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A Remark Which Makes Sense
Recently, Dr. Missling made a remark that when you overdose Blacamesine (or rather you can not overdose as…) the natral process by which autophagy runs shuts down or did I misunderstood what he meant, it just saturates? I used the word autophagy to concisely described the immensely varied therapeutic effects of Blarcamesine. I am going to leave it at this since I have been writing here about the cornucopia of physiological effects. You can find them to be shortly illuminated by a page from December 2021 Corporate Presentation
The fact that Dr Missling mentioned this effect (I think he might have this in mind) which is quite common in physiology as in a case of overproduction of signaling molecule whole cascade shuts down. My take on the timing of this remark is that as you all know AVATAR did not have a defined dose, and if the trial did not have a defined dose, it could experiment within wide range of doses only know to those who were privy to the FDA and $AVXL agreed protocol. AVATAR is in search of perfect dose, and it is entirely possible that some of the patients received dose large enough to be able to shut the therapeutic effect. How this impacts the results is hard to say, because the patients can all ultimatelly be given the optimal dose. But wait there is mor to it! See this page from the December 2021 Corporate Presentation. I hope the data will make this mystery clear on the 15th of December 2021.
The Key To The Other Half Of The Kingdom
mRNA expression of SIGMAR1 protein levels are positively correlated to the therapeutic effect of Blarcamesine on patient to patient bases. It means that if your body reads the DNA with the code for the SIGMAR1 protein (transcription)and makes more copies of it (translation), you are to have more Mitochondria Associated Membranes (MAM) with SIGMAR1 receptors. Blarcamesine is supposed to unlock MAMs and release plethora of signaling or beneficial to cellular health protein, which are sequestered in the MAMs, into the cytoplasm and the intercellular space. I had previously posted about a content of a paper suggesting that this is the mechanism of action for agonist of SIGMAR1 receptors.
The point I want to make is that the drugs like Blarcamesine of Anavex-3-71 which are the SIGMAR1 agonists are only half the key to kigdom. The other Half of the Kingdom might belong to hypotetical drugs that would make you produce more SIGMAR1 protein so that Blarcamesine or any other SIGMAR1 agonist might be even more potent. This implies nothing short of a revolution in medicine. Of course, I need here to stress the use of the word “hypotetical” since nothing is certain in the “solution” of 500 thousand proteins, lipids and sugars.
Any potential player in this field (increasing trascription of SIGMAR1 protein in patients) might be even larger opportunity than $AVXL is right now. The question is how long will it take till BigPharma realize this? Or will there be a small player licensing some academic endeavor to harness transcription of SIGMAR1 to bring the benefits of SIGMAR1 agonists to ever larger population? Or is BigPharma already on the ball and Dr Missling is receiving bids? When will the onus of the struggle to make it big alone be equal to the bid?
Back To AVATAR and Rett Syndrome
Dr Missling’s strategy is to present the FDA with data it can not refuse to accept for approval under any conditions. This data has to be superior to any competitor and inconvertible. Dr Missling the Steamroller.
Best Wishes to all and Happy Holidays, for those celebraing Marry Christmas!
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I was wondering why Dr.Missling recently mentioned several times that taking to much 2-73 resulted in not just plateauing of the therapeutic response, but decline of the response.
If I recall correctly, 60mg was the maximum tolerable dose, and 50 was then considered the maximum target dose. Also strange to me was that Dr.Missling mentioned this a few times, not just once as a passing remark.
I suspected that the lack of dose definition in recent trials fell under the category of “trade secrets”.
The recent Parkinson trial dosages were ‘high’ and ‘medium’. There has been no word, that I am aware of, that the high dose had any detrimental affect. In fact Anavex has shown plots showing improved response at the higher doses.
So I wonder where his recent comments come from. Could it be from some murine trials? I suppose it could be from OLE trials, where patients are being titrated above 60mg to better quantify the max tolerable dose and to see what the affects are at the elevated levels.
Can you shed any light on this question?
Helo Agent P,
I am no wiser than you are. One paper I read on the proposed mechanism of action of SIGMAR1 receptor agonists suggested that the Mitochondria Associated Membranes (MAM) which are implicated in folding protein and storage of synthesized on the Endoplasmic Reticulum compounds are just made by agonist to open and release the compounds to the cytoplasm and intercellular space. This is only a hypothesis or a proposal for the MOA. If there is a grain of truth in this then overdose can block the creation of MAM. Imagine that the rate at which MAM’s are created is lower than the rate at which they mature. The MOA of Blarcamesine is much more profound than this as not only the release of protein is involved but also the regulation of transcription. In Rett Syndrome, it seems the regulation of genes is affected when the mutated gene is supposed to regulate the expression of other genes. To turn it into a buzz word I juxtaposed, transcription and translation.
Regarding the dosage, I would like to point out that it seems that there is descending dosage from AD through PDD or PD and Rett Syndrome. The implications are that these diseases are having different pathogenesis, be it connected to translation or transcription abilities of Blarcamesine. AD responded at 50mg, if I remember correctly PDD at 50mg had a much better response to Blarcamesine than 30mg, which at AD was missing altogether. Then Rett syndrome moved the needle at just 5mg. I think Dr. Missling gingerly threads here in order not to haphazardly miss opportunities to include another disease under the column “works for” by inappropriate dosage.
I just had my dumb down period so I delayed the answer to your comment. Sorry for that.