GOING ONE SLIDE AT A TIME.. CTAD 2020. $AVXL BLARCAMESINE

SLIDE 15.

It is long standing tradition that $AVXL formats the data in such way that only a scientist can quickly recognoze the revelance of the data to currrent paradigm of the disease in question. The individual investor is left holding in his hand something so bewildering that I don’t dismiss the calls that there is nothing to it just cherry picking or “no good data” to be dismissed as another trick played on the individual investors.

Let us get down to it and elucidate as much knowelde as possible. The note on the bottom left relates to statistical method. J-T test stands for ;

The Jonckheere-Terpstra test is a rank-based nonparametric test that can be used to determine if there is a statistically significant trend between an ordinal independent variable and a continuous or ordinal dependent variable. The Jonckheere-Terpstra test tests for an ordered difference in medians where you need to state the direction of this order (this will become clearer below). It is also known as the Jonckheere-Terpstra test for ordered alternatives.

The ordinary independent variable is the dose the ordinary dependent varaible is the count of right or wrong aswers in the test of Episodic Memory. Most questionares are available on line, but CDR-CA Continuing Attention is available in software form only and is being controlled by private company. In light of this I do not know how many counts there are to be found in the test. All I know that the test takes about 18 minutes. I am not even cartain whether this is pertains to the particular battery tasks in question.

If we assume 100 counts then the improvement is about 20% from base line and 42% of the scale diffrence between outcomes. This seems to be too big a difference to be relevant in the context of procentages of assumed scale because there is some sort of nonlinear situation here as probably the test units are of varing difficulty to extend the scale from mild symptoms to severe.

The only conclusion we can make is that during the period of 14 weeks the deterioration of those on placebo arm is sufficient to detect the trend down and the same 14 weeks is sufficient to exhibit the trend up. (up = improvement) in both dose cohorts and placebo. There is no way we can say anything more at this point as we do not know enough to anchore it to some absolute value. To make a meaningful plot one needs the number of misses as well of hits. All we have is relative number of hits (mean) with bar of distribution.

Another slide with no absolute numbers but uses absloute vales of the changes from baseline of all the patients in population to arrive at realtive contribution of given populations. As you might remember absolute values do not have a minus sign and are always positive, it is just magnitude of change without direction. In the left side of the slide the contributions are changing in very small ways toward the dosed cohorts composed of SIGMAR1 Wild genotype and SIGMAR1 mutated genotypes. They all seem to be consitent with distribution of patients to cohorts (2:1). Then on the right side the population of SIGMAR1 Wild genotype in dosed cohorts (unmutated SIGMAR1=the good responders) increase their relative contribution. This proves that it is dosed SIGMAR1 WT who respond with greater magnitude of signal than the background of placebo. This gives greater confidence the dosed cohort privide statistical significance as they separate the signal from the background noise. As I said this does not measure the direction of change just its magnitude. From this plot one can see that average dosed SIGMAR1 WT is “improving” (if we assume that this only due to improvment, so we assume direction) 12.5% more than average SIGMAR1 WT undosed patient in placebo arm 6 weeks ago, compare this to 4.5% greater contribution of all dosed cohorts with both genotypes for the same period of 6 weeks. This makes the magnitude of change in 6 weeks 3 times larger for SIGMAR1 WT than between placebo and both dosed cohorts. One can say that SIGMAR1 WT signal to noise is 2.8:1. One has to remember that individual subjects due to variation in and nature of human performance will move up and down in zig-zag motion along some trend line, so there is noise and this can up as well down but will register in this measure as a positive value regardless of direction. There is one more piece of info to ponder here, as this is done within the confines of 95% confidence level, meaning the there is 95% chance that the result are repeatable, namely our beloved phrase “statistically significant”.

First thing which is a surprise is that that subjects have the SIGMAR1 Wild genotype in only 87 cases, these are the Good Responders. Remaining 47 patients are the mutated SIGMAR1 gene carriers. They are basically 1:2 represented in the test population. In other words the mutated version carrier represent 35% of trial population almost double that what is represented in the general poplulation. That is double overrepresentation of the 16 to 20% in general population. Does that mean the sufferers of PDD are more likely to be carriers of mutated SIGMAR1 gene? That would have two consequences, first that Population Intent To Treat would be a bit smaller due to greater mutated version of SIGMAR1 incidence among patients with PDD, second might be that mutated gene is innately connected with succumbing to PDD which supports thesis that the SIGMAR1 Wild genotype has protective properties.

Question of timing. From the Alzheimer’s Phase 2a we know that Blarcamesine given in lage enough doses results in sudden large changes in measured outcomes for the first 5 weeks then the pace of improvement, at least in the Super Responders became less steep but continued for few years. From the dosing on slide 11 and the info on the slide 17 it seems that in Parkinson’s Phase 2 the week 8th is comparable to week 5 in Phase2a and week 14 to week 11, Just keep this in mind.

In the above plot I wanted to convey the difference which grows with time when these trends as measured will continue. The slide 15 suggested 100 misses and 100 hits. this might be possible as the one test unit might be just few seconds (ten’s of seconds more likely). The scale here is just 50 misses. The 20 misses in just 14 weeks seems to be a very rapid decline, I think that the subjects range from those with MCI (mild cognitive impairment) to mild dementia so the decline in aggregate might persist.