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!
This is the final installment of three parts in the same question. Two previous installments are;
The Proper Mix
If we are to assess the chances of Blarcamesnie to better its results in Alzheimer’s phase 2b/3 then first we have to list the known factors impacting the response of the patients. These are;
- The baseline MMSE score of a patient
- Presence of the Wild Type genes for SIGMAR1 and/or right version of COMT gene
- Being a carrier of APOE4 alleles or allele
In sundry remarks during the time from phase 2a to present Dr. Missling has revealed that “we can rescue anybody above 20 MMSE score”. The phase 2b/3 recruits only those with the MMSE score above 20.
In another remark Dr. Missling has thrown light on the unexclusive character of the SIGMAR1 gene as the fact of being the carrier for the mutated gene does not preclude the patient from responding, just makes the response less pronounced.
The last but the most impactful point concerns the APOE4 allele. From the illustration below it is clear that APOE4 affects the chances of a patient to resond to Blarcamesine the most.
When read, this graph makes clear that in phase 2b/3 the predominant class will be Group1
- SIGMAR1 Wild Type
- Both APOE3 or other than APOE4 alleles
We are only looking into high dose cohort so we assume that all patients are all High Concentration. The same applies to MMSE scores, as they are all to be above MMSE 20.
As the patients number move from the smallest sample size in life sciences of 30 towards hundreds, the probability of mirroring the population distribution of these factors in the sample population grows.
The probability of having any other allele than APOE4 is 44%, combine this with 90% probability of SIGMAR1 WT and get ~40%. The suggested response is in the range of +3.5+/-0.7 MMSE as the illustration below suggests. Two highest scoring member of the set to be identified as member of this class of patients. This is 57 week dosing chart.
The class of patients in phase 2b/3 corresponding to Group2 minus Group1 that is carriers of APOE4 allele or alleles plus the conditions in Group1, which basically stand almost still. This Groups has been marked yellow. Probability of occurance .90*56=50%. The rest, that is 10% assumed as declining with palcebo or worse.
Assuming mean of 23 MMSE and looking at 16.6 +/-3.4 MMSE mean placebo with 24.5+/-2.4 MMSE mean projected for data after 57 (one year) weeks. Once we plug in these numbers into Cohen’s d formula we get Effect Size of 2.68.
Simufilam number from post number two were 1.63. The presented educated guess on Blarcamesine might not be on the money but I think it highly unlikely to fall under the number given by Simufilam. The difference is very large in terms of Effect Size.
The anecdotal “evidence” points to even larger Effect Size. Nevertheless I would like you to take these results with grain of salt. I do not know what precisely means Dr. Missling saying that ” We can rescue anybody above MMSE 20″. There seems to be contradictory evidence in source  but source  is not entirely clear on many aspects of the phase2a, at least to me. From the rudimentary probability calculations 40% of patients shall not succumb to the dreaded decline associated with Alzheimer’s. Further 50% shall dither between further decline or stable condition. 10% shall decline with the placebo or even worse.
The most significant factor in decline is the APOE4 allele. In article written on Seeking Alpha private blog link https://seekingalpha.com/instablog/20791881-gordon-gecko-was-a-commie/5613017-cortexyme-s-gingipain-theory-of-alzheimer-s-disease-pathogenesis , there is the only worth of attention explanation of the pathogenesis of AD connected to APOE4 allele. Let me quote the gist of it. I strongly suggest reading the post.
From this post it becomes obvious that Alzheimer’s might have very complex etiology and Atuziginistant might affect some aspects of the disease as well as Blarcamesine and Simufilam. It is possible that all three of these drug will be necessary to tackle the disease. I think it is worth to wait for the CTAD 2021 in November to see the data from $CRTX phase 3 GAIN study. Atuziginistat offers ways to cut virulence of the bacterium which might be involved in AD etiology, Blarcamesine starts regenerating mechanism reaching well beyond CNS diseases (my opinion), and Simufilam repairs the cellular scaffolding. All three might be necessary.
 Corporate Presentation on AD Phase 2a 2017.