ANAVEX 2-73 Phase 2a vs. Alzheimer’s Progress

  1. ANAVEX 2-73 Phase 2a trial has been discounted by some on the grounds that the sample size produced statistically insignificant results and that there was no placebo arm.
  2. Source of data for Natural Course of the Alzheimer Disease can be found in scientific literature and rudimentary comparative analysis can be made of vs. Phase 2a.
  3. Using data released for the first year and partial one after the first year, analysis revealed that:

1.  High Concentration Cohort data could signal strong therapeutic effect.

2.  Therapeutic effect might not  be explained away by a fluke distribution claim.

3.  Bifurcation of outcomes in High Concentration Cohort might explain the need for biomarkers to identify ITT population.

The management of AVXL has been criticized and even ridiculed by some over the choice of 32 patient for phase 2a trial of its Alzheimer drug ANAVEX 2-73. The tradeoffs here, were between risky and expensive trial, possibly, bringing the company down in the case of failure (in context of history of 98% trials ending in failure), versus trial aiming to seek putative signals of efficacy, without being statistically significant (standard of the industry) and having the advantage cost to be within the finances of yearly cash burn.  On a lighter note, I always find hilarity in PRs dishing words of some not closely defined “efficacy” together with dash of “statistically significant” to make you swallow the bait for further financing. No, this is not the case, here!

The analysis is done by replotting publicly available data and making assumptions explained in the text. The author has not been trained in statistics so any criticism and pieces of advise are welcome.  I cannot help myself but to quip that if you lower the threshold for things improbable even dragons are possible and stone might strike up a conversation (attributed to Stanislaw Lem).  To draw up on previous sentence, reality is not locked into statistics but shouldn’t be totally out of it, either. 

The crucial information here is data contained in paper Variability in Annual Mini-Mental State Examination Score in Patients With Probable Alzheimer Disease  Arch Neurol. 1999;56(7):857-862. doi:10.1001/archneur.56.7.857.  Link is given here: 

Natural Course of the Alzheimer Disease presented in the study can be best visualized as a bar graph with 3 classes of patients: Those who did not decline up to this moment (No Decline): Those who declined less than 3 points on MMSE scale in any year followed; classified as insignificant decline (Decline<3): Those who keep declining more than 3 points in a given period (Decline>3).  Since the data is formatted in that way, almost identical classes has been established from raw data of ANAVEX 2-73 study.  The raw data can be found on pages 23 and 29 of Corporate Presentation first released at CTAD 2017. 

To visualize Natural Course of the Alzheimer Disease see the first bar graph below. The trial starts with 372 patients, after first year there is 6% dropout, after 2 years the dropout is 39%. The dropout is mostly due of to rapid and profound deterioration. The class of patients No Decline quickly diminishes in numbers, and after 4 years they are nonexistent. Since human beings vary greatly in genotype and phenotype the variation of MMSE scores between individuals follows. The average MMSE score of the patients starting and staying on the trial can not be precisely verified since there is no raw date on that, but can be approximately taken to be around 20 MMSE. For the ANAVEX 2-73 study this was 21 MMSE, so these are comparable studies.

Ill one.pngIllustration of Natural Progression Of Alzheimer Disease


ILL two.png

Illustration of Progress of Disease in High Concentration Cohort of ANVEX 2-73

Since the data is limited to two years for the only cohort which displayed therapeutic effect (High Concentration Cohort) the comparison can be conducted so far.  Also, the number of people dropping out in the cohort were adjusted to mimic those in the Natural Course of the Alzheimer Disease.

These assumptions allowed to have the cohort to start initially with10 people, reaching at year one 9 (10% dropout), and again at the end of second year coming down to 6 (40% dropout rate at  year two).

Clearly, the graphs allow for direct visual comparison as they are almost identical in format.  Over first two years of the ANAVEX 2-73 trial there is an increase in probability of a patient, for those still staying in the trial, to be counted in the two classes (colors; yellow and green) defining the therapeutic effect versus Natural Course of the Alzheimer Disease.

When there is no putative therapeutic effect for given patient he is counted in the color blue Decline>3 class.  The presentation of results defines the probability of a patient at the start as 100% (certainty) to find himself/herself in the No Decline class and then splits the 100% into probabilities for the three classes. The goal is to show larger swats of yellow and green vs. blue.

iLL three.png

Probability for patient to find himself/herself in one of three classes as long as he/she stays in trial – Natural Course of the Alzheimer Disease.


Probability for patient to find himself/herself in one of three classes as long as he/she stays in trial – High Concentration Cohort ANVEX 2-73 Phase 2a 

As we are not informed on the dropout rate at 2 year end of Phase2a ANVEX 2-73 study we took liberty to assume that that is the same as for the Natural Course of the Alzheimer Disease, with this assumption the difference in probabilities for both studies are easier to be visually recognized.  The putative therapeutic effect can be measured in the width of No Decline, and in limited capacity in Decline<3.  This suggests expectations of a strong signal of efficacy in standard industry trials. 

The efficacy of ANAVEX 2-73 visualized here, might be dismissed by claiming that we are falling victims of skewed distribution of outcomes due to small sample size producing what is called statistically insignificant results, questioning their degree of validity.  Logically, had this been the case for the sample size one would have expected skewed distribution on the other branches of the study for ANAVEX 2-73 which did not shown therapeutic effects.  If this is the case then the argument gains on validity.  Refuting the argument bring us closer to raising the degree of signal validity even with the limited sample size.

ILL five.png

Average Declines for Populations in AD trials over one year (see legend above)

The lines for Natural Course of the Alzheimer Disease and Low+ Medium Concentration are almost identical so are their distributions so by extension Low+ Medium Concentration exhibits natural for AD distribution disturbed by any other effects.  This observation would bring increase confidence in existence of signal of efficacy in High Concentration Cohort.  

The High Concentration Declining patients decline at the rate of 165% of Natural Course of the Alzheimer Disease. There might be suspicion that ANAVEX 2-73 besides making some better can also make some worse, that might be called negative synergy between ANAVEX 2-73 and AD hence the efforts by the company to identify ITT (Intent To Treat) population to eliminate those who could potentially be harmed in Phase 3.  On the other hand the cohort seem to consists of two subsets; one of people who are healthier than average with higher initial scores who might have benefited, and on other side those below average that can not be rescued due to selective action of the drug and are naturally declining at higher rate.  This divide might be responsible for the bifurcation.  The clue can be seen in the fact that those who were helped by ANAVEX 2-73 (High Concentration Advancing) are having their initial average scores at 22.5 MMSE vs. for All Cohorts that is 21 MMSE.  

The delay with FDA go ahead might be caused by the need for some data to assuage regulator’s fears of realization of negative synergy between ANAVEX 2-73 and AD in some patients treatment. 

The hypothesis that the bifurcation is rather a natural phenomenon due to selective action of the drug, either before point of no return for patients with Alzheimer disease, or synergy with genotype/phenotype combination to trigger the drug action, could be vaguely supported or refuted by comparing average score for only High Concentration Advancing necessary to bring the High Concentration (whole cohort average) (High Concentration Declining’s score is known) to decline with the rate of Natural Course of the Alzheimer Disease. This turns out to be +1.33 MMSE per annum (vs. +2.53), close but not enough to be within first Standard Deviation (-3.8 avg. +/-4.3) of Natural Course of the Alzheimer Disease.  It might be that there is more at play than just higher MMSE score connected to point of no return.  In general, the author lacks analytical skills and data to move beyond this set of concepts, both should be found in presentation on results of genetic and phenotype patient signatures collections and analysis helped by Artificial Intelligence (automated due to overwhelming number of connections) and scheduled to be released at AAIC 2018 Chicago on July 25th, 2018.

The delay with FDA to go ahead with Phase 3 might be caused by the need for some data to assuage regulator’s fears of realization of the negative synergy between ANAVEX 2-73 and AD in some patients treated with ANAVEX 2-73, but this is only a wild conjecture. 

I am convinced that such population has been found, hints could be found in mentions by the company of some genes whose specific expression is connected to prevalence of sigma 1 receptors on the cell walls.  I should wrapped up with short conjecture on prevalence of ITT population.  Out of 9 patients 5 responded or rather tentatively can be counted as such.  If the High Concentration cohort had followed normal distribution it would suggest that combined factors of low MMSE initial scores and other factors might make it quite common to place patients in ITT population.  Ultimately, this can drive the Phase2b/3 to resounding success in the future and make ANAVEX 2-73 shoe in for next Standard Of Care status.


  1. There are reasons to conclude that Phase 2a points to strong efficacy in industry standard Phase 3 trials.
  2. Expected existence of genomic and/or phenotype signature for responders validates claims for efficacy even in light of small sample size.

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