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Avatar Rett Trial RSBQ Improvement (estimated)
2023 11-14
DEFINITIONS
AUC - - - - Area Under the Curve
A2-73 - - - - Another name for the drug Blarcamesine
Blarcamesine - The Anavex drug (a.k.a.A2-73) used to treat Rett Syndrome
Effect Size - - a statistical calculation used to compare the efficacy of different drugs by quantifying the size of the
difference between treatments1
NCT03941444 - The ClinicalTrials.gov designation for the Anavex Avatar trial
RSBQ - - - - Rett Syndrome Behaviour Questionnaire – a standardized test for measuring Rett severity.
Trofinetide - A Rett Syndrome drug developed by Neuren/Acadia
CGI-I - - - - Clinical Global Impression of Improvement. A standardized, 3 question, test measuring disease severity, overall improvement, and improvement due to drug.
RS001 - - - - Anavex's Phase 2, two part Rett Syndrome Trial
PURPOSE
Our previous Rett syndrome related articles, looked at the older and smaller, Anavex RS001 trial RSBQ score improvements. In this article, we will look at RSBQ score improvements, in the larger Anavex trial named “Avatar”. This data will be the most important Anavex Rett data to date. (Anavex has an even larger trial “Excellence”, but the data has not been released as of this writing.)
We would like to estimate the improvement in RSBQ scores for the Anavex Avatar study. RSBQ score improvement is easily understood by both clinicians and parents of Rett patients. However, Anavex has not published Avatar RSBQ improvement numbers, but has published some data, which will be used here. The primary tools we will use to analyze the Avatar data will be statistics, in particular Effect Size.
DISCUSSION
The Avatar trial was a 7 week long Rett Syndrome, phase 3, trial of 33 adults only. The drug used was Anavex’s Blarcamesine, dosed up to 30mg. This is the largest Rett trial Anavex has published data from. (There is a larger “Excellence” trial, but as of this date, the results have not been released.)
Anavex has not published Avatar data based solely on RSBQ points. The reason for this is that because the trial was small, having few patients, the basic RSBQ scores are not statistically significant.
Because of the small trial size, the FDA wanted to use techniques to increase the confidence level in the results. To that end, Anavex used an anchor based method, tied to area under the curve(AUC) RSBQ scoring. This is a quote from slide 8, of Anavex’s Avatar Top Line Data presentation.2 Anavex is quoting an FDA publication:
FDA:
Anchor-based responder method – linking of scores from one clinical outcome assessment (e.g., RSBQ) with scores from a simple reference “anchor” clinical outcome assessment with a clinically meaningful threshold (e.g., CGI-I) to facilitate interpretation of what constitutes a meaningful within and between patient change in clinical outcome assessment scores (e.g., RSBQ AUC)
Anavex, again in it’s Avatar Top Line Data presentation2, had the following graph showing the primary measurement investigated.
The chart shows the Avatar trial RSBQ AUC data that the FDA requested. This compares the RSBQ AUC of the drug A2-73/Blarcamesine versus the placebo. We are interested in the last bullet item: “Cohen’s d effect size 1.91 (very large)”. What this means is that approximately 97% of the placebo group had a score worse than the average of the treated group.
The Effect Size 1.91 is of particular interest. “Effect Size” is a statistical phrase. An Effect Size is a statistical calculation used to compare the efficacy of different drugs by quantifying the size of the difference between treatments. Dr. Stephen V. Faraone, wrote an excellent article describing Effect Size.3 Here is the equation for calculating Effect Size:
Drug improvement – Placebo improvement
Effect Size = ----------------------------------------
Standard Deviation
Effect Size is a powerful tool. Dr.Faraone nicely describes the usage and power of Effect Size3 :
”… effect size, which was developed to allow clinically meaningful comparisons of efficacy between treatment trials. Without using this concept, comparing 2 treatment trials can be difficult.”
(Note: The emphasis in the quote is mine.)
From the chart above, we know Blarcamesine’s effect size=1.91, and we want to know the numerator, that is, the drug improvement. We need to know the standard deviation. Unfortunately, the standard deviation was not published by Anavex. Now we will see the power of Effect Size shine.
Trofinetide is another Rett Syndrome drug, which was developed by Neuren, in partnership with Acadia. The largest Trofinetide P3 trial, had 184 child patients and was named Lavender.4 The Trofinetide Lavender trial had results published for both RSBQ scores and Effect Size, as shown:
Drug Improvement = 5.1 RSBQ pts.
Placebo Improvement = 1.7 RSBQ pts.
Effect Size (Cohen’s d) = 0.37
With Trofinetide’s data above, we can calculate the Standard Deviation(SD) as:
0.37 = (5.1-1.7)/SD
SD = 9.2
The Anavex trial was smaller than the Trofinetide trial. Here we will make an assumption that- if the Anavex Avatar were the same size as the Trofinetide trial, we could expect approximately the same SD for Blarcamesine as seen in the Trofinetide trial. So now, using Anavex’s Avatar study Blarcamesine Effect Size of 1.91, we can estimate the improvement , in terms of RSBQ points.
Drug improvement – Placebo improvement
Effect Size = ----------------------------------------
Standard Deviation
improvement
1.91 = -------------
9.2
Estimated Blarcamesine Improvement = ~17.6 rsbq pts
We do not know what the “placebo effect” value is, but again the Trofinetide trial saw 1.7 RSBQ pts for the placebo effect. So, if the same value could be used for the Avatar trial, the estimated “drug improvement”, by itself, would be 17.6 – 1.7, or 15.9 RSBQ pts.
What Does This Mean for Parents of Rett Children?
Now lets try to make our estimated 15.9 point RSBQ improvement, more concrete, in terms of the benefits Anavex saw. So here are hypothetical improvements, we might see, to the RSBQ questions, given a 15.9 point improvement.
Anavex found, in the Rett RS001 trial, that the most common benefits5 were related to “Nighttime Behaviors”, as shown below.
Applying our 15.9 point improvement to these benefits, we might see ALL of the following:
o “Spells of screaming for no apparent reason during the night”, might change from “2=Very Often” to “0=Not True”.
o “Spells of inconsolable crying during the night”, might change from “2=Very Often” to “0=Not True”.
o “Walks with stiff legs”, might change from “2=Very Often” to “0=Not True”
o “Abrupt changes in mood”, might change from “2=Very Often” to “0=Not True”
o “Spells of apparent panic” ”, might change from “2=Very Often” to “1=Sometimes True”
o “Makes grimacing expressions with face”, might change from “2=Very Often” to “0=Not True”.
o “Makes mouth grimaces”, might change from “2=Very Often” to “0=Not True”
o “There are times when breathing is deep and fast”, might change from “2=Very Often” to “0=Not True”
o “There are times when breath is held”, might change from “2=Very Often” to “1=Sometimes True”
We can only hope these numbers and benefits hold up with the soon to be released data from Anavex’s large “Excellence” trial!
CONCLUSION
I think this is an excellent example of using Effect Size to compare the results of different, but similar trials.
We used Effect Size to estimate the RSBQ point improvement, in the Anavex Avatar Rett trial. The estimated Blarcamesine improvement is 17.6 pts. With this 17.6pt estimated, average RSBQ improvement score, and the benefit categories that Anavex has seen, we were able to present an example of improvements that a parent might see in a daughter/son with Rett.
REFERENCES
1 “ESTIMATING THE SIZE OF TREATMENT EFFECTS: Moving Beyond P Values” by JAMES J. MCGOUGH, MD AND STEPHEN V. FARAONE, PhDe. From Psychiatry, October 2009.
2 “AVATAR Phase 3 RS-002 Rett Syndrome Top-Line Clinical Trial Data ANAVEX®2-73 (blarcamesine)”, Anavex Presentation, February 2022
3 “Understanding Effect Size: How It's Measured and What It Means” by Stephen V. Faraone, PhD. In Medscape, published November 14,2023
4 “Lavender Study Positive Top line Results for the Treatment of Rett Syndrome”, by Acadia. December 6, 2021