Nah…Just Another Patent Claim from $AVXL.
The recent patent claimes by $AVXL for ANVEX2-73 came without much cheerful response from “the community”, however Dr. Missling quietly positioned Anavex to sweep almost all the chips from the table of major CNS diseases. This lack of enthusiasm can be explained that in patent application one can justify claimes yet the ultimate trial is by the Phase 3 as designed by FDA.
A lot of Glutamate and little GABA found in Rett Syndrome and Autism.
There is a telltale of increased Glutamate presence in plasma of sufferes of Rett Syndrome and Autism. As far as I was able to research Glutamate is not synthesized in any other organ save the brain but large quantities are located in vital organs and muscles. The Central Nervous System regulates the amount of Glutamate by actively releasing it through the Brain Blood Barrier direcetly into blood stream. In reference #1 https://pubmed.ncbi.nlm.nih.gov/8916158/ the level of Glutamate in Cerebralspinal fluid was in normal subjects 204 nanomoles per liter S.D. +/-56, for Rett Syndrome subjects it was 355 nanomoles per liter S.D. +/- 109. In other words the Rett syndrom patients have 174% level of the normal subjects. On page 15 of the 2020 Corporate Presentation the drop in Plasma levels (that is the strained of red cells blood) was given for the Rett Syndrome girls to be “greater than 40%” from 50,000 nanomoles per liter to about 25,000 nanomoles per liter. That is about 50%.
Notice that the slide presents the data in micro moles which are 1,000 time larger units than nano moles because the two regions are separated by Brain Blood Barrier the concentrations of Glutamate in the brain is as suggested by these numbers about 300 lower than in the blood of the normal subjects, but to that we get in a minute, unless there is a screw up in the units and the graph should have been marked micro moles per deciliter (micromole/dL) , in which case it should read 500,000 nano moles per liter redused to 250,000 nano moles per liter. Without taking into consideration the possiblity of error we can read from the graph that the trial Glutamate levels for the girls started at 50,000 nano moles per liter and ended at 25,000 nano moles per liter. The former reading would fall nicely within the spectrum given in the reference #3 as noted below. The latter, within the data given in reference #2.
So if the cut in the Plasma levels is proportionate to the Celebralspinal levels than Blarcamesine, it might be inferred, brought the Celebralspinal levels to about 104% of the healthy phenotype (subject), hence presentation focused “on larger than 40%”. Such measurement is indirect but I have not found in a quick search on internet anything to believe that Glutamate is synthesized in large quantities somewhere else than in the brain which then actively transferes the excess Glutamate outside the Brain Blood Barrier. Glutamate can be sourced from food but such a big drop cannot be explained by diet change during the trial.
The amount of Glutomate in Celebralspinal fluid is just a fraction of the Glutomate synthesized in the brain, as 99% of Glutomate is stored in the CNS cells which release the neurotrasmitter as needed and additionally its level is regulated with the Brain Blood Barrier secretion mechanism to blood. If indeed Blarcamesine upregulates CNS homeostasis it should affect both these mechanisms. I can only speculate that if the disturbance causes excessive release of Glutamate to Celebralspinal fluid the Brain Blood Barrier can try to compensate by releasing more Glutamate into the blood stream.
In reference #2 https://www.sciencedirect.com/science/article/abs/pii/S0278584606002697
The Plasma levels for Glutamate for Autistic patients and normal controls were given to be 89,000 nano moles per liter (S.D. +/- 21,500) and 61,100 nano moles per liter (S.D. +/-16,500). Therefore the reading of micro moles per liter should be correct, and it makes for higher levels in both arms in the case of Autism. But this is not the only interpretation of the data.
Short note on variations of Glutamate levels in Plasma. These numbers go from ~100,000 nano moles per liter to 260,000 nano moles per liter for healthy individuals, the distribution in general is age dependent with younger subject on the higher part of the spectrum. See reference #3 https://healthmatters.io/understand-blood-test-results/glutamic-acid-plasma, which then makes equaly valid to suspect the error in the units and making the reading to be from 500,000 nano moles per liter to 250,000 nano moles per liter. In this case the Rett Syndrome levels of Glutamate are twice the upper bound of reference #3 spectrum. The reduced level is just coming to the upper bound of the acccepted normal levels.
On top of that comes the fact that every study comes with a bit different number and sometimes different units. I think the most essential is the procentage difference between the control arm and the diseased arm. In the reference #2 the diseased arm has the level of Glutamate in the plasma 146% greater than the controls arm. Also in Autism and Rett Syndrome there is disturbance in the ratio of Glutomate to GABA, as Glutamate discharges (excites symapses) so GABA prevents this process allowing levels of ions to be restored up on synapses. The restoration of that ratio suggests return to homeostasis on cellular level.
The Plasma levels have to be connected to the measure of severity of the symptoms of Rett Syndrome to validate the connection between what interests us that is the Celebraspinal fluid levels which give more direct insight into the nexus bewteen these neurotrasmitters and the neurodevelopmental diseases. The slide of the 2020 Presentation makes this connection somewhat valid and statiscally the probability of error has been judged to be below the accepted threshold.
And, now for something completely different…
When you look into the descriptions of the Rett trials and the list of primary outcomes, both the plasma concentrations of Glutamate and Gaba are listed as the least relevant. This might be due to the indirect relationship between the Celebralspinnal fluid levels and Plasma levels, and going even further the behavioral changes. There is only circumstantial evidence that they are connected but no direct link has been established. Nevertheless, as you can accuse me that I leave you in wilderness after looking at the numbers as if they would be the most relevant here, I have to point to a curious entry in the list of the primary outcomes in the Rett Syndrome adult trials. This namely is #4 “Lipid panel [ Time Frame 7 weeks] Significant laboratory findings”.
Why “lipid panel”?
I can make connections between few facts I know. I do not know whether this panel is for Celebralspinal fluid, blood or liver, but I realize that it is intrinsically connected with growth of new neurons as lipids are their necessary building blocks. Changed lipid metabolism might the the clue to expect restoration of brain plasticity. This is on conceptual level as I lack the detailed knowledge a person trained in the field would posses. Lipids are so important that in the history of human evolution the mere fact that our direct ancestors started eating aminal protein and fats (especially fats) is considerd as one of the enabling conditions for growth of the brain tissue which was the evolutionary gamble. I venture to say that in just 7 weeks of the trial dosing (not exactly but certailnly by the end of trial) Dr. Missling might know whether the Rett Syndrome girls brains are growing new connection. That is the early warning system for the possiblity of restoration of plasticity to Rett Syndrome brains under Blarcamesine dosing. That is not just decreasing the severity of the symptoms but reversing the destruction of the disease, however patial it might be.
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