You should not trade this blog as 4 billion years of evolution is against my judgment.
Give a guy a computer and ability to make colorful pictures and graphs and he sure is going to commit a crime against reason. This is a prime example.
I used some sources to make educated guesses to the number of all models of $TSLA car sold in the 3 major markets; the US, EU, and China.
From data on one place in Colorado ( have a history for good correlation to months numbers) I estimated all models in the US and multiply by 2.24 the number of avg 2 months in the quarter in order to account for those fabulous surges in sales at the end of the quarter, especially this one. So that is how I got Oct 19, Nov 19 and Dec 19.
I kept China months numbers steady for Nov 19 (comparing to know Oct 19) and applied scaling for the last month of the quarter (1.61 multiplier).
Europe was a bit more complicated. I have data for NL, NO, and SP, (Oct, Nov 19 (till 25th)), but I looked at the patterns in other quarters for the ratio between these countries and the missing rest of Europe. so the average of 2 front months was multiplied by 3.44 to get Dec 19. The number from Oct 19 was scaled by 1.55 from know deliveries to NL to give an estimate for Nov 19.
Since I am not that bright I just press a few keys and this is a plot of global demand all models of $TSLA cars by 3 main markets.
I am also lazy so I pressed another button and I got this trendline (second-degree polynomial) for all models demand 3 main markets.
I only pressed buttons, blame Gig Oil. It seems that the trend is right here and $TSLA’s demand is starting in even very continuous fashion declining (as smoothed over quarter’s 3 months). The information is in the monthly data. I want to find out what the final numbers for the Q4 2019 are to update.
The clues point to the descending trend in global demand. All markets seem to be poised to roll over. Crucial to this being true are the numbers for the last month of Q4 2019. Each market peaked and then started rolling over after going organic. The trendline equation parameters are given their current values by the weight of a sudden drop in the last 3 months. If my estimates are off than we probably have to stay content with steady demand or even rising, but that would imply going from the bottomless pit to blue heaven.
There is a sudden drop in the world number for Oct 2019. A similar situation was seen in Q1 2019 with demand in the US. The explanation was that tax breaks and the backlog of backorders were exhausted or ended. $TSLAQ has begun to appreciate the resourcefulness of Elon Musk in “keeping up appearances”, both in accounting and demand. So I heard voices claiming that the Oct, Nov 2019 drop is a “honey trap” for the shorts. Having lived once in a dictatorship of the proletariat reading between the lines can save you a lot of grief. There is the expectation of disappointment when Elon conjures up ~70,000 cars sold in Dec 2019. Mr. Musk sealed all leaks and is baiting potential longs with numbers, both in the accounting of his business and the future orders of the already notorious #Cybertruck.
Model 3 has died (dying a slow death), long live Model Y. Oh! Wait it is a reincarnation of Model 3. If indeed the numbers for reservation are in tens of thousands then #Cybertruck has been sorely needed. $TSLA Q3 2019 results and the reservation numbers for Cybertruck seems sounding like a Wall Street’s siren song to Longs and a $TSLA’s swan song to $TSLAQ. Let’s see how the snowfall in the US affected global sales.
$TSLAQ community had many more clues on production and sales. Now, it seems that the expectations for the quick demise of $TSLA have subsided the information has been a bit sparse. That is why the clues and the methods rely on correlations from previous quarters. Are they false? I don’t know till it will be too late to explain to anybody how Elon Musked my numbers. In this way, Elon will disgrace another Short.
By my reckoning, only God knows things and we all are kept in the dark. Since I am humble enough to celebrate my ignorance I think I shall be rewarded. Please, spare me standing on the street corner and begging.
Sincerely yours, Beer Fund
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Four billion years of evolution is against my judgment so don’t trade on this.
Synthetic Placebo Arm and Statistically Significant…
Alzheimer’s Disease Neuroimaging Initiative ADNI also was given data on placebo arms by a number of companies in the industry. This data can be used to create a model of a statistically significant synthetic (virtual) placebo arm. The recruitment of patients can be limited to only those in the dosing arms since the placebo effect working in one trial is identical to workings in another. Namely, the placebo bias is identical from trial to trial. Many Alzheimer’s trials involve hundreds if not thousands of subjects so doing away with the onerous and expensive placebo arm might be a great help to many companies.
We might not believe it initially but the placebo effect has been even traced to genetic markers. I have checked myself for it and I am a highly susceptible person to the placebo effect. I have to confess that it is true that I always feel better after seeing a physician or getting any medical help, or even expecting it.
If you want to see your genetics material in terms of trait relevant to health, personality, intelligence and physical abilities you can transfer the DNA results from one of those ancestry sites to Genomelink . These markers have varying degrees of reliability but sure it is fun.
Of course, the final thing here is the selection of those patients whose genetic make up allows them to be responders. This is certainly in the scope of ADNI activities.
I hoped that Dr. Missling would also use this opportunity to present data on the plaque deposits changes in the brains of the responders. I don’t think or remember that such data had been collected at the beginning of the phase2a. It would be very helpful as FDA considers, it might have changed since that amyloid deposits are the only valid biomarker of the disease. Proving that these deposits were reversed in those who responded versus those who did not is from the standpoint of the regulatory body hard evidence of undeniable progress. I would appreciate it if anybody would remember this hence my memory barely serves me. Please, leave a response to the post.
Another aspect of this is that statistical significance is related to the background noise. I am here revoking the image of statistics as looking for a signal in background noise. It is like making out a word in a very loud night club. LOL. Similarly, I can compare the placebo arm in Alzheimer’s to very low-level noise as the outcome for patients leads to quick deterioration in a very predictable way. Any word spoken over this din can be clearly discerned. This nature of Alzheimer’s progression moves the bar low on validating trials with even small samples of patients who respond to medication aa statistically significant study.
I have a dog in this hunt, not only financial but my reputation if it ever existed. I went on the limb many times making wild guesses about the Anavex 2-73 and $AVXL. Some were grossly wrong, but now I face the ultimate moment as data on Blarcamasine is to be validated (hopefully) and the extent to which the drug is to help the patients can be at least given initial numbers.
So without much ado.
That is the composition of the population of High Concentration Cohort when corrected selection for SIGMAR1 and COMT genotype will look like. You can judge me upon how well this model fits the upcoming data from the LB20 presentation at CTAD 2019.
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Four billion years of evolution is against my judgment so do not trade on it.
Three main markets for $TSLA are the US, Europe, and China. See the graph for the number of cars sold in these markets per month. Data for China since January 2019 only.
Model 3 was introduced in 2018 and in Europe and China has not been sold till about March 2019. Now, let’s see the sum of all models sold in the main markets.
The equation of the line fitted to the data is bearly rising. y=14.90*x + 28350.
If we assume that a quarter consists of three months with the number of cars defined by a point on the line, then we can estimate the future quarter sales based on simple extrapolation into the future. Since this is an extrapolation of line fitting a set of data points for any 3 months the middle point is the quarter estimate.
The decline of sales in the USA accelerated after April 2019 so the trendline is based on this period.
It is obvious that since about March 2019 the sales entered into definitive decline. y=-796*x+19420.
The trendline suggests
rising sales. y=325*x + 7050.
The trendline suggests declining sales. y=-172*x + 4610.
The sum of all main markets extrapolated from trends documented until October 2019 for the next 14 months.
This suggests that the sales keeping with trends would be about 70% of current sales barring any sudden event after 14 months that is Q4 2020.
This never happens.
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We fret that this company has no respect from anybody but we know with all our hearts that this is the drug. The press taunts us with “next miracle drug soon to help the sick” meantime short-sellers drive the stock price up and down in order to squeeze few dollars from the hopefull “millionaires” as the $AVXL faithful look at their statements and wish the worst upon the short-sellers. To add insult to injury $BIIB goes up by $15 billion in market value over a day on news that its failed drug can marginally slow the disease.
Fear no more since Dr. Missling goes into the offensive.
In the CTAD 2019 program, there is an oral presentation LB-20 by $AVXL. It references in description to data provided by Alzheimer’s Disease Neuroimaging Initiative ADNI . The ADNI collects and disseminates data on Alzheimer’s patients including imaging and seeks to identify early-onset dementia and Alzheimer’s disease biomarkers. This data collection involves also documenting the progression of the disease, that can be used to validates the biomarkers. Information covers PET (using a radioactive marker for amyloid plaque imaging), FDG-PET (glucose activity in the brain) and structural MRI (cortex thickness) and I believe staple of Alzheimer’s research; cognition and daily living tests and DNA data. The activities are broadly based in many research venues and rigorous proceedures are applied in collecting data for the industry. What is most important the data can be used to create a comprehensive statistical and clinical profile of disease progresion.
So it seems that $AVXL wants to validate Phase2a data in two ways. One is by comparing the cognitive performance of the Phase2a patients to some data substitute for the placebo arm. The above mentioned ADNI data is to be taped with this purpose in mind. The other part of it is adjusting this data for “propensity” (DNA profile: SIGMAR1 and COMT genes), and again ADNI data is used. Since no other data was collected (?) save the one on cognition the validation only includes cognition. This is adding to the data virtual placebo arm and eliminating the 20% who do not respond to Blarcamasine making the study virtually statistically significant. I have spent some time here making educated guesses on Blarcamasine performance. I was thwarted by the company always formating the data in such a way that comparing it with the previous set of data involved multiple assumptions.
Now to the main course
The other thing is that Frederico Goodsaid from Regulatory Pathfinders (US) is listed as one of the authors. For more info form the horse’s mouth visit Regulatory Pathfinders Webpage. I think this quotation from the webpage should ring the bell:
The value of medical product development knowledge is maximized when it can be shared between its source and regulatory agencies and integrated into coherent information.
Strategic Regulatory Intelligence is a useful tool to drive regulatory discussions about novel precision medicine products. In addition to this tool, however, the global strategy for regulatory approval of precision medicine products may require the identification of regulatory paths which do not have a prescriptive designation associated with current regulations. Regulatory pathfinding identifies regulatory paths which are not prescriptively defined :
I venture to say that Regulatory Pathfinders are very likely to negotiate with FDA on behalf of $AVXL. The implications are that the “augmented” performance of Blarcamesine has a good chance to be used to convince the “new” FDA to grant accelerated or conditional approval.
I say, fantastic, but will not guarantee the approval by Christmas!
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Yours truly is a moron…but I can read text and graphs. since I have not been trained in spacecraft engineering and have a bachelor degree in mechanical engineering I always reference my old and trusty Ninth Edition of Mark’s Standard Handbook for Mechanical Engineers. So armed with this information I am looking at the $SpaceX Starship..and I see..
Two sets of surfaces, aft ones which might be rotated around those red lines I had marked on the photo, and the bow surfaces which might have a dual purpose and possibly two axes of rotation. It is kind of obvious that the aft ones are for creating lift, which is force perpendicular to the direction of motion of the Starship in the atmosphere. The bow ones might serve the same purpose and additionally if they can be rotated about secondary axes like surfaces on modern fighter jets they can be used to maneuver the Starship (in the atmosphere upon reentry). It also is possible that the surface can be folded and will not generate lift at all, only some drag (force working against the motion of Starship in the atmosphere).
The angle at which a spacecraft enters the atmosphere is shallow and the drag force slows the craft against air at the same time gravity pulls it down toward the center of the planet but lift force pulls it up from the planet.
The speed with which craft moves through air dissipates the kinetic energy in air friction and backpressure (lower pressure behind your car sucking it back) ultimately resulting in heating air around it and then transferring that heat to the surface of the craft. Not all so dissipated energy goes into heating craft surface.
From the picture, I gather that $SpaceX intends to vary the lift drag ratio of the vehicle in reentry.
Russian Soyuz capsules are shaped almost like balls. These have 0 lift and some drag so lift drag ratio is 0 for Soyuz. What it means for reentry? High dynamic pressure working to decelerate the craft (due to drag) and high stagnation-heat rate compared to craft with lift equal to drag (lift/drag=1). Yet, it is stated on page 11-123;
Decelerations and temperatures are drastically reduced with increasing lift-drag ration (Fig. 11.6.13) and decreasing W/Cd*A (Fig. 11.6.14 and 11.6.15). This effect is particularly beneficial at steeper entry angles. The combination of longer flight times with lower heating rates may, however, result in larger total heat input into the vehicle.
The term W/Cd*A is referred to as ballistic ratio and the designers of Spaceship intend it to be as large as possible so that the kinetic energy to drag force ratio is large, kind of aerodynamic inertia.
The use of stainless steel is a telltale sign that the name of the game is to lower the heating rate. Stainless steel conducts heat at rate 3 to 4 times lower than the aluminum used in aircraft design. The other element is coming into the atmosphere at a steeper angle and deploying the surfaces at different stages of reentry. These are the strategies to lower the heating rate and the amount of heat conducted inside.
The question I have is whether the stainless steel surface is going to be covered in ceramic tiles? The information contained in the graphs is just to inform you about the shape of the solution and does not cover this particular case. One thing which I want to add here. It was reported that the surface of the stainless steel skin was polished after assembly. There is a graph on page 11-123 Fig. 11.6.11 representing the fraction of energy dissipated going into heating the craft on reentry. At about 100,000 ft to 0 ft and at high speeds of reentry, the surface of the craft is among others (convection and conduction) heated by infrared radiation of hot gas enveloping the craft. The polished surface would reflect the infrared radiation lowering the heating of aircraft. There is no other reason to rationalize polishing the surface (save esthetics) and yet Wikipedia article quotes using thermal glass tiles. LOL. Try to figure out what really is going on here!
So Starship weights 120 ton in 200 miles orbit on reentry; this is roughly at the least 3.6 x 10 to power 12 Joules of kinetic energy. To raise the temperature of ~10 tons (1mm thick cladding) of stainless steel skin to the limit of retaining full structural strength (870°C) is needed 3.9 x 10 to power 9 Joules, which is roughly 1000 times less than the energy to be dissipated. There is no way that “bare skin” can do the trick unless the energy will be dissipated by expanding rocket fuel (theoretically). Ergo tiles are a must. (just for laughs, imaging reentry angle of 90°) Nevertheless, a new idea of liquid cooling stainless skin was advanced. (Wikipedia). Let’s look into it. You need to remove halve of that 3.9×10 to power 9 Joules. How much coolant you need to lower skin temperature to 435 °C by rising coolant temperature 200 °C? You need 3800 kg of coolant (ethanol specific heat). That is probably a generational supply of Whiskey. Now add pumps, redundancy, power supply, and installation to direct flow. Meantime your temperature of cladding is 435 °C.
The most astounding thing is that aluminum alloy used in aviation (7075) has 4.5 times the strength to weight ratio of 316 stainless steel. I don’t know the alloy used by $SpaceX so I might be missing here something. This is astounding since the weight of the aircraft cladding could have been smaller by a factor of 4 at the same strength. This additional weight adds to the total energy to be dissipated. The question is: What advantage has stainless steel cladding in reentry at the cost of 4 times structural weight? I do not know how the structure’s strength requirements would change by the added weight of tiles, which anyway have to be added. Wikipedia lists all kinds of new developments put into the design. One of them is cryogenic treatment and cold rolling of the stainless cladding. I doubt that cold rolling alloy can increase its yield strength 4 times without making it brittle, even if it at all would be possible. This cryogenic treatment seems to be full baloney since the cladding is at least now welded together and you are as good as your welds; cryogenic treatment and cold rolling not there anymore in the welds.
In conclusion, this seems to be another $TSLA; somebody tries to be clever by half by making choices and selections of solutions rejected by others on the assumption that if he were “a contrarian engineer” he would beat the system (technological limitations) and win the crown of genius but what is defeating his intentions is lack of attention to details. At this point in the game Starship Mark 1 & 2 are testing beds for ideas that seem to be a gamble. This is not rigorous testing of complex systems but testing ideas whether they hold any water. The steeper reentry angle can only be gained at expanding rocket fuel, which had been previously brought into orbit. So everything comes with some cost, the question is what you buy with that expenditure? I once worked for a company where a strategic decision was made with one almost insignificant factor missing from consideration and vast investment had to be written off. The story was repeated to all newcomers as a lesson. The Starship is a list of revolutionary ideas never seen before but usually given a sentence or a paragraph in Science Fiction literature. Engineering is also about proving that something can not be done now. ;). The answer to that will be known after trials, either “nobody had tried that before for good reasons” or “why nobody had tried that”. As always in engineering, the devil is in the detail.
In the heyday of the Soviet Union, the railway designers faced pressure from management (activists of the communist party) to increase the size of locomotives because the bigger engines could pull larger loads. Yet, the length or weight of the engine was limited by the radius of the tracks on with the previous generation engines traveled without problems. The management deemed any resistance from engineers as a lack of faith in the Soviet Genius and forced its hand. End of story, the engineers were never heard of again.
The calculations I presented are so-called “back of an envelope” numbers setting physical limits on what is possible or required. On Wikipedia, the article on the Starship lists Elon Musk as the designer of the craft. Since that time radical changes were made to the rather conservative design of the Starship. As one writer (The Noble prize winner) was fond of saying; intellectuals (engineers, too) are hired guns for the powerful and mostly doing their bidding (paraphrasing). Sometimes, rewards of a genius (a stickler for truth) can be penury or prison cell. Those who have enough resources (money, political power) can enjoy doing what they want to do and ignore the rest of us.
What is in this for $TSLAQ; Elon does the $SpaceX too.
I tried to compare the reported results from Green Valley Pharma drug GV-971. I did discuss it two posts before. Any meaningful data was presented in ADAS-Cog 12 improvement of 2.54 over placebo. This scale is 70 points with the healthy starting at 5 points and the deterioration is monitored by adding 65 more points till the scale reaches its limit. This is an inverted scale to MMSE (just 30 points altogether), both measure cognition. It is impossible to express the relation between two by a ratio since there are tests giving varying weights to different cognitive components. From a quick search on internet, I found out that in one subject the ADAS-Cog score of 18 corresponded with MMSE 23. I chose this to be my point of departure and I expressed the change as a line with a slope connecting the score at 36 week with the score at the base. Of course, this is a gross simplification as I suppose the correlation between both is nonlinear. With that assumtion, I created this chart to gain insight into the relative performance of placebo, Blarcamesine, and GV-971. When you look at the chart you have to remember that increasing score means deterioration, not an improvement.
Two horizontal lines show the ADAS-Cog 12 score and corresponding MMSE scores. The thick red line is the deterioration for those on placebo, derived from MMSE scores by multiplying by a factor of 2.16, (the ratio). The thin black line is the performance of Blaracamesine also derived from MMSE sores and adjusted to the timeline of 36 weeks. And finally, the red thin line is the GV-971. The difference between the placebo cohort at 36 weeks was 2.54 points so this how I constructed the line.
It is obvious that GV-971 does impedes the progress of the disease. I wonder how different GV-971 is from BIIB037. Before I finish this I want to point out that the performance of Blarcamesine is taken from the High Concentration Cohort which was not subject to selection with the genetic markers for response to the drug. In other words, this is the response in the general population so the comparison is more on the leveled playing field.
Let’s get crazy and extrapolate into the distant future. 312 weeks is 6 years.
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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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.