Rett Syndrome Phase 2 (RS-001) Which was Really Phase 1 Which Turned Almost into Phase 3 $AVXL

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To start talking about the 15 person dosed cohort in RS-001 Phase 2 one has to get on the subject of the dose right away. At 5mg/daily, it seems that $AVXL thought it was dispencing poison to the girls, when the maximum dose is 50mg/daily. By all accounts, that is only 1/10 of the maximum dose. I am of the impression is that we were really dealing with phase 1 trial turning into phase 2 which might then turn out to be phase 2b/3. Was this by Dr. Missling design or by FDA’s? Nevertheless, we have three trials cascading. Of course, there was a bit of a specious reasoning in what I said. Nevertheless it illustrates the astounding results and the relationship between dose and the results.

The companies PR on the results reads like a scienfific paper on the merits of SIGMAR1 platform not just regular PR with few data points dispersed words of “statistically significant” and “clinically significant”. The earlier analysis of the 6 pharmacokinetics patients seemed to imply slightly higher scores to the RS-001 but they were lacking depth. Link to Post: https://piotrpeterblog.com/2020/12/07/rett-syndrome-data-already-out-anybody-pays-attention/. The extremely low p-values suggest that the probability of these results being just part of dispersion of placebo is very low, if none. Moreover, almost all measures point to improvement over placebo.

Quoting from the PR:

The RSBQ demonstrated balanced improvements across all the instrument’s subscales during the trial period of 7 weeks, including general mood, breathing, hand behavior, repetitive face movements, body rocking, night-time behavior, fear/anxiety, walking/standing.

This is unidirectional change leaving no possibility to some statistical event, or rather what we call a fluke. The most important is the night time behavior. The sufferes of Rett Syndrome often wake up in the night and scream or moan. Sleep belongs to the most underappreciated CNS functions, unless you don’t sleep deeply for two or three nights. Depriving somebody of sleep is a form of torture and can even lead to death. On YouTube one can find the horrific results of Soviet experiment with sleep need-stopping gas. The whole thing reads like a horror story, not a scientific experiment. This anecdote conveys the importance of sleep like no other. Through all the trials of Blarcamesine the thread of sleep quality weaves from one trial to another but never becomes the main story. In RS-001 it becomes salient, for care-givers it is very disruptive of the their lives and the lives of the girls. It testifies to the ability to assuage the suffering of the girls.

I wanted to point to a type in the data and one important point. Let’s see the slide.

in the data for CBI-I those for the dosed with Anavex2-73 the none responders should be marked 15.3% not 60%. Just a remainder but an essential one.

These scales are very subjective. You can see that when you compare CGI-I and RSBQ scales and the resultant numbers of none reponders. CGI-I is completed by medical practitioners. RSBQ consistes with responses from care-givers. The practitioners saw only 2 cases with no improvement whereas the care-givers saw just 5. This discrepancy spreads to the evaluation of those on the placebo arm, practitioners seem more improvements than care-takers. No wonder, paractitioners must rely heavily on memory for assesment, but on the other hand, care-givers will not notice subtle changes as they are easly habituated to them.

Comparing results on RSBQ scale with the pharmacokinetics cohort we see that we have the same fraction of the non-responders as in the previous release of data. we don’t have the initial RSBQ or CBI-I scales to give any percent improvement vs. the initial score. On average, the RSBQ score of a patient with Rett Syndrome is about 45 points. Phamacokinetics cohort specified this at 50 points on RSBQ scale. So we have 29% improvement in just 7 weeks on miniscue dose of 5mg/kg daily.

Though, the number of reponders on ADAMS scale is just 60% of the 15 patients vs. 66% on RSBQ scale the same pattern of unidirectional improvement follows.

ADAMS is 84 point scale, improvement of 12.9 points makes 15.4% of the scale. Usually, the average patients is somewhere on the scale so that improvement starts from there. If it is comparable to RSBQ we couldd have about 27% improvement from the average initial score. Larger Cohen’s d (1.31 vs RSBQ 1.11) suggests even greater improvement from the initial score or lower initial score on severity of Anxiety, Depresion and Mood Scale.

What is important, is that Cohen’s d Effect Size is 1.31 for ADAMS and 1.11 for RSBQ scales. In the land of drug development these are very good number meaning very large and large respectively Effect Sizes. Effect Size ~.50 is considered large enough to warrant an approval.

That is all folks, on a trial named Phase 2 but being more of a phase 1 and turning into phase 3 by Effect Size alone.

SIGMAR1 is a platform, not a drug. Blarcamasine is the first drug interacting with SIGMAR1 receptor. The sigma 1 receptor from an obscure begining has evolved to position of providing explanation to incidence of CNS degenerative diseases as solely connected with its expression and action. That makes sigma 1 receptor to be another player in the etiology wars for AD. The response in AD and PDD happens only with the maximum dose but in Rett Syndrome it appears at just 1/10 of that. If indeed the SIGMAR1 platform drugs are ubiquitous in their actions against CNS diseases, as it can be seen in their abilities to improve patients in AD, PDD and Rett, we might soon be addressing the need for the disease under the umbrella of Autism Disorder Spectrum diseases. Autism Disorder Spectrum might be an concoction, and the underlying etiology might be different for similar phenotypes. I am not stating that this is the case but it is the worst case for disease as it might see diversity of yet not fully known or unknown etiologies. But there is possibility that SIGMAR1 platform drugs can address them.

The arena of AD and PDD is crowded. It is my perception that the ADS field is not that full of competition as AD’s. The numbers of patients and the need might be even larger than AD. The results in Rett Syndrome and soon Fragile X might have ushered the need to raise additionally money as opportunities in ADS field need to be explored.

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