Athira Pharma, Synergy or Competition to Anavex? $ATHA $AVXL Blarcamesine ATH-1017

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor!

What I called the Unified Alzheimer’s Theory calls for the root cause of Alzheimer’s to be some hypothetical disturbance in cellular homeostasis, cascading into disfunction leading ultimately to wholesome destruction of neurons through/or with runaway autoimmune reaction.

I have been talking about the possibility that the SIGMAR1 receptors agonists, in varing degrees, bring back the homeostasis present in the growth during the embrionic development as if in some sense Anavex2-73 would be not unlike a rejuvenating agent. In my mind, I have made the connection but I do not have sufficient and detailed knowledge of cellular physiology to express it properly. If the idea indeed has any value then MCEP2 mutation which is connected with disabling the protein silencing genes expresion after embryonic development should demonstrably altere the course of Rett Syndrome in patients receiving Blarcamesine before the regression onset (about 18 months post birth).

Athira Pharma wants to use HGF/MET Hepatocyte Growth Factor/MET ATH-1017 to treat Alzheimer’s. From the name itself the protein should have something to do with growth of liver cells, and I believe that is where it was first identified. After reading Wikipedia page on HGF/MET one can see that it is present in wide set of growth or rather cellular differentiations in embryonic development. In adult physiology, it is connected with healing of wounds and regeneration of liver cells, hence the name. This protein is so ubiquitous in embryonic development and differentiations of cells that the Phase 1b conducted by Ahira Pharma was only 8 days of dosing. And no wonder why, since the same agent is connected with oncogenesis and with the ability of cancer cells to atain motility (ability to move within body) so that they can metastasize. Nevertheless, as measured this drug achieved astounding effects on Alzheimer’s patients.

The 8 days of dosing is a period too short to measure any difference in cognitive measures like MMSE or ADAS-Cog. There is intense search for benchmarks of the early onset of the disease. The most likely are connected with the time delayed in reaction time and the wave forms of neuronal firing, changing paterns of electric potental on synapses. A standard procedure is placing an earbud into the ear of a person and producing a startling sound ever so often. The brain of the subject reacts in a certain pattern to this stimuli. By comparing the average pattern between the diseased subjects and healthy differences can be found. Athira Pharma presentation from October 28, 2020 presents this on the slide 20.

Slide 20

Notice that the peak of wave after 300 milliseconds marks the benchmark for researchers looking into Alzheimer’s as it correspondes to the timing of accessing the memory in order to recognize the startling sound. Alzheimer’s hallmark sympotm is the gradual loss of short and long term memory.

slide 22

Two aspects are measured, the amplitude and the delay between the healthy response and the diseased one. Of course, with the progress of the disease these discrepancies increase. The primary measure, though is the latency of P300 wave form. It in absolute terms it ranges from 300 milliseconds for healthy individual to 400 milliseconds for those in mild and moderate Alzheimer’s disease. The slide listes number of studies measuring the discrepancies in many combinations of disease progress and electrode placement on subject’s head. The measure is consistent and has been validated.

Illustration of disease progress and its relationship with the P300 latency.
P300 Latency improvement in ATH-1017 (HGF/MET) patients over 8 days of dosing.

These are the results of dosing ATH-1017 for 8 days on latency of P300 wave form. The reduction goes form somewhere 380-400 milliseconds to about 300-320 milliseconds, that is from diseased to almost healthy.

Can we compare this with Blarceamesine? Anavex did measure the responce in P300 but only the amplitude which the above presentation described as less pronounced measure of deterioration of synaptic health.

September 2017 Corporate Presentation slide 28.

This is just a long term plot indicating the return or even improvement over the healthy state. Notice the initial response and the resulting long term change separated by a period of some decline and stabilization followed by very unusual improvement over the healthy level (enhancement of mental abilities?). There is a correspondence between your neuronal processing speed and the most important to your cognitive skills indicator, that is IQ. Would Blarcamesine increase your IQ? This is the Holly Graal in psychology.

October 2017 Analysis of Anavex2-73 Phase 2a Data (Anavex.com)

In just 6 days, comparable to 8 days, the amplitude is going from 6 microvolts (different protocol than used by Athira Pharma) to 7.8 microvolts (130%). The problem is that this is for P3a wavform present in word memory recall, not audio P300, hence the different range of voltages (different electrode locations?). What is essential here is that the patients experienced in both cases initial large improvements in commensurable amounts.

Disscusion

  • $ATHA Athria Pharma ATH-1017 in 8 days of dosing caused comparable improvements as $AVXL Blarcamesine in the same time frame and measured by P300 latency/amplitude.
  • Blarcamesine has 3 years of safety dosing. ATH-1017 seems to be involved in many places in the body to provide for potential safe drug profile. Involvement in oncogenesis might prevent long term dosing. Further testing will tell. Follow Phase 2/3.
  • Blarcamesine sets in motion some fundamental process in cellular physiology, specific to cells with SIGMAR1 receptors. ATH-1017 is a growth factor working in multiple sets of cells, is not specific to neurons only. Two different types of MOA.
  • Currently, great effort has been expanded in search in neuronal growth factor. As more is becoming known about embryonic development and differentiation of cells from stem cells new growth factors of that type can become considered as drug targeting neurodegenerative diseases.
  • PRO $ATHA, the similar performance in 8 days as $AVXL Blarcamesine
  • CON $ATHA, safety doubts for long term dosing.
  • PRO $AVXL, proven record of patient improvements in multiple diseases, not only Alzheimer’s. Blarcamesine – prospective mental abilities enhancer?
  • CON $AVXL, in this comparison Blarcamesine is held as the standard so we won’t list any.
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Landenburg Thalmann Symposium.

This is one is going to be personal. I have missed the webinar but I have read some impressions and quotes from the webinar on iHub. What struck me was the use of the word “happier” or “happy’ in description of Rett Syndrom patients response to Blarcamesine. This ties with my own life experience.

At the age of 33-34 years (1994-1995) I began losing launguge, thought and the well being associated with being healthy physically and mentally. My launguge has lost the element of abstraction, it became reduced only to concrete aspects of life, my thought lost abstract quality and I became thoughtless. I lost abiility to interact with people as I could not access the depth to these interactions in real time. In my head I experienced numbing buzzing with sense of severe discomfort of just staying awake. The only respite from the torture was to go to sleep. The pleasures one experiences in life from socializing to the most basic ones have been gone. Loss of memory, loss of sense of time, and loss of emotions

Some 5 years ago I started experiencing gradual improvement. The most pronouced is the partial lifting of thoughtlessness and the discomfort borderline on mental torture. The rest of these are here to stay. Not unlike in a bad joke I am feeling like I am 20 someting again and whole life is in front of me. This is an illusion, but a welcom one at age 60.

From the description of Rett Syndrome symptoms I can generate the picture of the mental of torture they can live through but can not grasp it. I can though imagine the lifting of the torture the aflicted live through.

Thank you for reading this.

Rett Syndrome Continued. Blarcamesine $AVXL

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor!

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.
Follow patient 107001!

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)

Follow patient 107001!

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.

Waking at night and crying or screaming is one of the symptoms.

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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Rett Syndrome Data Already Out – Anybody Pays Attention?

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor!

Not So Subtle Changes in RSBQ

RSBQ stands for Rett Syndrome Behavioral Questionnaire. It consists of 45 questions, each questions have 3 answers, valued 0, 1 and 2. The highest possible score is 90 and represents the strongest extend of disease symptoms. Value 0 on a question corresponds to “never”, 1 to “sometimes” and 2 to “always”. The first question I had was “what is the average score of Rett Syndrome patient”. I found the immediate answer in this paper https://jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-015-9104-y

The questionnaire divides the symptoms into 8 categories and these are having varied number of questions making some weight more than other on the final score.

Let’s see what RSBQ data was presented by $AVXL on the 6 open label patients in PK arm of the first Rett Trial.

From the outmost left graph we read the average combined score for the 6 patients was 50 on RSBQ scale of 90. 50 is above an average score as given by the Welsh survey. Now, let us discuss what that means for the patients and the care givers. There is a drop of 15 points, which in general makes these patient to have scores below average Rett Syndrom patient from a score above the average, from 120% of average to 83% of average. The 15 points for an average patient could have meant change from (2) “always” to “sometime” (1) or from “sometime”(1) to “never”(0) on 15 questions. Please, observe the p-value for just 6 patients which suggests besides a good distance between means. The downgrading of the symptoms on 15 questions out of 45 happens on low dose. Dr. Missling has revealed that was the case, in this pilot program aimed at dosing with potentially the least “harmful” dose since Blarcamesine has never been tried on Rett syndrome patients. The low dose is the reason we can only expect greater efficacy in the second Rett Syndrome trial. The confidence of Dr. Missling in Blarcamesine is corroborated by making the first 6 dosed patients in PharmaKinetics Open Label so that we have early reading of the trial. The Part B is to obtain better p-values on the test which by the Part A p-values is kind of redundent. Yet, the next 21 patients can be expected to lower the p-value score even further, unless the dose after the Open Label PK Arm has been increased, and then it becomes vey interesting, especially witht the 12 weeks open label extension. Just a remainder, the p-values below .05 are taken as a threshold to assume the outcomes are statistically valid.

The timing of the 3 Rett syndrome trials is such that the results of the previous feeds into the next, probably having written in their protocols some dose of flexibility. Ergo, FDA allowing such arramgement of trials exhibits high confidence in Blarcamesine and practically expedites the whole process without approving the drug outright on some contigency due to high efficacy, which though might not be excluded from possible scenarios once the trials confirm it be overwhelming. Anavex is basicly almost having Breakthrough Therapy protocol without calling one. I believe that the initiative to have such expedited development schedul was all due to Dr Missling. FDA just acquiesced to it, already recognizing the high efficacy in murine studies, and maybe Phase 2a Alzheimer’s. The Orphan Drug designation is more like a recognition that you play in the field of Orphan Diseases. The voucher after approval become a realized incentive. These are perks for playing in the field of Orphan Diseases and by themselves are part of the package. These facts should strengthen the case for FDA already recognizing the looming efficacy of Blarcamesnie.

The plot on the left represents the distribution for those 6 patients on measures of improvement. CGI-I is just 7 point scale, very subjective and dependent on the physician knowing the state of the patient before dosing.

Source: wikipedia page for CGI-I.

Since we have distribution of RSBQ scores for all 6 patients and we make certain assumptions like that we have over 50 subjects in an arm with the same distribution of score like the 6 patients before dosing, we can calculate Effect Size under these assumptions. Also we assume that the SD about the mean before dosing is the same as for the average patient listed above then simplified Cohen D calculations for Effect Size give us the results seen below.

To qualitatively put it, it is a “very large” effect. If decent Effect Size to approve a drug is, the threshold of, 0.50 then indeed on the first Rett trial Blarcamesine earned its approval. Remember, I can tell you what Dr. Missling can not. I am looking into the future using clues from the present. I can be wrong but most likely I am only wrong in matters of details not the shape of things. The Effect Size might be different but the judgement on its quality should stay.

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After Conference of 3rd of December 2020….On Alzheimer’s.

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor!

Dr. Missling reveals internals of the phase 2a

The number of patients remaining in the phase 2a for Alzheimer’s trial versus normalized to 32 patients patients remaining in placebo study (link below)

Link to paper https://jamanetwork.com/journals/jamaneurology/fullarticle/775209

By the end of the first year the number of subjects dwindled from original 32 (would these 7 be below 20 MMSE and mutant SIGMAR1? – their genome was never read) to 25 (accordingly to Dr Missling) and among these 25, 20 had had there genome read. Those 20 then separated into 15 SIGMAR1 wild type and 5 mutated. Interesting would be to find out how many patients out of the 9 who were in the High Concentration Cohort were SIGMAR1 mutated and how many were below MMSE 20. From this illustration visible is the staying power of those dosed with Blarcamesine. It seems that the 21 who did not dropped out by the third year end are all SIGMAR1 wild type and are at the least dosed with 10mg/d, as we don’t know whether all patient got the highest dose. As I was saying, with time the Effect Size will increase between synthetic placebo and the patients on Blarcamesine, if this trend continues.

Dr. Missling on Phase 2b/3

FDA has not allowed for the patients to be selected by their genetic variants so the trial results are the same as for the general population including both wild type and mutated SIGMAR1 individulas. The break down is 80%/20-16% Wild Type/Mutated (low responce). Only after the trial the SIGMAR1 mutation can be taken into account in the analysis. Dr. Missling said that the patients in Phase 2b/3 are all at or above MMSE 20 score. In light of what he said about Phase 2a, those at and above the MMSE score of 20 improved and were rescued whereas those below the score of MMSE 20 were “stopped from declining” (I assume that they were both SIGMAR1 wild type and High Concentration), at least for the first 48 weeks of the Phase 2b/3 the same is expected. The importance of this information cannot be exaggerated, whenever the data is available it will be overwhelming, any doubts of obtaining approval will dissipate. I will later do calculations on the possible Effect Size, preeliminarly I can see it to be between 2 and 1.5 (200% to 150%). Regularly, 50% or .50 is needed for approval. Denozepil was approved on 28% (.28) Effect Size.

The Episodal Memory in Phase 2 Parkinson’s Disease Dementia as the interim results for Phase 2b/3 Alzheimer’s

Selection of patients. In Phase 2b/3 Alzheimer’s patients have MMSE scores above 20 per Dr. Missling. In Phase2 PDD the scores are in another measure, the Montreal Cognitive Assesement (MoCA) scores from 13 to 23 were used to select the volunteers, these correspond to MMSE scores 18 to 28 respectively. Ergo, the patients are similar in their initial scores.

The link to source of info on MoCA vs. MMSE can be found here https://pubmed.ncbi.nlm.nih.gov/26346644/

The duration of Phase 2b/3 Alzheimer’s is 48 weeks. In the first 5-7 weeks Blarcamesine makes the greatest strides against the disease, then for those above MMSE 20, it brings steady but slower improvement. Ergo, 14 weeks might serve as a good indication of progress in next 34 weeks, a good and reasonable interim results could be infered from the Phase 2 PDD trial on basis of duration.

In order to calculate the Effect Size from the Episodic Memory battery of Phase 2 PDD, I made few assumptions. The First Standard Deviations are shown by the red bars. I assume that the extend of SD to be as large as possible as the bars are not symetrical. Upon making the calculation the Effect Size between the Placebo Arm and 50mg Arm might be 1.4. Wikipedia page on Effect Size lists these ranges to describe them qualitatively.

https://en.wikipedia.org/wiki/Effect_size

In 70% of cases the ADAS-Cog measure of cognition moves in the same direction with Episodic Memory measurments, taking this as adjustment; In the worst case the Effect Size in ADAS-Cog should be at least ~1.00, reading half way between Large and Very Large. And this is for the first 14 weeks of the trial. Had the data be obtained after additional 34 weeks the gap between the placebo arm and the dosed 50mg/d arm should increase even more creating posibility of even greater Effect Size.

Some time ago, Dr. McFarlane said that Blarcamesine showed 1.10 (110%) Effect Size, unheard of in the realm of Alzheimer’s research. It is hard to ascertain to what particular trial he was referring. Just as a remainder Donezepil was approved with Effect Size 0.28.

Now, with computerized tests subtle differences in your cognition can be detected, in some measures overlapping with MMSE and some not, to indicate mental decline above the age expected decline. With constant testing, let’s say every few months, early detection is possible and patients can be rescued from Alzheimer’s at least for few years. The 20 points on 30 point MMSE scale is quite deep into decline, as it is not a trivial difference, the people with the decline to the 20 points should be easy to detect with a common computerized tests, making Alzheimer’s much less of a death sentence if not at all. Such scenario hinges on the ability of Blarcamesine to rescue those above the MMSE 20 score.

Dr. Missling was explaining that the SIGMAR1 agonist like Blarcamesine has been setting in motion a mechanism of cellular repair so fundamental to cellular physiology that it can only to be best described by evoking the concept of homeostasis. Homeostasis is the concept in molecural biology to address the paradox that the life on basis of sheer probability of errors in its molecular machinery should not function as entropy could over take it and scuttle it. In my thinking Rett Syndrome shows how far the SIGMAR1 agoinist can go into restoring the cellular homeostasis, this I will tackle in the next post.

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Glutamate, Rett Syndrome, Autism and Patent Claimes as of Recent. $AVXL Blarcamesine ANVEX2-73

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%.

Page 15 from 2020 Corporate Presentation for $AVXL

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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