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!

## Etiology Battle Won

The first paragraph says it all.

*ANAVEX®2-73 treatment resulted in significant increase in the expression of the SIGMAR1 mRNA biomarker that significantly correlated with improvements in the primary and secondary clinical efficacy endpoints CoA (p = 0.029) and MDS-UPDRS Part III (p = 0.024) and MDS-UPDRS Total (p = 0.038)*

Wherever Blarcamesine has been treating patients increased SIGMAR1 messengerRNA has been detected, this direcetly connects the drug with the biomarkers and the therapeutic effect. Clear and known Mechanism of Action has been established. Blarcamesine is a pathblazer for other SIGMAR1 drugs making iself the first of a new class of drugs. This warms considerably the icecold feet of FDA.

## Parkinson’s Disease Dementia Addressed

.*……which correlated with clinical efficacy as measured by primary cognitive efficacy endpoints, CDR system Continuity of Attention (CoA) (p = 0.029) and CDR system Power of Attention (PoA) (p = 0.015),….*

*Broad and statistically significant improvements in CDR system Cognitive Domain of Attention assessed by Choice Reaction Time (p = 0.039) and Digital Vigilance (p = 0.008) and CDR system Episodic Memory (p = 0.047), representing complex cognitive tasks with impact on quality of life such as making a choice between similar objects and remembering daily personal experiences, which are mostly impaired in both PD and AD.[15] Statistically significant dose-dependent (p = 0.003) improvement of Episodic Memory, which has been shown to be highly correlated (70%) with the Alzheimer’s Disease Assessment Scale–Cognitive score (ADAS-Cog; r = 0.7).*

See my previous post on Episodic Memory as was reported initially. link: https://piotrpeterblog.com/2020/12/04/after-conference-of-3rd-of-december-2020-on-alzheimers/ . I have calculated the Effect Size for Episodic Memory which in my reckoning was supposed to be about 1.40. We don’t have and other data than what is given in the quotation. Firstly, CDR is composed from few subtests like Continuity of Attention, Episodic Memory, Choise Reaction Time, Digital Vigilance and Power of Attention. Those subtests measure errors and speed of response. The only metric given here is the p-vales of each subtest. P-values refer to the probability of the results being part of the characteristic dispersion of data among the placebo cohort. The lower the number the better results, or data points are better separated from placebo. They are both statistically significant, with Power of Attention being the best. Nothing more can be said at this moment. This calls for deeper research than done by me at this time, and a separate post.

## Did Blarcamesine Put Parkinson’s in Its Bag of Tricks?

I shall not engage in speculation right now. (Just for a moment) Let me quote from the PR.

*….and secondary Parkinson’s efficacy endpoints Movement Disorder Society-Unified Parkinson’s Disease Rating Scale* *(MDS-UPDRS)[4], MDS-UPDRS Part III (p = 0.024) and MDS-UPDRS Total (p = 0.038).*

Let’s us analyze the MDS-UPDRS test. It consists from 4 parts. I read through the questionnaire and tried to evaluate the maximum score obtainable which equates with scoring the worst on all measures. I can approximate the number of points to be about 230-240. The average Parkinson’s patient in the Phase2 PDD trial scores about ~77 points (1/.189*14.51= 76.8)(at the end of 14 weeks). Quick search revealed this to be about right.

Let us engage in pure speculation. We have the two mean values at 14 weeks and one of the standard deviations. We could explore the possible values for the dosed cohort standard deviation in order to calculate Effect Size for the Blarcamesine as Parkinson’s disease drug.

- The placebo score is 77+/-32.8
- Dosed score is 62.5+/-30 (assumed sdandard deviation of +/-30)

**The Effect Size @ 14 weeks is 0.45**. This is almost enough to approve the drug (minimum) but we would expect this to increase witht the duration of the trial as Blarcamesine Effect Size in progressive neurodegenerative diseases increases with the duration of the dosing. We have to remember that Donezepil was approved with Effect Size of 0.28 after six months of dosing (24 weeks).

Not without a reason, Dr Missling singled out the Part III (p-value of .024) from the MDS-UPDRS Total (p=.038). Part III is the motor examination which loss of is characteristic for the disease. Here, the implication is that patients on Part III score “better” than on measures of dementia and daily living, and the drug is engaging the core etiology of the disease.

Additionally, Blarcamesine improvement has been twice the empirically established cutoff score for spurious improvement of -7.1 points of MDS-UPDRS. We have remember that all this is happening at 14 weeks of dosing. As I previously pointed out, Parkinson’s is a progressing condition so even staying in place makes for larger Effect Size with time. A relatively small Effect Size is due to large size dispersion around a mean. The same reason might be behind the empirical cut-off of -7.1 points as such small difference in between the two mean is not sufficient to separate the two dispersions for any meaningful effect. After pluging the numbers into the formula for Effect Size we arrive with the number of 0.22, which qualitatively is below small. I guess many trials produced somewhere below -7 points only ultimately to disappoint. One might compare it to gravitation and Blarcamesine breaking away from it to leave its pull permanetly.

**The Phase2 PDD has given us enough of data to claim that Blarcamesine is not only able to treat Parkinson’s dementia but also Parkinson’s disease itself. The experience with the extension of Phase 2a Alzheimer’s give us confidence that the effect of the drug will not wane with time but might reverse the ravages of the disease.**

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