ANNOVIS BIO, Mirror Mirror on the Wall…. $ANVS $AVXL $SAVA

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor!

How good are results from 25 days exploratory trial in Alzheimer’s and Parkinson’s?

For those accustomed to measure of dementia in MMSE (Mini Mental State Examination) it comes as a shock that the actual Posiphen score are lower than placebo in MMSE. This is due to two unrelated facts.

FACT 1: MMSE is notoriously insensitive to dementia among patients near healthy or MCI (Mild Cognitively Impaired)

This is illustration of the sensitivity of the scales in the range in question. Arithmetically, scale of 70 points divided by 30 gives 2.333 ADAS-Cog11 points per one point MMSE. In fact these scales have different ratios between them at different ranges.

For $ANVS Blue takes MMSE 25.4 initial baseline mean to ADAS-Cog11 15.0. Green takes ADAS-Cog11 10.4 (-4.4) to MMSE 26.8

FACT 2: Among the people sick with Alzheimer’s the MMSE scores can spontaneously improve, especially among the MCI (MMSE ~25).

The difference in MMSE scores interpreted from ADAS-Cog scores is +1.4. This is comparable to Blarcamesine scoring +1.2 MMSE in initial 5 week. Compare this with the tests on the dosed cohort of AD patients which is just +.8 (~60% of interpreted value, I came to the conclusion that $ANVS became victim of the random statistical events which we try to fend off by both spreading the tests in time and having large enough sample size. There is also the fact that the newly diagnosed sometimes spontaneously score better on the MMSE test in the first three years of the duration of the disease. By pure fluke the patients in placebo scored better than 25 days ago. See this illustartion from reference link https://pubmed.ncbi.nlm.nih.gov/10404988/

Now let’s compare this with the six months results from $SAVA. First see the Press Release https://www.cassavasciences.com/news-releases/news-release-details/cassava-sciences-simufilam-improves-cognition-and-behavior . This PR states that there was improvement -1.6 ADAS-Cog11 and that improvement was 10% from baseline over 6 months. That gives the baseline mean score to be 16 points.

For $SAVA over 6 months Green takes initial ADAS-Cog11 score of 16.0 to MMSE score of 24.9. Blue takes improvement of -1.6 ADAS-Cog11 to MMSE 25.4.

The interpretation of this chart suggests that the MMSE scores improved only +.50 points. This is on a bit lower than the performance of the whole n=8 High Concentration Cohort in $AVXL Blarcamesine exploratory Phase2a at the same time. But there are also conspicuous differences. Simufilam treats population on average ~25 MMSE whereas Blarcamesine treated one at ~21 MMSE. The High Concentration Cohort ,had as it members subject moving up 2-3 points and those declining 3-4 due to prevalence of 75% of APOe4 carries and scores below 20 MMSE. Had the cohort had more people over MMSE 20 and less APOe4 (50% of population) carriers it would have been few points above the baseline at this point. The cognition improvements of Posiphen are larger than those experiences by Simufilam in much shorter time frame save the spontaneous event. This bodes well for $ANVS drug as similar pattern had been developed by $AVXL Blarcamesine. After first 5 weeks the mean on the almost 30 patients went up +1.2 MMSE points. Unfortunately, some of these patients years later declined, yet the initial reaction to Posiphen is similar to $AVXL Blarcamesine. See my blog for more information.

I would like to make few remarks on the particular AAIC 2021 presentation slides.

You probably wonder what those numbers after ADAS-Cog name are? These are number of chapters added to the test. ADAS-Cog14 consists from 14 parts and is used to assess patients who are most mild Alzheimer patients like those who are participating in this trial. The scores for ADAS-Cog11 range from 0- to 70. THe range for ADAS-Cog14 is 90. the graph translate from percent to points as -3.3 points of ADAS-Cog14.

The improvement in part 3 is the smallest as it is only 2.7% that is about 1 to 2 points on the total MDS-UPDRS part 3. Part 3 deals with motion. Part 1 deals with behavior and mood. Part 2 deals with Activities of Daily Life. Part 3 is assessed by properly trained staff and concerns the motion status of a patient. Part 4 deals with complications of the therapy. It is obvious that the parts 1 makes the most progress. Part 1 is more connected with the well being than with motion improvement. I bet more information will coming soon on those 40 Parkinson’s patients in cohort 3. Though the bars convey visualy something different, the greatest disparity is between placebo and Posiphen in part 1 (~10%), I expect the the nascent change in the part 3 will increase with time. It is just right now almost 1/3 of that in part 1. I would say that part 1 is most likely due to placebo effect as patients expect to get better, of course, on top of therapeutic effect. This is confirmed in very small difference in the placebo vs. dosed in daily living part 2 which is very close to the 2.7% observed in the part 3. With time we can expect this to reject the distortions due to placebo effect.

Where Posiphen shine is the cognition improvement. Notwithstanding the problems with testing for MMSE and the distortions in testing scores in placebo cohort, the WAIS Wechester Adult Inteligence Test elucidates the tremendous change in cognition with the drug. One has to make an observation here that the improvements speed of movement and thought has been exposed with better sensitivity than it was done in MDS-UPDRS part3. Here again, placebo improved, so the placebo change was happening due to the possibility of the subjects in short time interval to improve spontaneously, especially that that placebo is just few subjects (AD n=6, PD n=5).

Cognition changes are the key to tackling Alzheimer’s. I think it was a mistake by $ANVS to have a n=6 placebo cohort. It was a right decision on part of $AVXL to dispense with it as in those exploratory trial distortions like this can happen with low n=6 and 25 days of dosing. Up to this moment I would place $AVXL first in effiacy, $ANVS second and then $SAVA. Remmber that that picture can change tomorrow evning.

How good are results from 25 days exploratory trial in Alzheimer’s and Parkinson’s?

For time being they are second best but stil can l improve.

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