Rett Syndrome Continued. Blarcamesine $AVXL

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Please, watch this video. It is presentation by Dr, Kaufmann (Chief Scientific Officer $AVXL) on the Pharmacokinetics OPL cohort of first Rett study. https://youtu.be/4IgtFhrVwIY

I would like to highlight following points/info.

• “n=6 18-36 years old with MECP2 mutation“. What was the most important, was that the subjects were all MECP2 mutated. Rett Syndrome is just a collection of symptoms. It is possible to be not mutated and be diagnosed with Rett Syndrome. As matter of fact only about 77% of Rett Syndrome patients are mutated. There is an extensive effort to match any particular genetic fault to symptoms or severity of symptoms.
• Safety. I quipped that the dose (of 5mg/day as it turned out) was so low that it seemed the protocol was so written as if it would be dispensing a poison to the patients. That is only 1/10 of the effective dose in Alzheimer’s. In this case the phase 1 was dropped but the concern over toxicity made the planners to lower dose to bare minimum. There were just 3 episodes, and the emphasis is on the word “episods” of grade 1 or 2 adverse effects. I think we cleared that hurdle.
• Very interesting thing was said about Glutomate blood levels. In MECP2 mutated people, the peripheral neurons (the one which are running nerves all over your body) release excess Glutomate to blood stream. Dr. Kaufman said that Anavex used two technics to measure the levels of Glutomate in blood. One of those technics had validated norms for levels present in Rett Syndrome sufferes as well as normal levels. He did not reveal whether the levels receded to the normal. In this context, I was dead wrong as I suggested that it was the process of releasing extra Glutomate by Brain Blood Barrier at fault here.
• Continuing out thoughts on Glutomate levels and their reduction. Blarcamesine levels as measured in the blood precede levels in the brain. If we put it in order we have to pass the intestinal wall first then we get to blood past the liver which can break up the drug either slower or faster and finally we get to the brain through Brain Blood Barrier. Glutomate levels in blood on other hand are mostely produced by the peripheral neurons and are first to come into contact with molecules of Blarcamesine. Drop in the blood levels of Glutomate is due to therapeutic effect of Blarcamesine on the peripheral nervous system which we can reasonably believe to be extended with the same degree to the brain as all those neurons share similar genetic make up. I was wrong on this point in my previous post.
• The Effect Sizes were given for two measures. I previously calculated one of them (RSBQ) from simplified formula. The one I reported was 1.20 whereas Dr Kaufmann presentation had it as 1.47. The difference did not altered the reached conclusion. The Effect Size of Glutamate reduction and on the RSBQ scale both match. That is very significant and high correlation connecting both.

The patient 107001 goes from 58 on RSBQ scale to 14 on RSBQ scale. Just to give you insight this is equvalent to responding on 44 out of 45 quesstion from 2 (always) to 1 (sometimes) or 22 questions from 2 (always) to 0 (never). See my previous post here https://wp.me/p2IvqX-eJ (this post corrects some misconception I had in my previous post)

Patient 107001 goes from 5 (out of 12 possible) to 0. The involuntary hand movements are the hallmark of Rett Syndrome. They are gone from patient 107001.

The Rett syndrome patients experience troubled sleep. They often wake up crying or screaming. The quality of sleep goes down in many neurological disorders. Cmax is the maximum concentration of drug in blood (units unknown). This important measure improves with the peak concentration of Blarcamesine in blood. This is quite tricky as every person’s metabolism is different so that the action of the drug is dependent on many variable as I tried to explain above. The drug needs to get through intestinal wall and then the liver can very quickly lower the concentration in blood so that the impact on brain can be diminished. Your liver is the metabolic engine of your body as it breaks down all sorts of chemical entering your bloodstream. Measuring the concentration of the drug in blood can be part of personalized medicine. Of a greater importance however, could be matching the genetics to Cmax so safe and efficacious dose can be selected to patient’s make up. This is another study not covered by Anavex at this junction in time as this would entail increase in cost and scope. Nevertheless, higher concentrations or rather higher maximum concentration of the drug in blood point to greater benefits. Would that also imply that higher doses could salvage even those who do not respond that well as patient 107001? Well, we might see soon.

Just one note here, the graph above has one patient scoring 0 on this scale. Is it the patient 107001? If indeed this is patient 107001 then implications are that the cconcentration is more important to therapeutic effect than the dose. The interaction between liver and the drug might be here to blame for the lower efficacy among other patients and not the he drug itself. This might be interesting conclusion but its validity has to be confirmed empirically.

The note under the x-axis on the graph says “Spearman’s rho=-0.841”. This measure correlates changes in one statistical variable to another. The sign says the increase in one makes the other go down. Value of 1.00 implies identity between sets of data points. The absolute value of 0.841 is pretty high correlation so that corresponding move in concentration results in opposite move in CSHQ score about 84.1% of the time.

What is in store for the Rett Syndrome data as we go from first trial to the next?

• Dose can be expected to go up so higher concentration of the drug in patients bloodstream. Ergo larger fractions of RSBQ scores down.
• But possibility of episods of adverse effects also increases.
• Effect Size should increase, from large/very large to huge. (from 1.47 to between 2 and 3)
• The implications for the pediatric trial might be “unhealthy” to investors (pun intended) as they might be too high to account for how much time is needed for well grounded “cures” to emerge.
• Pediatric trial Excellence first posted March 2020 and still recruiting, but might be already dosing. Study completion July 2021. Protocol indicates “dose escalation safety, tolerability and efficacy study”.
• Secondary Outcome Measures lists Motor Behavioral Assesment-7 (MBA-Ped7) among others we have seen before. In Rett Syndrome motor skills are severly affected (Brain+peripheral nervous system). Is Dr Missling expecting restoration of these motor skills in pediatric trial? This implies reversing the regression.
• The age >=5 years to < 18 years, post regresssion stage, that is loss of spoken launguge or motor skills, CGI-I >= 4, ergo the same level of affliction as the patients of the first Rett Trial had presented.
• The regression takes place at about 18 months of age, so this is not looking to dose at this age to prevent the regression but if possible to reverse it, to a degree. It is just a foray into pediatric dosing.
• Pediatric trial protocol is not to look for a “cure’, but for just about the same reduction in RSBQ scores as the first Rett Syndrome trial have had on patients. Adjust Your Expectations Accordingly. Everything else is just extra goodies.

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