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!
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!
- 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?
- Recruiting for Australian study NCT03941444 (AVATAR) proceeded before completing of NCT03758924. Is this the “Fast Track” designation at work?
- 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?
- 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?
- 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.
Make a one-time donation
Make a monthly donation
Make a yearly donation
Choose an amount
Or enter a custom amount
Your contribution is appreciated.
Your contribution is appreciated.
Your contribution is appreciated.DonateDonate monthlyDonate yearly