About Rett. $AVXL ANAVEX2-73 Blarcamesine

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! And I am long $AVXL.

The study of Anavex2-73 in Patients With Rett Syndrome NCT03758924 being just a repeat of AD Phase 2a that is expolaratory turned out to be a shocker. A measure of behavioral “disruption” droped 30% from baseline which is 21% of the entire scale of 70 points. Even at just 6 patients the drop is statistically significant p<.05. Two measures RSBQ and CGI-I both moved in the same direction with steady correlation. Neurotransmitter Glutamate deacreased by 40% from base, GABA, its antagonist, increased, in inverse relation. All of this was achieved on 5mg daily dose. Or is this a typo? The results come from 6 patient which comprised a pharmakinetics cohort of the study. This reference gives the values for glutamate concentration in Rett patients and healthy controls. https://pubmed.ncbi.nlm.nih.gov/8916158/

In the patients with Rett syndrome, the mean of cerebrospinal fluid glutamate concentration was 355.2 nmol/L (SD +/- 109.2 nmol/L). In the controls it was 203.9 nmol/L (SD +/- 55.5 nmol/L). … Glutamate may therefore play an important role in the primary pathogenesis in Rett syndrome

After drop of 40% the concentration shall be ~213 nmol/L which comparable with healthy controls. There is great divergence in those number bewteen ages as at age 20 young healthy person might be around 2.5 that much what is the concentration in brain of a 35 year old mature person. The numbers given where for girls in ages spaning from 3 to 13 years old with average about 8 and similar thing for controls. The subject in the study are all over 18 years old to 45 years old so this calculation can only give us certain amount of insight. And their level of concentration is 250 times than normal given in the above reference as reported on page 14 of ANAVEX Corporate Presentation, February 2020. Drop of 40% lowers this to 150 times. This is indeed a stunning development as the levels are brought to almost normal levels, at least in the context of the above reference but not the presentation numbers. I think that measurment methods can be different here, or is this a typo? Only long term dosing will tell how far Rett syndrom sufferes can be rescued. How quickly can we know the results of 14 weeks extension? Through my own experience I can imagine the mental torment these poor souls go through. Your brain can be affected by chemical and even a “better” ways is through microelectronics or direrctional electromagnetic waves. Russia for example boasted of a naval weapon, an electromagnetic beam, able to disrupt the sight of naval personel. The stories in the news have not reached a threshold of widespread public awarnes. They are just dripping not yet pouring. Microelectronic implants are the next wave of dealing with CNS disorders but your privacy is gone after implanting.

Since I am a lay person, what is not seeming to scientis might be quite forgivable to the one not worshipping at the altar of scientific ortohoxy. From referrence on RSBQ I learned that one of the telltale sign of RS is unconsloable crying at night or screaming, and seizures. If indeed operation of locus coeruleus (location of “circuit” regulating panic and fear) is out of balance due to the mutation and it causes flooding of the brain with neurotrasmitters like glutomate and they return to almost normal levels, so it seems, the question is how deep is this homeostasis restoration ability of ANAVEX2-73? In some posts I advanced the idea, the Romans used to say “paper never blashes”, the Blarcamesine’s MOA is connected with embryonic development when rapid growth requires increased “quality control” of all processes in the cell. The earliest you can see the onset of Rett is about 6 months after birth, no indicationas are present in the prenatal period. The implications are that Blarcamesine can work just like gene terapy if introduced early enough.

iHub user Xena left a comment with a link to a paper about leads into the mystery of autism. The paper listed pletora of neurotrasmitters with deregulated levels and other neurvous system compounds with information from studies attepting establishing links to autism spectrum disorders. The Rett Suprise might be repeated on Autism, which is the conviction of Xena, and with some dose of incredulity of it all, mine too. Thank you, Xena!

  1. Study NCT03758924 puropose was to explore the dose and pharmakinetics of Anavex2-73 in Rett Syndrome, hence 5mg dose, probably driven by mouse studies. Duration is interesting 7 weeks dosing and OLE extesion of 12 weeks. Would we be soon informed about the results of the extensions?
  2. Recruiting for Australian study NCT03941444 (AVATAR) proceeded before completing of NCT03758924. Is this the “Fast Track” designation at work?
  3. The Clinicaltrial.gov page listed 31 patients for NCT03758924, in the presentation we have 21(!) and the study is conducted in the US. It is possible that study is suspended in light of reaching statistical significance?
  4. AVATAR study has 22 girls in dosed cohort, but what is interesting is that Primary Outcomes Measures are all Pharmakintetics, also dose in not given. Is the drug is effective but optimal dose has to be determined?
  5. Study NCT04304482 ANAVEX2-73-RS-003 (EXCELLENCE) is the Phase3 study due for completion July 2021. 46 dosed to 23 placebo. 12 week duration plus 48 weeks extension. 5-18 years old.

This is so called “telescopic development”; each trial is nested in previous one, timewise, the information cascades to next level once it is obtained. We are on the Fast Track.

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CTAD 2020, PDD Phase2, way to partnership? $AVXL ANAVEX2-73 Blarcamesine

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! And I am long $AVXL.

Alzheimer’s trial as widow makers

Dr Missling by choosing to have only 32 patients in Alzheimer’s phase2a proved that he was very conservative with company’s resources and not overly enthusiastic about ANAVEX2-73 prospects. Ask questions first, shoot later. The run up to $14 on hopes of “quick cure”=”quick riches” was indeed a disappointment to shareholder or speculators (not much I think, at least to the experienced ones) in $AVXL stock. On the other hand Dr. Missling tactics of incorporating genetics, Ariana’s AI, microbiota and ingenuous financing, just to mention few, are a proof of strategy aiming to build lasting value.

The Parkinson’s Dementia Disease study phase2 has about 44 patients per cohort. By looking back, one can see that the initial miserly 32 subject spread over 3 cohorts dwindled to 9 patients in High Concentration Cohort who could be used to prove the hypothesis of ANAVEX2-73 efficacy, but they were too few to do it outright, they did it over span of few years. When looking at the PDD trial phase 2 every cohort has ample number of participants to end up with at least ~30 patients needed for minimal sample in life sciences. This alone suggests that Dr. Missling as much as trying to economize on sample size has now full confidence in Blarcamesine. Remember, for 20 or so years 95% of trails for Alzheimer’s drugs ended up as failures, making AD a proverbial widow maker. I guess that on 9 patients in High Concentration cohort you can discount any chances on an approval or partnership in the world so intensely afflicted with bipolar disorder of hype, dashed hope and failure. The bipolar condition afflict the small companies to a greater degree than the Big Pharma companies, who are more observers than actors in this field. Though those who speculate bet more on Big Pharma. However strong the signal was in AD Phase2a most of the people in the field plus the pundits were skeptical as “great discoveries” can be had a dozen at a time and even cheaper a 2 years later.

Let us go over in details why and how PDD phase 2 is relevant for Blarcamesine and $AVXL.

  1. Duration of trial: 14 weeks. In AD Phase 2a the patients who responded positively to ANAVEX2-73 did it over period of 7 week in very rapid fashion and then they split into one group slowly improving and one slowly descending in their MMSE scores. Repeating this pattern in 14 weeks would corroborate AD Phase2a with at most 44 patients and had it been weighted statistically as significant when seeing the same strength of the signal this would be complete. The therapeutic result can even be greater as Dr Missling pointed out that even the 30 mg cohort responded.
  2. The use of Cognitive Drug Research Computerized Assesment System Continuining Attension measurest among others reaction time both in mental aspects as well as motor skills. Nice name comes here to mind, psychomotor. Wikiepedia pages lists the know etiology of Parkinson’s:
    The motor symptoms of the disease result from the death of cells in the substantia nigra, a region of the midbrain, leading to a dopamine deficit.[1] The cause of this cell death is poorly understood, but involves the build-up of proteins into Lewy bodies in the neurons.[4] So another undetermined primary cause neurodegenerative disease with the most conspicuous cause (dopamine deficiency) and neuron death located in one region due to homeostasis deregulation spreading from origin to Lewy bodies in particular. Is Lewy Bodies Dementia next target? This is kind of like a cross between AD and Rett. On conceptual level only.
  3. If CDR-CA would measure the amount of rescue extended to motor neurons on global level, just beyond pure dopamine deficiency, at least in the context of Blarcamesine study, anti-neurodegenerative properties of Blarcamesine would be buttressed. CDR-CA was also validated as a measure in AD. Dr Missling mentioned that notable strong signal was detected in memory measurement. If response in psychomotor skills would be statistically significant and would be better or equal to the existing therapy, we have killed two birds with one stone. This is another evident reason to think of ANVEX2-73 as neuronal broad-base homeostasis drug than one working on one single chemical reaction in a cascade like most of the old guard drugs do, or SOC.
  4. Members of the Ariana team are co-authors of the presentation. Are we again pursuing the genetic signature of perfect PDD patient? I am not a scientist so I do not know a lot of details about the genetics of the disease. The approach taken by $AVXL is not to only concentrate to bring the drug to trial but to create knowledge base so that a drug like ANVEX2-73 can be assured to beat all possible ways FDA can find to make life difficult to $AVXL. Dr. Missling creates a franchise not just a one wonder-drug company.
  5. PDD phase2 with very brief exposure of just 14 weeks corroborates AD Phase2a the exploratory trial. I called AD Phase2a “exploratory” because with the least of money Dr Missling was trying to find out whether there is anything in the AD field for $AVXL. The extremely low number (in absolute terms) of very strong responders determined the way forward without destroying the company financially. The penalty is time. I don’t think that anybody in FDA would risk giving, even at this junction, green light for approval without a partnership; a foot into the door of the club.
  6. The coming Rett results and PDD Phase2 results to be broadcasted at CTAD 2020 in Boston validate the attractiveness of $AVXL to join with Big Pharma company in partnership, or rather they quicken the time for it. On how Dr. Missling will play this out will depend the future of the company.
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What about CTAD 2020? ANAVEX2-73 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! And I am long $AVXL.

For number of years I have been speculating, fantasizing and making dumb-ass data analysis on ANAVEX2-73 Blarcamesine. My conviction that there, is there there was unwavering. We are coming into harvest season, though.

Phase 2b/3 for Alzheimer’s was posted since January 2nd 2019, so we are 22 months into the 48 weeks (11 months) dosing period and we are still recruting. Many a times, FDA allowes sponsor to to cut the trial short when the statistical significance had been reached with clear therapeutic outcome. AD Phase2a was conducted without the help of precision medicine (being pioneered by $AVXL by eliminating, ~20% of general Population, patients potentially unresponsive ) and with ridiculous High Concentration cohort of just 9 people. I was looking at all those factors connected with the decline in Alzheimer’s but one aspect of this study is the riduculous low number of subjects, had it represent any semblence of real population distribution of these factors like SIGMAR1, APOEe4 gene or any other known or unknown it would have squarely pointed out to drug approval. So I created this plot of possible outcomes in time for an average general population patient based on High Dose Cohort from AD Phase 2a.

Now, please compare the above graph to the natural course of the disease.

A drug test makes hypotesis that only 5% of outcomes in the dosed cohort could possibly be claimed to be due to dispertion in the placebo cohort or in other words natural outcome of the disease. The larger number of particpants in the trial the better defined are these cohorts. They revert to their mean or average values. With degenerative diseases like AD one factor can be the time over which the study is spread so that these two cohorts have two separate outcomes models with time. Phase 2a Open Lable Extension has just done that for me. The Phase 2b/3 is currently having about 150 subjects to each cohort and looking at 48 weeks time to detect theurapeutic effecacy. If the effect is so strong that even at 40 or let’s say 70 patients for the 48 weeks converges on p<= .05 that is statistically significant grade given for a pass in this test then could FDA declare achieving the criteria for approval?

It is possible that Phase2b/3 might be cut short due to results already hitting 95% probability of dosed patients showing therepeutic efficacy.

It is possible that similar pattern of efficacy has shown up on 14 week Phase 2 PDD trial boding for approval for PDD.

Now, cool down, it does not have happen this way, $AVXL has more enemies than friends, and I hope you count in the number of friends.

I am starting to collect for my subscription bills, do you want to defray my cost?

Thanks to Richard RR and Joseph F for donations respectively $10.00 and $5.00.

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15th of October 2020…comes another confirmation of blockbuster status of blarcamesine Anavex 2-73. $AVXL

Every investor and his aunty fret over the company not releasing yet the statistical data or “raw data” from PDD (Parkinson’s Disease Dementia) phase 2 Clinical trial. From what the Dr. Missling said even the cohort with 30mg dose responded and that all the targets have been achieved with statistical significance. The last two words require some explanation or rather some discussion. The threshold for statistical significance is the power of study threshold <= .05, that means there is only 5% or less chance that the results are a fluke.

I am not a statistician, but I was taught to think in terms of the smallest sample size for a large population. The number cited was 30 specimen. The PDD Phase 2 had cohorts of roughly 44 patients. I think the reason was twofold, on one hand the savings for the company on the cost of trial, usually about $10-30,000 per subject, and the other was that the there were expectation of strong signal so small cohort would not obscure the efficacy. The rather shocking truth is that $AVXL can not afford a drug with low efficacy and 1000’s of patients to justify approval. Biogen in point. $BIIB

The goal of a statistician is to detect signal, useful information in the sea of random change. That is why we have a placebo cohort to measure the noise. In medical practice outcomes are subject to variation and this creates a background noise against which one has to detect the signal in the cohorts receiving the drug. The larger the sampling population the more clearly the noise and the signal converge to their mean so there is less ambiguity in distinguishing one from another. Converging to the mean implies that with larger sample size approval is more likely even if the therapeutic signal is of lesser strength. On a very superficial level, you get a number with standard deviation, the mean and the spread around the mean. The ultimate goal is to separate the mean so much that standard deviations don’t overlap, and you have a clear signal. People cheering thousands of subjects in trial miss the point. It should rather be a sign that likely the drug is barely to make it through the trial, as it crafting the trial to the drug and not the drug to the trial.

The Phase 2a of Alzheimer’s did achieved statistical significance in few measurements, if my memory serves me well, PDD Phase2 even at this small sample size reached all targets, i.e., all measurements showed presence of a signal of the required strength for approval. Had the sample rate in AD (Alzheimer’s) Phase2a been ~44 patients per cohort the same could have been expected? Time again we, the longs, have another signal that efficacy is strong and undeniable. The periods of time between the old guard AD or PDD drugs and $AVXL drugs proves that SIGMAR1 receptor drug did open a new vistas in CNS therapeutics.

It seems that the projections in my blog were not entirely wishful thinking or extrapolations on unrealistic assumptions, but one of possible outcomes to which the reality of Blarcamesine clinical trials results seems to converge.

But as they say in the world of investing better to be stupid and lucky than wise and wrong.

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