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OK, what you say makes sense mostly it is what I figured too. So, toxic a-beta gets produced even by normal cells at homeostasis. Cells eject a-beta into the extracellular space where they clump with other a-beta. Normal cells produce enzymes that (I assume?) go extracellular and can then help digest the a-beta and amyloid? But, in a stressed cell not at homeostasis, those enzymes are misfolded and then can't do their job. Is this summary correct? If so, Anavex should have spelled this out long time ago! a-beta formation
Caveat - I also know the endoplasmic reticulum (ER) functions to get rid of waste proteins, besides just packaging proteins. A cell not at homeostasis will lose the ability of the ER's to break down waste proteins I'm guessing. I thought maybe this aspect is why the a-beta could persist; however, right after a-beta is formed in the plasma membrane, it is ejected from the cell so I assume the ER wouldn't then be able to digest a-beta? It has to get digested some other way? Need to research how it is normally gotten rid of. Do specialized cells do this, do enzymes go extracellular to act on a-beta and amyloid in space, etc?
As an aside, damaged prions inside neurons act like a-beta. They can cause CJD (Creutzfeldt-Jakob disease) in elderly people. Damaged prions also cause Mad Cow Disease, which can affect even teens and punch holes in their brains. The prions act like infectious agents, spreading from cell to cell. I wonder, if damaged prions act like a-beta, why can't a teen's brain, assuming it's healhty, get rid of the prions? Maybe the teens that died were in the minority of teens whose neurons weren't at homeostasis and thus couldn't deal with the prions? IDK.
amyloid and Tau formation
Alzheimer's is deemed a protein misfolding disease by many. Which protein(s) is the misfolded one in question? A-beta, Tau, potentially any protein folded by a dysfunctional endoplasmic reticulum, or other?
Anavex has done a poor job delineating the Alzheimer's Disease biochemical process inside cells from start to finish. And then pointing out where their drugs interrupt that process.
I thought on average, a non-medicated person with Alzheimers drops 2 points on the MMSE chart/year
Does Anavex want to do infantile spasm this year too? Thought Missling mentioned that.
IR told me Anavex 2-73 is under patent for many years to come. They referred to a patent, but I think it was for the patent specific to melanoma. If Anavex 2-73 doesn't need a patent, then why has Anavex been trying to get one for Anavex Plus?
They haven't proven synergy to the patent examiner's satisfaction.......yet. Patent Office said Anavex has shown one time point showing synergy, would like more. Anavex is working on that. Patients on dual therapy most certainly showed improved efficacy however.
TWST: Is ANAVEX 2-73 potentially a drug that somebody could take and an early stage when they are pre-symptomatic in order to arrest the disease? I know many of these medications ideally should be taken pre-symptomatically if and when we can get the appropriate diagnostic tools.
Dr. Missling: Yes.
TWST: But can you elaborate on the stage that this could be taken?
Dr. Missling: We presented preclinical data that ANAVEX 2-73 could halt the disease and it could improve cognitive function. It was also published that ANAVEX 2-73 might be able to prevent the symptoms of Alzheimer’s in a pre-clinical animal model. So the answer to the question is, it could be both; it could be possibly utilized for either situations or time points.
Aducanumab will be $$$, require shots at Drs office, has high incidence of brain swelling, someone in trial lost pulse on the drug, and it was only trialed in cherry picked patients that had pre-alzheimers - mild alzheimers
Doesn't FDA allow co primary endpoints? Such as insomnia and alzheimers?
She doesn't know wtf she's talking about. Anavex's Ph2a results kicked butt at every time point, especially for the monotherapy subgroup. Gee, I wonder why she failed to mention the final results at THE END of the PHase 2a reported over a month ago or the abstract that just came out saying stabilization and some improvement at 15 months. Bastards never acknowledge that the market is manipulated up the wazoo with the help of rags like Motley Fool and so called "experts" like her and AF
Who is Thiel?
McFarlane said Anavex would most likely include some sites around the world, besides just Australia, for Ph 2/3
You forget, Trump is President in 2017 and he'll probably appoint a new FDA chief whom will be tasked with carrying out his agenda (ie getting promising safe drugs approved ASAP and removing burdensome regulation).
Personally, I'd think Biogen would love to partner with Anavex for the Ph 3 trial. Why? Assuming Aducanumab is approved, its side effects are considerable. 2-73 reduces brain inflammation and has been hypothesized as a good preventative of strokes. Those are the potential serious side effects of Aducanumab. The two could be given in combo and what is great is, unlike the 273-donepezil combo, the two drugs have different MOA's and do not compete with each other at receptor sites, nor hinder each others activity.
"ph2 successes" is a relative term and is subjective. Their "successes" were modest at best and often on extremely thin ice. 273's Ph 2 success is legit, unprecedented, and significant. There is a Grand Canyon of separation between their Ph 2 success and 273's
Thanks. I figured it was probably recorded last spring, just after the news story broke featuring the painter and pianist.
This ABC interview aired today, going by the date of the linked article, but when was it recorded? Sounded like it was recorded a long time ago.
The Spriranza trial was probably Ph 3 and FDA is probably more lax when approving drugs for serious, rare diseases
The abstract neiu released for the upcoming march 31st conference summarized results at 15 months. It said patients were on NON OPTIMIZED dosing
The abstract gives the jist. Stable mmse and adcs at 15 mos and improved cogstate and erp's. I don't think that is "useless" at all.
"nothing to glean"
"Exploratory Efficacy: 15-months data demonstrate that ANAVEX2-73 preserves average MMSE and ADCS-ADL scores and shows benefits over baseline for Cogstate and QEEG/ERP."
Researchers and Anavex just figure the drug class would be most effective in cells that have lots of sigma 1 receptors, such as neurons and muscle cells. So, for now they're targeting tissues with lots of sigma 1
Have you ever in any Alzheimers patient seen a P300 score actually GO UP after 13 months? It is rare that in ANY Alzheimers patient their MMSE and ADCS is stabilized and held near baseline after 13 months, let alone that being the case for a cohort group of 25. Why don't you talk to some neurologists and see how often the aforementioned happens with their Alzheimers patients.
The Cortina v Anavex suit, did you, like Adam Feuerstein and Jean Founteneau, give that serious consideration as a potentially legitimate grievance?
Shocking as it may seem, volatile developmental stage microcap biotechs are manipulated up the wazoo, more than any other sector in the stock market. If you're gonna accuse Anavex of 'data mining' I'd like to see some proof to back that up. It is easy to throw that out there without giving details.
To play Devil's Advocate, if sigma 1 drugs so great, why have no others been approved to treat CNS, or few other diseases? They also post some favorable results pre clinically. But they've gone nowhere and no one else has pursued sigma 1 drug development all these years. Does Anavex know something BP doesn't? Are their sigma 1 drugs special/different than the rest?
The longer they can hold out without a partner, the better deal they could eventually strike.
I still think you got it wrong. Read this paragraph taken from the linked article. It clearly says that the 5 week Part A portion was "...followed by a 52 week, open label, extension trial...":
The 5-week, randomized, dose-finding, crossover trial started one group of patients on 30 or 50 mg/day oral ANAVEX 2-73 for 11 days after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 11 days of 3 mg/day or 5 mg/day intravenously. A second group first received 11 days of 3 mg/day or 5 mg/day ANAVEX 2-73 intravenously after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 30 or 50 mg/day oral ANAVEX 2-73 for 11 days. This was followed by a 52-week, open-label, extension trial of 10-50 mg/day orally, titrating each patient to the maximum tolerated dose. The extension phase was originally planned to last 6 months, but patients and caregivers wanted to continue on the medication, so the company extended it to 12 months. It is ongoing.
I still think you got it wrong. Read this paragraph taken from the linked article. It clearly says that the 5 week Part A portion was "...followed by a 52 week, open label, extension trial...":
The 5-week, randomized, dose-finding, crossover trial started one group of patients on 30 or 50 mg/day oral ANAVEX 2-73 for 11 days after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 11 days of 3 mg/day or 5 mg/day intravenously. A second group first received 11 days of 3 mg/day or 5 mg/day ANAVEX 2-73 intravenously after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 30 or 50 mg/day oral ANAVEX 2-73 for 11 days. This was followed by a 52-week, open-label, extension trial of 10-50 mg/day orally, titrating each patient to the maximum tolerated dose. The extension phase was originally planned to last 6 months, but patients and caregivers wanted to continue on the medication, so the company extended it to 12 months. It is ongoing.
2-73 is also a NMDA antagonist like memantine btw
Thanks. I got right how you came up with the $75, what is more confusing is how you came up with the $3B mc for your example.
Mind explaining how you calculated all that? The $3B figure and the $75/share figure. Thanks
Do you understand that weeks 52 to 57 is NOT post Phase II? Part A was 5 weeks. Part B was 52 weeks beyond the conclusion of Part A. Part A + Part B = 57 weeks total
"Some patients went from combo to Mono someplace along the way in the last year of testing."
I read your link, it squares perfectly fine with what I wrote.
If you look at the charts for trials done for donepezil, often get a placebo effect at 5 weeks, but beyond that, no.
Tissue that has high demand for ATP, after brain, I think of muscle (skeletal, smooth, and cardiac)
Possibly one of the posts of most consequence to Anavex, and our, fortunes if true.
Nice article. Sigma 1 agonist drugs such as 273 are most helpful to rescue cells that require A LOT of ATP (energy). Cells of the nervous system and musculature burn the most ATP (energy). The heart is nothing but a muscle after all. If heart tissue/cells aren't getting enough blood supply b/c of blocked coronary arteries, those cells become stressed and cellular 'homeostasis' is lost. Lack of blood to cells = lack of oxygen and glucose = reduced ability of cells to make ATP (energy). 273 can step in and 'goose' a cell to step up ATP production when it is stressed. How? Binds to sigma 1 receptors on the endoplasmic reticulum's (ER) membrane surface. That opens up calcium ion channels on the ER's membrane to release calcium from the ER into the surrounding cytoplasm. Adjacent mitochondria take in all that calcium. That calcium tells the mitochondria to make ATP stat! That increase in ATP can help recouple the ER to the mitochondria and restore homeostasis (and thereby proper functioning of that cell)
Keep in mind, the article states, "The sigma-1 protein is expressed in the left and
right ventricle (of the heart) at even eight- to 10-fold higher levels than in the cerebral cortex, striatum, or hippocampus (of the brain)." So, sigma 1 receptors are extremely plentiful in the heart, which bodes well for 273's potential for treating heart disease.
Thanks for the info Ziggs, not sure I follow though. How does a combo patent protect 273 monotherapy for 20 yrs? And, what the heck is public pair?