 1.015.  Again the v-shaped braces do nothing.  I have a tendency to drill down to the basics and experiment with alternatives.Link Simple Extruded Tension 1000lbf.png

This is my alternative to the Tesla link.  The factor of safety went up to 1.838 (164 percent of Tesla’s design).

Link Simple Extruded Compresion 1000lbf.png

Here, we are in compression. The factor of safety is 1.838 (164% of Tesla design)

Let’s see how susceptible these two designs are to buckling under compression.

Tesla’s Link

Link Rear Suspension Buckling Mode 2 11.85 Load of 1000 lbf..png

deformation at 11.85 Load

and my simplified design

Simple Link Extruded Buckling analysis 1000lbf load.png

deformation at 5.58 Load.

The simplified design is 147% more susceptible to buckling, the only problem is that it would have failed in either way (tension, compression) before it would be deformed to buckle at all.  The factor of safety of one means you are failing right there.

This is proverbial WTF!  Had the designer wanted to just guard against buckling he wouldn’t have created the convoluted design violating the basic law of constant strength throughout the part.  The buckling analysis gives a good picture of how the part deformes differently on top and bottom.

 

 

 

Properly designed link with web between top and bottom.png

Properly designed link (a bit more expensive but not much) with the thin web connecting the top and bottom.  21 Loads at buckling.

The design of the link might be a proof that indeed INTERNS designed $100-140k car because neither cost or weight or guarding against buckling or ease of manufacturing can justify making ludicrous design mistake like this.

That’s all folks. 4:30 AM.  This is basic engineering shit!  Believe me.

 

 

$AVXL Meant to Write This Long ago…

Whatever you do don’t trade on this blog!  I have been proven wrong before!

 

I have read through the whole article on my sleepless night.  Staying in focus really hurts but I somehow managed to get to the end. The link to the paper is here:

Paper on AD hypothesis

Great paper listing some AD theories I have never heard of.  It really increased my horizon on AD.  I bet I will have to reread it a few time to absorb the content.  I recommend reading it.

Among many clearly described theories, there was one fact about fluoxetine (Prozac) and the fact that it affects more positively women than men.  Another supporting fact was that women are more frequently victims of AD and dementia than men.  This can be found in the few last paragraphs of the paper.

At one point in time, I explored this phenomenon but I think I never wrote about it here (forgive my memory lapse if I did).  When ANAVEX 2-73 was tested in Tg2576 mice there was a distinct difference between sexes.  From the biological viewpoint the sexes differ in the ability of females to carry a fetus i.e. genetically distinct organisms in its system.  Another observation; the incidence of autoimmune diseases in women is greater than in men.

Tg2576 Male

Tg2576/Water i.e. impaired male mice did not reduce much their swimming time with trials and their improvement was marginally better with ANAVEX2-73 relative to “healthy” Wild Type/Water mice. The improvement of males for Tg2576/A2-73 is 50 points on a scale of 90 points.  This happens with quite higher dispersion vs. females.

Tg2576 Female

The Tg2576/Water female mice learned much better than the males, with about three times greater improvement (10 points vs. 30 points (females) out of 90).  The improvement of Tg2576/A2-73 females is 60 points on a scale of 90 points.

The pattern is interesting to note and remember. It seems that ANAVEX 2-73 behaves like other active CNS drugs.  Just another reason to like ANAVEX 2-73.

p.s.

Writing here comes to me with some difficulties and things change on a daily basis so once in a while I have an idea for an article but I feel I always fail with putting this into words.  I can not regularly write but I thank all who read this.

Looking at The Whompy Wheel.

I am a mechanical engineer, and if I am going to look at the Whompy Wheel thing it is through the prism of what I know about designing mechanisms so prepare to meet some wonkish explanations on way out.

Firstly, let’s look at the way Tesla cuts cost.

Tesla Rear link One.jpeg

The dirty part is what was initially used in rear suspension assembly, the second clean part is the replacement.  When an engineer looks at the early part he sees that it was extruded and then sliced (sawed-off) to thickness.  This is as cheap as it can get in manufacturing.  Extruded parts are the most inexpensive to manufacture.  The part has multiple cavities in part to keep the wall thickness constant (as nearly as possible) and/or to lower the weight of the part.  When you are in engineering school they tell you that if you apply load to a part imagine that stress flows through the part as if it would be liquid. Any sudden change of direction, cross-section or sharp corner creates stress concentration.  Stress concentration is a condition where stress and the possibility of failure is larger than just the stress obtained by dividing the force by cross-section area (average stress at the point) would imply.  The replacement part seems to be nonplanar, it is probably die-cast or even forged so it seems that the initial part (which is in one plane only) uses rubber to adjust to the 3D mechanism, though this could be just optical illusion on my part.  The consequences of the using rubber at the pivot points was simply explained by the gentleman who had commented when posting the picture.  The new part seems to be a better design by shape and load-carrying capacity. It is plain from this example that Tesla’s philosophy of design is to shoot for cost-cutting as the primary goal in design and then leave the questions of reliability to be answered later.  

Another picture tells another 1000 words.

 

teskla drive two.jpeg

 

This is rear axle assembly I think from Model X.  We can identify here two links, most likely extruded, which failed. On first look, Tesla uses cast or die-cast parts for structural elements and some links in the suspension mechanism.  Cast or Die cast parts hold the punch of being inexpensive to manufacture relative to multiple features and complex shapes they can have built-in them.  The rub is the properties of materials as they are cast.  When you melt metals atmospheric gases and other inclusions (oxides) dissolve in the molten metal and when cooled they form bubbles and flaws in solid parts. Also varying rates of cooling build in stresses in parts. These problems are inherent in the process of casting.  In general, these cast materials are more brittle than materials processed by forging, cold-rolling and machining.  From the picture, I have the impression that the materials are probably alloys of aluminum.  Since aluminum alloys are 3 times more elastic than steel and 1/3 strength of steel designer has to create beefier parts ( more involved than this alone).  The danger of more brittle materials in suspension is that these materials are more likely to catastrophically fail (Whompy Wheel) then forged, cold-rolled or machined components, and without warning due to susceptibility to form cracks (leading to failures) because of inherent flaws, surface corrosion, fatigue (repetitive loading), shock loading (impact) and stress concentrations.

The first exhibit points to a tendency to place cost-cutting as the primary objective in taking design decisions.  As properties of cast materials can be improved by additional processing (but not entirely ameliorated) this adds up quickly to higher price of components.  For the explanation of the Whompy Wheel phenomenon, the adoption of cast parts for suspension design as a cost-cutting measure can be seen as the simplest one leaving other aspects of the design sound, though the extruded links seem to fail as they are indeed the weakest links.