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!
Hat tip to Tom Dean.
Let’s start with a pretty picture.
I broke down the “variety” of patients into two groups 6 Patient SUPER RESPONDERS and 9 Patient HC Cohort. What can I say about HC Cohort:
- In light of other developments it seems that HC Cohort contains some SIGMAR1 Mutated Variants patients who basically behave like under placebo.
- The “performers” in HC Cohort should be all SIGMAR1 WT type carriers.
- Among the “performers” and “placebo like” are spread carriers of APOEe4 allele which contributes to severity of decline. There is 75% of APOEe4 carriers so the results are skewed toward under performance. In general population the number of APOE e4 carrier is about 48%. See info on impact of APOEe4 at a post on my blog at this link https://wp.me/p2IvqX-7q
- The distribution of performers to “placebo like” patients is such that we can assume it to be the worst case for accessing the possiblity of approval by FDA it is even worse than natural distribution of SIGMAR1 WT gene. This has been made void by use of Precision Medicine by $AVXL.
What can we say about the SUPER RESPONDERS:
- It seems that all 6 patients are carriers of SIGMAR1 WT who respond to Blarcamesine in significant way.
- Among them might be scattered carriers of APOEe4 allele whose severity of decline is affected by the genotype.
- We assume this to be the best case for application for approval from FDA known to us at this time.
What “statistically significant” mean:
It is similar to the phrase beyond “reasonable doubt”. If p is greater than .05 then there exists reasonable doubt to the hypothesis trufulness and for all pratical purposed it should be rejected. Otherwise the hypotesis find itself beyond reasonable doubt. Still, p-value might be below .05 and the effect might be not satisfctory. Results can be have low efficacy but valid statistically. Enter Effec Size into the picture.
What effect size is:
We can calculate Cohen’s D between two samples with defined mean and standard deviation to assess the Effect Size of a drug in trial.
The biggest hurdle is to assess the decline per year and standard deviation since number of studies exist and in case of annual decline I have seen numbers like -2.15, -3 and -5.7. They all are very sensitive to the mix and match in the placebo cohort of the MMSE, age and genetics. The same applies to standard deviaton as I have seen -2.15+/-.31 through -3+/-3.4 and -5.7+/-8.2. The closes to the ADNI Syntetic Placebo (standard of the industry) is -2.15+/-.31. I assume that the extremely narrow standard deviation in this model should be changed to at least vaule of 2 so that allow some not to decline even after one year.
How to interpret these findings?
The Best Case. 2.98 Size Effect is well beyond the .50 acceptable level for drug approval “no questions ask”. This is the same magnitude (2.8:1 “therapeutic signal” to “placebo noise” ratio) effect as was conveyed by the slide 17 with the placebo SIGMAR1 WT patients “noise” vs. SIGMAR1 WT dosed patients “signal”. Donezepil showed in highest dose cohort Size Effect=.28 and was approved. Even at the severe disadvantage Blarcamesine has 125% of ES of Donezepli, and this is done ove the period double that of Donezepil’s beneficial effect, of just 6 months. The ES=.35 is strongly influenced by decline from average, I assumed this to be the 21 MMSE points and decline of -2.15+/-2.00. If the placebo decline is just one point more, we get following change in ES result. This proves how sensitive is ES to placebo model.
- One should be very appreciative of the management by Dr. Missling, as instead of pursuing outright a decisive trial which could possibly disappoint and shatter the company and prospects of ANVEX2-73 he probed all possibilities and collected enough data to create a juggernaut of a drug. For a small company and a giant in waiting that is not a small feat.
- Once Dr. Missling said once we get approval we will understand why he went this way not another (paraphrase).
- The emphasis on Precision Medicine is the exapmle of the sentiment I expressed in above point. Without it the we would not be unaware of the real healing power behind this drug.
- Placebo and its composition (initial MMSE scores, age and genetics) is very important as it determine the deterioration of its patients. As ES is very sensitive to placebo metrics so is the approval process but at ES=.28 (Donezepli) the hurdle is low.
- Yet, if ES=.63 even at being unaware of Anavex2-73 would have had a clear path to approval. Without Precision Medicine all depends on placebo relative performance.
- The SIGMAR1 WT show the same performance in PDD Phase 2 as the same genotype in AD Phase 2a.
The question whether there will be an approval has been answered; all the ducks are in a row. The rest is in the nature of the game of being a biotech stock, the science has spoken, it seems to be settled.
I am planing to partial change profile of my blog so I am not going to blog about $AVXL mostly, may be there is some cash in other subjects.
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