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## I was asked….

…to comapre directly the performance of $ACAD Trofinetide to Anavex2-73 in RS-002 Avatar. It took me some time to analyse how to do it, and I found the only possible way at this time to use the data supplied by $ACAD to apply the AUC treatment to its results. The available data included the plot of RSBQ socres at 2, 6 and 12 weeks, for both Placebo and Trofinetide.

All I had to do was to apply and measure the area under the curves.

The Area Under The Curve for Dosed Cohort is 41.8 and for the Placebo Arm is 34.9. The unit is weeks times mean RSBQ score from baseline. Let’s see another slide.

The RSBQ scores are presented not with Standard Deviation in parethesis but Standard Error which is SD devided by square root of n. The n-numbers we can read from previous slide. After this calculation we have :

- Placebo Arm mean=-5.1 +/-8.7
- Dosed Arm mean=-1.7 +/-9.1

The problem is that we have only means and Standard Deviations, from the plot we can aproximate the mean RSBQ-ACU but the in order to calculate Cohen’s d for RSBQ-ACU for Trofinetide we need the to approximate the Standard Deviations for both arms.

In order to approximate Standard Deviation for the RSBQ-ACU I created a spreadsheet with theoretical sample distribution of the Standard Deviation value of both arms. They were both centered on zero mean and perfectly symetrical. Then, I factored out time multiplier from mean RSBQ-ACU scores and multiplied the distribution values. Then I calculated Standard Deviation approximation for RSBQ-ACU means. Then I took 70% of their values, to account for any possible error. These are not exact values but approximations.

Why the Cohen’s d is so small for Trofinetide? The original Cohen’s d so 0.37 for RSBQ data. That is way smaller than the calculated for RSBQ data for RS-001 which was 1.10 and RSBQ-ACU for RS-001 Cohen’s d=0.517. The original data for Trofinetide had very close means and relatively large Standard Deviations meaning that their respective data points deeply overlaped.

My calculations shall be taken with grain of salt but they are giving the insight into going with more sensitive measure of therapeutic effect of Trofinetide and Anavex2-73. They are relative and not absolute.

I prefered here to err on the side of caution end corrected the Standard Deviations for Trofinetide by 30%, I made them smaller by 30% increasing the value of my approximation of RSBQ-ACU Cohen’s d. There is a nice progression from Lavender to RS-002. In terms of RSBQ-ACU and the same could be suggested in RSBQ sequence. I just tried to fill the missing result by looking at the ratios between results, both horizontally and vertically. **With Cohen’s d that large on the side of Anavex2-73 vs. Trofinetide, there should not be a question which drug leads the race**. **With better demographics for Rett syndrome response, inclusion of younger patients as Rett Syndrome is a neurodevelopmental disease, larger Cohen’s d is expected for Excellence RS-003. **

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