New Presentation and New Data on Phase 2a Dropouts. $AVXL ANAVEX 2-73

Disclaimer! Better late than ever.  Do not trade this blog since the author might be wrong and the 13 billions years of evolution of the Universe might be against him.


Welcome the slide 5 of ASENT 2019 presentation:

Slide 5 ASENT 2019

Also, ASENT 2018 gave the number of patients at 104 weeks to be 21.  Previously, I did a graph of remaining in study patients in Reference1 so that one can compare apples to apple number of patients staying in Phase 2a study with those in reference1 as I normalized it to 32 patients. Now added to this graph is the plot of Phase 2a patients over the time of 3 years:

Dropout of Phase 2a .png

I noticed that the Reference1 study from year1 to year2 has an almost identical slope as between year 0 and year 1 for Phase2a.  After that Phase2a does not follow the exponential decay curve of Reference1.  It seems that the therapeutic effect of AVXL 2-73 is not limited to High Concentration cohort as in the span of 3 years only 35% of patients have dropped out. See Reference1 dropout plot:

6 years of placebo Alzheimer

If we compare Phase 2a performance to the Reference1 dropout plot then we can see that the Year 1 to Year 2 in Reference1 corresponds to Year 0 to Year 1 in Phase2a.  In Reference1 drop during period Year1 to Year2 is roughly 33%, drop during period Year2 to Year3 is 40% (the rate increases by 21%).  For Phase 2a these are 25% for the period from Year 0 to Year 1 and 12% for Year 1 to Year 2 (rate decrease of 40%).  The first full year (Year 0 to Year 1) of Phase 2a is still within limits of the natural course of the disease but the next two years break away from the mold.  I can recall that when the early data on Phase 2a was presented, $AVXL looked at the data to establish the minimum effective dose.  I do not remember the criteria used to do so, I only recall the dose to be 14mg/d which was to provide the patient with the benefit of stabilization.  The dosages used are in three increments from 10mg/d to 30mg and 50mg/d, the odd man out.

Anavex has been changing its ways to look at the data at every release.  That is not the case that the company is hiding something from the investors but rather that AD is so complex that there are many aspects in assessing the performance of the drug and this is a dynamic process (changing in time).  This early assessment might not be included in the currently presented data but numbers of diminishing dropouts among Phase 2a patient might indicate there is some truth to this early conclusion.  On the other hand, Reference1 defined dropout as patients who did not show up for testing.  Here, the reasons can be connected to AD progress or lost interest in participating in the study.  If I am to make an assessment of the Reference1 curve I would conclude that after the first year the curve seems to be more consistent with natural phenomena than it would seem from the first year alone. When looking at Phase 2a curve the conclusion is that even lower doses (20mg/d and up) of ANAVEX 2-73 might have had some therapeutic effect as the lowest dose was 10mg/d vs. 14 mg/d needed.  The prevalence of SIGMAR1 and COMT genotypes, which respond well to the drug, is 80% in the general population.  At 148 weeks we have 21 patients still in the trial, that is 65% of 32 patients starting the trial. Would the first 8 people to drop out have been the ones on 10mg/d dosage?  I think that combination of conditions might be in play;  The genotype, low dose, and initial scores. Would the combination of these have covered the 35% dropouts out of the initial 32 patients? The concentration and delta parameters obscure the dosage and initial score as it is highly dependent on the individual’s physiology and disease history.

The set of potential patients to stay in the Phase 2a would contain most likely those in the genotype which is 80% of the general population, high initial scores and large enough dose (>14mg/d?).  Let’s make another set of very simplistic (Hail Mary pass) calculations, all based on assumption verging on a miracle (or is it?)  that the distribution of the genotype in 32 and 24 patient sample (smallest sample size valid in medicine) is the same as in general population.  At 57 weeks we have 24 patients of record (26 on the presentation page).  If the High Concentration Cohort from CTAD 2018 is just 9 patients and 7 “survive” (2 most deteriorating are deemed dropouts) then it 77% of cohorts who survive.  The remainder is 66% of the 24 patients (17 counted), Low and Medium Cohorts. If we take 80% of 17 patients and round it a bit, we get 14 patients (Low /Medium) plus 7 (High) which after addition gives 21.  This makes for, however shaky, the argument supporting the claim that both the genotype and the more than 14mg/d (low no-deterioration dose) “work”.

Phase 2a lost 8 patients in the first year.  That is losing about 25% of the population.  In other words, the survival rate for the first year is 75% then goes to 88% (after the second year) and then to 100% after the third year!  Steadily converging to 100%! The survival rate for Reference1 from Year 1 to Year 6 is; 66%;60%;58%;71% and 60%.  This is as steady as it gets, of course, I disregard the first year.

The author has to cope with cognitive problems so some of these arguments might be disjointed or just tautologies.  I have to confess that it took me some time to comprehend what I had written before I set to rewrite this post (this is the second version) and my memory is pretty poor.  What I am trying to do is to replot the data to make it easier to assimilate or attempt to reconcile one set of the data points with others, given at a different time.  If my style improved that is due to Grammarly software, LOL!

Conclusion: If indeed the 12 patients who dropped out of the study were prime examples of overlapping sets of “bad” genotype, low initial scores and aggressive disease progression then ANAVEX 2-73 might perform at the level in the graph below or even better with the general population.

Micheal Tavares has attended Anual Shareholder Meeting 2019 and talked with Dr. Missling.  Dr. Missling said that after 148 weeks the patients had an option to be given full therapeutic dose instead of the dose assigned at the onset of the trial and that data on 208 weeks might be released in due time.  Hat tip to Micheal Tavares.

 

Untitled 4 copy

.  See post After Digesting CTAD 2018…

The above graph depicts in the performance of ANAVEX 2-73 in General Population under high dose!!

 

Look at 148 Week Data for Alzheimer Drug Anavex 2-73.

The data presented for the 148 weeks period gave readings for 26, 5, 96 and 148 weeks adjusted for the SIGMAR1 and COMT gene variations from the pool of patients previously reported as High Concentration.  The data points are separately given for two measures; ADCS-ADL and MMSE. One has to remember that ADCS-ADL is on 70 points scale and MMSE is on 30 point scale so the drops at 148 weeks are commensurate.  Here is a graph of the deltas from the base:

ADCS-ADL and MMSE over 148 weeks Patients SIGMAR1 + COMT for A2-73 till 148 weeks

Our premise is to identify patients by matching averages by trial or inspection to individual patient scores as given in previous data releases.  This might be fool’s errand but it might be also instructive yet not conclusive to see either discrepancies or even convergence of averages.

The presentation of the 148-week data listed the ADCS-ADL first as for the patients selected through the filter of the full list of co-variants in MMRM-LME model (previous ones, plus SIGMAR1 and COMT).  CTAD November 2017 lists patients data for 57 weeks on the slide 24:

Slide 24 CTAD 2017

Out of the 9 patients, 8 are listed, patient 2002 has to be discarded as his drop is over 20 points making any average out of agreement with 148-week data.  It is equally possible that the pool can be just two patients or all 9.  Upon the knowledge that the 80% of the general population is carrying genes assuring therapeutic response to Anavex 2-73 the percentage of such population within the pool of 9 patients in the cohort with High Concentration can indicate the degree to which therapeutic effect in Phase 2a can be replicated in the general population.  The average for all other patients is:

(7.8+3.7+2.0-.9+.9-1.9-4.0)/7=1.09  compare this to the reading of 1.0 at 57 weeks on 148-weeks data and we come near to the mark.

Inspection of the performance of patient 1013 reveals drop in ADCS-ADL score at 96 weeks of -14 points. This can be found on the slide 29 of CTAD November 2017 presentation.  Such a big drop would require the other patients score to go up in order to keep the average at -1.0 reading.  If we remove patient 1013 then:

(7.8+3.7+.9-.9-1.9-4.0)/6=0.9333 which is even closer to the reading of 1.0 (148-weeks data).

Let’s see if the MMSE data confirm one or the other pool of patients.

Slide 23 CTAD 2017

For seven patients this is:

(3.7+2.8+2.2+3.8+.1-2-6.2)/7=0.63  vs. the reading of 0 for adjusted to MMRM-LME model.

The same for six patients:

(2.2+2.8+3.8+0.1-2.0-6.2)/6=.12  This gives a closer match to 0 than the previous seven patients average.

Out of the pool of 9 patients, 3 are excluded.  Only patients 1013 performs well and then declines which is statistically within probabilities of the natural course of the disease.  Patients 1002 and 2002 are deteriorating quickly and to such extent that the given averages cannot include them.  The inclusion of the SIGMAR1 and COMT gene variation whittles the pool to six patients, that is 60% of the initial population which is congruent with the 80% of the general population to be with the “right” genes.  The data points are for averages so they include those who declined and those who improved or kept their scores unchanged. In conclusion, the p-numbers given with the 148-weeks data leave little doubt that the data is not a fluke.

The slide 29 does not include all patients in the pool of six so we can not try to have a second data point to assess the validity of the presented conclusions.

Due to some problems with my health, this could be my last post.  I thank everyone who read these rather simplistic posts.  Thank you, again.

 

Pelosi and Trump Walk into a Bar….

Due to my disabilities, I am not much of a writer so I only present here a train of thoughts…..

Nancy Pelosi dismissed the possibility of pursuing impeachment of President Trump.  Trump accepted it apparently with relief.

Trump is as close as it gets to one man army inside hostile territory.  The people associated with him have been prosecuted just to put the fear of establishment (Deep State) in him.   Trump at least in image evolves from disruptor into establishment figure (vaguely).

The Crisis of Middle-class

In the Housing Bubble (2001-2007) Middle-class households existing homeowners benefited from excessive credit creation as their houses appreciated in value.  The next generation though would have to work twice as hard to get into a house of their own.  Another illustration of harm done by excessive credit creation.

Relatively wealthy Middle-class supports through its consumption the wealth of the elite rich. Otherwise, their assets bring less income.  Even in poor countries, the value of assets is linked to the purchasing power of the Middle-class in consuming countries, directly by demand on products these assets produce or through the creation of capital to possibly acquire them.

The impact of the wealth of the Middle -class has been eroded by excessive credit creation, replacing its wealth with debt founded consumption.  Middle -class is in the process of reaching the point of exhaustion of its debt taking capacity in face of rising costs of assets and living.

The next generation sees that the opportunities to accrue wealth have been diminished for them just like in the case of the post Housing Bubble (2001-2007) homeownership.  This touches on healthcare, education, homeownership and job prospects.

 

The Trends Are ..Not Your Friends

The industrial revolution started with the primacy of manufacturing prowess by states with corresponding importance and growth in its financial branch.  In the XX century, the financial branch takes over and replaces manufacturing as the greatest source of wealth.  The current allocation of credit is based on the capitalist premise of rewarding efficiency and profit creation (the idea of competition between individuals), yet at the same time is corrupted and displaced by excessive credit creation and regulating competition by the state (mostly to protect larger players).  The idea of an economy with “rational” (arbitrary) credit allocation takes root as the utopian idea of Socialism, leaving to the individual toothbrush and bedroom, his shoes are already the property of the state.

Socialism, the Live Preserver of the Millenials and post Millenials.

The squeezed next generations in face of crisis look to transform the system, wrongly called capitalism as it had gradually died over the XX century, into the utopian vision post-capitalist society.  They rally around promises of infinite credit creation (Modern Monetary Theory), Climate Change (formally knowns as Global Warming) calling for “rational” credit allocation, and Socialism (social utopia) as embodied in percepts of Cultural Marxism (namely destruction of Middle-class based on consumption and private property).

Naming names:

Bernie Sanders:  Socialist Utopia, the XX century type, with the roots in Thomas Moore’s “rational response” to the irrational world shaped by human nature and history, in Utopia.

Alexandria Ocasio-Cortez: Millenial response to the crisis due to the corruption of capitalism caused by excessive credit creation. Uneducated and irrational.

 

Let’s see what the currently sitting system does.  Federal Reserve creates money out of nothing, among others to control interest rates by buying treasuries.  Then the money goes into the banking system which by its virtue of giving loans to people and businesses (debt/credit) multiplies the money in the economy.  The control of interest rates by the Federal Reserve makes for lower interest rates with time to facilitate refinancing by businesses and people. This innocuous statement hides the deadly sin of creating businesses which can only survive if the interest rates are even lower.   Interest rates determine which businesses are viable economic enterprises as they have to compete for capital with deposits and other forms of investments (the essence of financial markets (free markets)).  The low-interest rates and excessive credit creation allow for the existence of unviable economic enterprises, which is called malinvestment as these will fail once interest rates go up.  Unimpeded interest rate lowering and credit creation lead to an increasing gap between GDP and Total Credit/Debt of the entire economy.  See link Total Debt to GDP USA

The Total Global Debt to Global GDP is not at 327%.  Before 1980 this was 120%.  It doesn’t matter how we got here, what matters where we go from here on.  For the USA if the annual credit growth falls to the vicinity of 2% of all the outstanding credit then the USA catches the disease of recession.  If the discrepancy between debt and GDP (the proxy for ability to at least service the debt) blows up then either we enter a series of borrower defaults followed by deflationary depression (like The Great Depression II) or the Central Banks would create large amounts of currency to fill the gap.  The first is politically painful but short in duration with great losses to almost everybody, but at least after the storm, you have the new economy not burdened by excessive credit/debt and capitalism can build wealth up for all again. Let me mention here that the banking system would become a victim of its own making.  The second option entails basically keeping the system alive and bringing it into logical conclusion by creating so much currency that old debt is inflated away with nobody defaulting on their obligations, but ultimately bringing new currency after the previous was destroyed in hyperinflation, so-called reset.  Inflation of that sort already exists in the system as old debts are inflated though slowly (we need hyperinflation for clean slate).  Yet, it is at a scale not significant to bring this about in short time frame. The concomitant here is the erosion of wealth of Middle-class as their earnings do not go up as quickly.  The GDP numbers go up as the country suffers a decline in real wealth as expressed in the buying power of the Middle-class.  The elite’s assets are meantime inflated by the new money due to excess credit creation.  In both of these scenarios, the banking system is either completely wiped out (Great Depression II) or cut severely in size and importance (Hyperinflation).

Let’s visualize something first….

USA Debt-Credit and GDP graph

In 1954 the Total Debt of the USA was 170% of its GDP, by 2009 it was almost 400%.  For the banking system to come unscathed either the debt has to come down to GDP – repaying by reaping benefits of higher growth – not possible as of yet due to departure from self-regulating capitalism going too far!  Or the GDP go higher to catch up with Debt/Credit.

If the GDP growth is greater than Debt/Credit growth then GDP can catch up to Debt/Credit over time.  Yet this is impossible since the malinvestment lowered the return on investment in the economy. Among others by creating businesses like Amazon bringing nearly no profit and destroying the margins of the competition (this was all done with cheap capital and promises of monopoly).

The only option is to drive the GDP higher by monetary means.

GDP=Quantity of Money * Velocity of Money=Consuption+Investment+Government Spending+Exports.

Enter Here The Modern Monetary Theory!

So by inspecting the identity for the GDP it is obvious that one can increase the quantity of money without increasing debt and with the same velocity to raise the GDP.  For now, the velocity is low due to the heavy burden of debt.  In the real world of complex economic reality, not that thought in Universities, this immediately causes inflation so Modern Monetary Theory advocate price controls, like they have done any good in the most recent example of Venezuela.  Rose by any other name…

Wait, there is more..The second identity has two components dear to the hearts of MMT creators;  Consumption and Government Spending.  The first to be “lowered” and “streamlined”, second to be managed in order to “rationally” distribute resources into sectors needing, accordingly to great washed masses of bureaucrats, “investment”.   The narrative for both is to be provided by global warming a.k.a. Climate Change.  What it means is that some sectors of the economy are to be eliminated or reduced so our economy has to be just simplified to be manageable within bureaucrat’s mind.   The other means to heavily invest in industries with a negative return on investment like reusable energy boondoggle since “capital” is to be created at will.

It is said that the economy is the science of scarcity, and this scarcity makes the markets which in turn make the prices.  MMT does away with the corrupted vestiges of capitalism and brings this corruption to a logical conclusion.   Excessive credit creation is made into outright money printing, inflation due the former is dressed with price controls to destroy any rationality of production, and the latter to be supplanted by a command economy.

USSR thanks to simplifying its economy build a splendid war economy but after 70 years this one also died.  Nameless are millions of its victims.

Is it possible for Pelosi and Trump to unite their efforts in order to battle the socialists in USA?