Do not trade on this post as 4 billion years of evolution is against me and God might not agree with me either. LOL

 

It Pays off Being Suspicious. Only the Paranoid Survive…

I suspected that the curve for deterioration of the general progress of Alzheimer’s disease might likely contain a region of acceleration. I was for a short while looking for it on the internet but quit it all too soon.  Fortunately, I looked today at iHub and gentleman going under the moniker of amstock82 shared a paper illustrating the general trendline for Alzheimer’s patients.  Here is a link to the paper:

Rate of decline in Alzheimer’s disease measured by a dementia severity rating scale

again the illustration will tell more:

• First 2 years: y=-2.15*x
• After year 2 to year 5 y=-3.88x
• After year 5 y=-1.6*x

I have included this new info in a graph which old version can be found at this link:

 

Nothing like Blarcamesine..

So after updating the graph, it looks like this:

• Blue Line: Actual data till week 148 (~3 years) Blarcamesine High Concentration Cohort Phase 2a; extrapolated to year 9 with the rate of decline the same as between year 2 and 3; y=-1.3*x  (236%) (previously y=-.55*x).  This is an assumption which is in line with the general trend line for Alzheimer’s found in the above paper as after year 2 the rate increases from y=-2.15  to y-3.8 (173%) The prevalence of APOE e4 gene among High Concentration cohort (75% of carriers) has not been addressed or adjusted.  If we follow the adjustment numbers for the decline rate due to additional 27% of patients with APOE e4, from the previous post (link provided here), then the rate becomes
  y=-(1.3-.3525)*x=-.97*x and y=-.97*x is 172% of y=-.55*x (wow, what a coincident (?))
• Yellow Line: Quadratic equation fitted to 3-year data for the above cohort. The worst-case possible with ever-increasing acceleration in the decline of patients.
• Green Line: ADNI Synthetic Placebo Trend Line y=-2.2*+20, actual data till year 2, afterward extrapolated till year 9. This should not be the case as far as we know from the above paper.  48% APOE e4 of carriers.
• Red Line:  General Trend Line, from the above paper.  Described above.  30% have no APOE e4 and 45% at least one copy of the gene. Comparable to ADNI synthetic Placebo.  The first 2 years for both are identical.  It is expected for the GREEN Line to follow Red Line.

 

The above-mentioned post was looking at the worst case.  Now let us look at the best case, but still not adjusted for APOE e4 gene prevalence in the High Cohort, at least not yet:

• The Blue Bar:  MMSE points over General Tred Line for Alzheimer’s.  Observe that the difference between Blarcamesine patients and placebo grows up to the sixth year, and even there it holds.
• The most important Green Bars illustrate the expected delay Blarcamesine gives to an average patient at the current rate of decline.  An average of 65 year old patient expects to live with Alzheimer’s 8.3 years, for 90-year-old this is 3.4 years.  In reality, at about 10 MMSE independent life is impossible but Blacamesine can buy about at least 6 years of life.

Conclusions:

• The CTAD 2019 presentation dwells only on the period of 2 years because data from ADNI had been collected only for that period, and I suspect that the regulators recognize as Synthetic Placebo Arm only the data from ADNI due to its versatility and statistical significance.  ADNI was set up by the industry with this purpose in mind.  Most trials might never extend for more than 2 years so there is valid logic for limitation on the duration of collection.
• Some people raised questions as to why $AVXL used only 2 years of data, suspecting that Blarcamesine did not hold much efficacy as treatment advanced.  The prevalence of APOE e4 gene in the Cohort might lower the comparative performance of Blarcamesine over ADNI Synthetic Placebo Arm. In the very imperfect study conducted by me, the APOE e4 could have contributed about 60% of the absolute decline rate these two years.  Is this correct; I don’t know.
• The ADNI Synthetic Placebo Arm for 2 years behaved as the above reference would call for. The graph of general Alzheimer’s progress was done with over 500 subjects. I don’t think there are problems with being not statistically significant.  Yet this data might not be valid to create a synthetic placebo arm since placebo effect exists.  Is this applicable to dementia?  I am not an expert.