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!
So called previous post link https://piotrpeterblog.com/2021/08/09/cassava-science-results-vs-anavex-life-sciences-projections-sava-avxl/
This post is rather a continuation of that post.
$SAVA, The First in The Race Contender
The share price of $SAVA has taken some beating over the alegations of, let’s say it outloud, fraud. Nevertheless, the price has been staging some comeback. Either, due to short memory of the market participants or the flimsy character of the accusasion. The data presented for Simufilam 9 months duration trial will be here compared with $AVXL phase 2a trial data which was presented in similar manner. There is a 3 months mismatch between those two sets of data, but our excercise is to gain an insight into any substantial future advantage to be achieved by any of those companies in the future.
The Differences Are Important
There are substantial differences between the general level of deterioration of the patients in both of those trials. In previous post I pointed out the discrepancy between both mean base point as they where expressed in MMSE and ADAS-Cog11 by $SAVA. I used the graphic calculator by Steve Balsis et al. (see previous post) to assess these. In terms of MMSE scores there is a rather substential difference between 24.3/22.6 MMSE and $AVXL phase 2a 21 MMSE. This discrepancy will be addressed in $AVXL’s AD Phase 2b/3 due in second have of 2022.
On the other hand $SAVA presents just 9 months of data vs. $AVXL’s 57 weeks. If the deterioration vs. therapeutic effect accelerates with time the advantage goes to $AVXL. From the data the therapeutic effect of seem to have a steady progress with just 1/3 of patient lagging for Simufilam and in case of $AVXL phase 2a only the 1/2 half of the High Concentration Cohort responds but with very strong therapeutic effect. Simufilam seems to affect all but in very mild manner.
The illustration to both of these characteristics of response have been presented in previous post.
Effect Size: Cohen’s d
Cohen’s d measures the effect size of a drug vs. the placebo arm. It is proportional to the distance between the means of distribution of the two bell curves. It is also inversly proportional to sizes of the standard deviations of those two bell curves.
The Question of the Choice of the Placebo Arm
Neither the $AVXL phase 2a or the Simufilam data contain any information on a placebo arm. We could use the industry standard ANDI 2.1+/-.4 MMSE but we have a different population in case of $AVXL phase 2a, the lower concentration cohorts. They can be seen on the illustration in the previous post. If we take the entire High Concentration Cohort 8 patient group and measure it performance to the Lower Concentration Cohorts the Effect Size Cohen’s d is equal to 1.39
If we use as the placebo arm from the reference  on the previous post with decline of -3.4+/-6.1 MMSE and run the same calculations we get Cohen’s d equal to 0.95.
Once we have done this we can look at the $SAVA data. Again we have question of the placebo arm. I decided to use the annual decline from the reference  and use the Steve Balsis et al. graphic calculator for transfering the measure of dementia from MMSE scale to ADAS-Cog11. I settled on +10+/-11 ADAS-Cog11 points. The use of annual data, 3 more months of decline might enhence the Effect Size for Simufilam. I am not worried about this error since I am looking for insight, not predictions or forecast. The Effect Size Cohen’s d for Simufilam (9 months data vs. 12 months decline) is 1.63.
Simufilam has on its side the higher baseline MMSE scores, less advanced into demntia patients. This might be a decisive factor in the pursuit of higher Effect Size as it seems that the more advanced people are into dementia the therapeutic effect is all that smaller. $AVXL phase 2a gave the same indication as in the High Concentration Cohort patients who responded to Blarcamesine were all above 20 MMSE. In contrast Simufilam trial has average MMSE score above 22.6 MMSE, at least. It is unceratin how this is spread but possibly it can include some below 20 MMSE. In $AVXL phase 2b/3 all the patients shall be above or equal to 20 MMSE. That is why a whole set better results are expected from $AVXL Alzheimer’s phase 2b/3.
In the case of $SNPX and $ATHA we discussed the appearing distinction between “preventative” and “regenerative” CNS drugs. https://piotrpeterblog.com/2021/08/20/neurotrophic-factors-in-curing-alzheimers-and-other-neurodegenerative-diseases-snpx-avxl-atha/ .
The distinction might not be clearcut, some overlap is possible. $SNPX is trying to develop narrative of pure regenerative drug. Yet as I further researched, the SIB (Severe Impairment Battery) can be as well as a 133 point scale. In the light of this any translation of performance into MMSE score card is even more dobtful. Initially, I thought it could be 80 points. Bryostatin can provide a signal in a sea of noise, but the signal can be almost drawing in the noise making it clinically insignificant. So, unless I am entirely wrong about Bryostain, I would wait for more data.
We are still waiting for data from phase 3 of $CRTX drug which as I was reporting holds the only scientific explanation of the mystery of APOE4 alle and higher incidence and severity of Alzheimer’s among the carriers. Very well researched article can be found under this link https://seekingalpha.com/instablog/20791881-gordon-gecko-was-a-commie/5613017-cortexyme-s-gingipain-theory-of-alzheimer-s-disease-pathogenesis .
Dr. Missling has been changing the narrative around Blarcamesine from neuroregenerative drug to neuropreventaive drug. I also ventured into pure speculation when I published post where I stipulated that Blarcamesine has not only removed the morbidity due to Alzheimer’s or dementia but also improved overall life span on the small initial sample of 32 patients. link: https://piotrpeterblog.com/2021/06/12/is-there-more-than-just-alzheimers-parkinsons-and-rett-syndrome-in-blarcamesine-bag-of-tricks-avxl/ .
Let us return to the leader ($SAVA) and the ugly duckling ($AVXL). $SAVA has produced 50 subject study and the n=50 did the trick, it instilled confidence in $SAVA when competition has been timidly dipping toes in phase 2a trials with just a tens of subjects. What was suspicious about $SAVA is its management structuring a large payout when stock price would have reached certain value. Fortunately for the stock holders ((?) equivocal statement) the market just spooked before the share price was reached. It seems like get quick rich scheme. On top of that, add accusations of use of doctored images in publications.
From the above calculations of Effect Size Cohen’s d for both drug, Simufilam has not have an upper leg on Blarcamesine. Equivalent study of Blarcamesine is still in the making, double blinded. I would like to see ~18 months duration of study of Simufilam to compare both in the most direct way it is possible.