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I updated a general biology post I did sometime ago on investorvillage
https://www.investorvillage.com/smbd.asp?mb=9414&mn=1037&pt=msg&mid=20308273
If anyone wants to repost here, please do as I don't have the time given the embedded diagrams.
Alzheimer's disease in the USA and the future of Anavex
An estimated 5.8 million Americans of all ages are living with Alzheimer’s dementia in 2019. This number includes an estimated 5.6 million people age 65 and older and approximately 200,000 individuals under age 65 who have younger-onset Alzheimer’s, though there is greater uncertainty about the younger-onset estimate.
Of the 5.8 million people who have Alzheimer’s dementia, 81 percent are age 75 or older (Figure 1).
Out of the total U.S. population:
• One in 10 people (10 percent) age 65 and older has Alzheimer’s dementia
• The percentage of people with Alzheimer’s dementia increases with age: 3 percent of people age 65-74, 17 percent of people age 75-84, and 32 percent of people age 85 and older have Alzheimer’s dementia.
Source: https://www.alz.org/media/Documents/alzheimers-facts-and-figures-2019-r.pdf
The number of people with Alzheimer's disease in the world is estimated to be ~ 44 million.
There are over 2 million new Alzheimer's patients per year.
Assume that around 3 million people in the world would have the resources to treat Alzheimer's disease and would buy A2-73. That is a huge population. Given the patent protection, and relative low cost of making A2-73, Anavex could easily get $1,000 per patient per year (after shipping, handling and manufacturing costs). That is $3 billion new free cash flow per year just for Alzheimer's disease.
Some of the new drugs in the pipeline from other companies that could work for Alzheimer's disease are IMO likely to be drugs that could be taken together with A2-73. The ones I've looked at from other companies have other different mechanisms of action not related to the mechanism of A2-73. There are also other diseases like Parkinson disease that would add to the number of potential patients for A2-73. My view is that since the mechanism of A2-73 is to reduce cellular stress and cellular inflammation, A2-73 would likely end up being helpful for other autoimmune related diseases. This is of course only speculation at this time. But it would not be the first time drugs that are developed for one thing end up being used for many. What all of it adds up to is that A2-73 and their follow on drugs would have a very wide range of application and they could go from an unknown small company to a large company in literally a year or two.
"WHEN IS AVXL GOING TO PRESENT EVIDENCE THAT A2-73 ACTUALLY HAS EFFECT ON GABA?"
Check the latest presentation for AVXL and check slide 14.
"GABA changes demonstrated an inverse correlation of the magnitude of Glutamate changes (2-tailed Spearman’s rho = -0.829, p = 0.042)"
"AVXL IS NOT EXPECTING FULL ENROLLMENT LET ALONE APPROVAL FOR THE RETT PEDIATRIC TRIAL IN 2020!!!!!!!"
LOL. That slide doesn't mean that.
The check marks are for those things that they have already achieved to drive value.
The next things that they expect to achieve to drive value are the RETT trial enrollment. Which will probably happen soon (on the order of days or weeks).
Second poster >>> "IF THE BELOW WAS ACTUALLY FACT, A2-73 WOULD HAVE ALREADY BEEN GRANTED PROVISIONAL AND ACCELERATED APPROVAL!!!!!"
Quote:
first poster >>>>"BECAUSE NO OTHER DRUG OR REMEDY HAS SHOWN THE POSITIVE RESULTS THAT A-273 HAS SHOWN."
That is total BS that A2-73 could be granted provisional and accelerated approval simply because it works better than any other drug so far.
The reasons why:
1) Data set is too small.
2) There is another primary drug for Alzheimer's disease (does not work very well but it is approved).
3) There is a huge population that has Alzheimer's disease (meaning that huge numbers could be harmed by a poor medicine if it were approved). When large numbers are impacted, the FDA must be more careful.
If there was no drug for Alzheimer's disease, then it would still be difficult for the FDA to grant approval due to the small sample size - and the large numbers of people with Alzheimer's disease.
With RETT syndrome, the FDA can consider the Alzheimer's data to help with determining the safety along with the RETT data. Also, the number of patients is very small and there is no RETT drugs. Which means that the FDA can consider provisional approval based on a smaller data set. With a small population potentially using the drug if approved, it is much easier to track the results.
A liquid form is used for people who have difficulty chewing and swallowing.
If the FDA approves Anavex 2-73, it means that they the medicine is approved for RETT disease. The medicine can be sold in the most appropriate form for the patients. I.e, a liquid for those who have difficulty chewing and swallowing. Or a pill for those who would prefer that.
Anavex had not set a price months ago. So, IR probably gave you the generic price that people normally pay for drugs that are for something like RETT.
Is it really a different formulation that is NOT suitable for Alzheimer's disease?
Provide a reference.
I agree that most orphan drugs for most diseases cost $250,000 or so.
That is because most orphan drugs are for a small number of people and the drug is a biologic. That means that they need probably at least a $100 million dollar facility to manufacture enough of the drug for a small population. Then the manufacturing costs are maybe $50,000 or more per person (no profits at all).
They have to sell the drug for a large amount to pay for the $100 million manufacturing facility and for likely another few hundred million for the R&D and approval. So, assume the orphan drug manufacture starts in the hole for $300 million when the drug is approved and they start manufacturing. Probably this is a low estimate.
Anavex's costs will be much lower and the R&D that they did applies to multiple things.
The Advantage of Fast Track status for Anavex 2-73
Most new drugs have huge manufacturing costs. For example, many of the new drugs are classified as biologics. A factory to make a biologic drug cost around $200 to $400 million. Biologics are complex molecules which typically are mainly proteins. Quite often, they are made inside of living cells that are grown in the manufacturing plant. The cells are often coaxed to make the protein via genetic engineering. I.e:
http://theconversation.com/biologics-the-pricey-drugs-transforming-medicine-80258
Anavex has a small molecule drug that can be much more easily manufactured. The company can hire many different labs to manufacture their drug for a very reasonable price. This is in contrast to some biologic drugs which may cost $40,000 to $50,000 per patient just to manufacture the drugs that they need not including the cost of R&D and profit.
My rough estimate is that Anavex could manufacture the drugs a patient needs per year for ~ $1000.00 per patient in a quality facility or they can build their own facility when they are ready to sell in volume.
If Anavex is able to get the drug approved for any indication via a fast track process, - for example for RETT syndrome, then once it is approved, other doctors will consider trying it for different diseases so long as the disease has no satisfactory medicine. Typically, insurance companies won't pay for the off-label use. But doctors will prescribe. This actually happened to one of my family members. A doctor prescribed the medicine for 2 years before it was finally approved. Meaning out family paid the full price for 2 years. This was obviously expensive costing over $6,000 dollars a month. But nothing else worked.
If Anavex 2-73 is approved for RETT syndrome, then the drug becomes commercially available. Doctors can look at the clinical trial results and decide to ask their patients if they would like to try Anavex 2-73 for Parkinson's disease or Alzheimer's disease. Here is a reference:
https://www.webmd.com/a-to-z-guides/features/off-label-drug-use-what-you-need-to-know#1
Given the low cost of manufacturing Anavex 2-73, the Anavex can sell the drug for a low enough price that it can be essentially sold to a mass market. If Anavex 2-73 were to be sold to 1,000,000 patients and the company sells the drug such that they make $1,000 (after manufacturing and distribution costs), that would amount to $1 billion in free cash flow.
Lots of excitement here .....
Latest Presentation....
The presentation: https://www.anavex.com/wp-content/uploads/2020/02/Anavex-Presentation-February-2020.pdf
contains some new information that I think is very significant.
Slide 8: Left half of slide shows is how well the drug activates the sigmar-1 receptor. The drug is supposed to work by activating the Sigmar-1 receptor. The data is based on brain imaging PET scans. These show that indeed the drug does occupy the receptors and that occupancy is related to the dose.
So, the next question would be is whether occupancy of the sigmar-1 receptor will really have a positive impact on the illnesses being tested for?
On the right side of slide 8, this shows corresponding changes in functional outcomes based on dose. This shows a strong correlation between the theory that sigmar-1 receptor occupancy should help with the disease.
Going forward in the presentation...
From slide 14, here is some of the p values....
REPORT on PART A: INTENSIVE PK SUBCOHORT
• Plasma levels of the biomarker Glutamate decreased significantly (Week 0 vs. Week 7; 2-tailed
Wilcoxon signed rank test, p = 0.046)
• Levels of Glutamate at Week 7 directly correlated with CGI-I scores at Week 7 (2-tailed
Spearman’s rho = 0.837, p = 0.038)
• Greater decreases in Glutamate associated with greater improvement in these efficacy scores
• GABA changes demonstrated an inverse correlation of the magnitude of Glutamate changes (2-
tailed Spearman’s rho = -0.829, p = 0.042)
===================
The p values of 0.05 or less is considered significant meaning the result is likely significant. All the p values show it is likely significant. More over, since there are more than one test, it means that the results can be considered to be more significant.
For slide 19, Anavex was wise to continue to collect data. The data shows that there is a very significant difference between low to medium dose patients and high dose patients. The number of patients is small - but given they are at 148 weeks, the results are very significant with very low p values. Since a p value of less than 0.05 is considered to be significant, the p value of p < 0.0001 is the best I've noticed in any presentation on a new medicine.
How significant is it? Consider a p < 0.05. If a person thought that A 2-73 didn't work and calculated a p value for it and it was p < 0.05, then it means that
A p < 0.05 means there is a 5% chance that the observed drug results were due to just random error. If p < 0.01, then it would be a 1% ... When you get to p < 0.0001, then the probability is 0.001 %. Not very large.
The more time there is and the result remains consistent, the more likely it is that the results seen are not some random statistical anomaly. Of course, there might be some other unknown variable impacting the result introducing some error - but I can't think of one especially given the MMSE results are correlated with the ADSL over that time range.
Everything looks good so far....
Have the demographics ever been released?
I checked my notes. From 2016, the average age of the 32 participants when starting the study was 71. (Age range is 55 to 85) 40.6% were female. The average MMSE was 21. 53% were apoE4 carriers.
146 weeks - MMSE declines by ~ 1.6 points (Putting it in perspective)
From a study showing how MMSE scores decline once a person contracts Alzheimer's disease:
In contrast, the MMS declined an average of 2.15 points per year (95% CI 1.85-2.46) during the first two years, accelerated to 3.83 points per year (95% CI 3.28-4.38) during the subsequent three years and then slowed to an annual decline of 1.63 points during the last two years (95% CI 0.21-3.05). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014643/
The MMSE test has a maximum of 30 (30 being perfect). Typically, a score of 24 or greater indicates normal cognition. A score of 19 to 23 indicates mild impairment. A score of 10-18 is moderate impairment. And any score below 10 is severe impairment.
The average length of time someone lives who gets Alzheimer's disease is ~4.5 years if diagnosed after age 70. The average MMSE for people diagnosed with Alzheimers is around 24 to 26. These patients if not treated can expect their MMSE score to decline by 4.3 in the first 2 years. They would be more forgetful and start to forget some names and have trouble doing various things. In the next 2 years (4 years total), their MMSE would decline another 7.66 points. They would be down a total of 11.96 points. By this time, the average person won't be able to drive and will need someone to watch them. They are moderately impaired and can still do things on their own - just not complex tasks. They will begin forgetting who their friends were and won't recall common facts. Can't be trusted with their finances. In the next couple of years (total of 6 after diagnosis) if they live that long, the average person will become severely impaired and MMSE will have decline by 15.63. Can't cook, will start forgetting everything in their life. Quality of life near zero.
Consider that in three years, Anavex 2-73 data for high concentrations show a decline of about ~ 1.6 and an even smaller decline in ADCS (Activities of Daily Living Inventory). A smaller drop in ADCS is consistent with the brain and person learning to compensate for loss of cognitive ability. I.e., learning to spend more time and think harder about activities, write down important things and etc., If the trend continues, by 6 years, their would be a drop of 3.3 and by 9 years, there would be a drop of 4.8.
What does this mean? It means that the average person who gets Alzheimer's after age 70 who takes a high dose of AVXL 2-73 would be able to live out their life until death still remembering their life while being able to live on their own if they are otherwise healthy enough to do so.
It is not a complete cure - but enough of one that people can keep their dignity until death.
For those who have earlier onset Alzheimers disease (before age 70), on average they live 10 to 12 years.
For those people, if not treated would end up needing comprehensive care after 5 or 6 years until death. They will live to forget their entire life.
If AVXL 2-73 works as well on these type patients, they would have many additional years of good life and would probably still die remembering the majority of their life, friends and relatives.
The probably determined early on - maybe even by week 5 that they had to take into account the weight of the person. For high dosage, the measurement is >= 4ng/ml (measured in the blood for high dosage).
There may also be some variation between patients (irrespective of weight) as to how much that take and how much arrives in the blood).
This type of substance is a relatively small molecule that moves through the blood brain barrier and is taken into the individual cells. The blood concentration of anavex 2-73 is what determines how much gets into cells.
The effectiveness will be determined by the blood concentration and some individual characteristics related to genetic background.
In any case, to get the requisite blood concentration of the medicine, they have to take into account the weight of the person.
Answer: "don't recall seeing you posting here before"
I don't post that often. I have had AVXL for about 3 years. I studied the company in detail before and posted about my results. Then I had very little new to add.
My study of AVXL is located on this board - don't remember where. Also on:
https://www.investorvillage.com/smbd.asp?mb=9414&mn=701&pt=msg&mid=17024130
Answer: "WHY DID ANAVEX ONLY BRIEF 104 WEEK RESULTS IF ALMOST 4 YEARS IS AVAILABLE?"
Because they are looking at the two year extension data for high dose patients only.
After the two years extension, they extended again.
Once the two year extension was complete, one of their researchers studied that two years of data and published the results. Part of which was the MMSE data. The first year data was studied previously and showed very low decline.
The latest speech/talk given by the CEO about 2 or 3 months ago, he mentioned that they had almost 4 years of data and said the results were good.
MMSE Scores and the latest AVXL announcement about ANAVEX®2-73 (blarcamesine) Data
AVXL recently announced the results of a study of ANAVEX®2-73 (blarcamesine) Data. Basically, they looked at what happened to the group of people who have been taking Anavex 2-73 after 2 years.
The compared the changes in MMSE scores from the high dose long term Anavex 2-73 group of patients to a similar group of people who were not taking Anavex 2-73 (the control group).
The MMSE scores of the control group decline by 4.4 points.
The MMSE scores for the Anavex 2-73 high dose group declined by 1.1 points.
Both groups of patients had had MMSE taken several times at the start of the study. The MMSE test has a maximum of 30 (30 being perfect). Typically, a score of 24 or greater indicates normal cognition. A score of 19 to 23 indicates mild impairment. A score of 10-18 is moderate impairment. And any score below 10 is severe impairment.
Looking at another drug called Donepezil sold as Aricept:
Comparison of Donepezil and No-Donepezil Groups
As indicated in Figure 2, the 148 California patients who completed the study and received donepezil treatment had an average one-year decline of 1.3 points (3.5 SD) on the MMSE compared to a 3.3-point (4.4 SD) decline in the 158 completers who received no donepezil or other anti-AD drugs during the study period.
From page 5 of 8 of: https://med.stanford.edu/content/dam/sm/svalz/documents/publications/aloth11.pdf
Another study shows:
In contrast, the MMS declined an average of 2.15 points per year (95% CI 1.85-2.46) during the first two years, accelerated to 3.83 points per year (95% CI 3.28-4.38) during the subsequent three years and then slowed to an annual decline of 1.63 points during the last two years (95% CI 0.21-3.05).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014643/
Above, the Mini Mental State Exam is abbreviated as MMS instead of MMSE. But it is the same exam.
The number of patients in the Anavex 2-73 in the Phase 2a ANAVEX®2-73 was 32. There were low dose patients, some that were mid dose, mid to high dose and high dose patients. The high dose patients ( 6 of them) show very low decline in MMSE scores since they began taking Anavex 2-73 about 4 years ago. Unfortunately, this study is not conclusive due to the low number of high dose patients. I find the data very persuasive because the high dose patients do very well, the mid-to high dose do well and those with lower doses do less well. The correlation here makes the study much more persuasive than it otherwise would be.
If the data is taken at face value to mean that the Anavex 2-73 at the high dose slows the decline to about 1.1 per 2 years, then Anavex 2-73 is much better than anything else being studied. Additionally, it works long term. The competing drum Donepezil falls in its effectiveness over time. Some studies show it is not a cost effective drug when used up to 2 years. If the results of Anavex 2-73 hold up in a larger study size of patients, then it would be the only effective long term treatment for Alzheimers given the group of Anavex 2-73 2b study patients have been taking Anavex 2-73 for almost 4 years with good results.
Hopefully the doctor that prescribes the drug is aware of the side effects and carefully considers the side effects of drugs before deciding what to prescribe.
For many patients hoping their doctor is aware of and carefully considers side effects, this would be a false hope. Most doctors have little time and mostly go with the flow and prescribe drugs based on checking a reference and based on what the industry as a whole tends to prescribe for the particular condition.
I read the same thing in the slides. And it doesn't mean the opposite there either.
"Higher levels of microbiota families i.e. Ruminococcaceae and Porphyromonadaceae ?? associated with improved ANAVEX®2-73 response at week 148 (p<0.01 and 0<0.04, respectively)"
Scientifically speaking, there are several possible reasons for something like this to happen. Here are some of the most obvious to me:
1) It is meaningless - a fluke and statistical anomaly.
2) The 2-73 has some direct impact on these microbiota families.
3) The 2-73 has some indirect impact on these microbiota families.
3A) The indirect impact is due to lower inflammation.
(Note since it is associated with improved anavex 2-73 response, there could be a genetic component - some people respond to anavex 2-73 better (based on genetic background). Or anyone with lower inflammation has better microbiota families - (this is already known to be generally true.)).
You didn't understand the gut Microbiota Biomarkers paper.
The studies author hypothesizes, "Numerous pre-clinical studies demonstrate beneficial effects of SIGMAR1 (S1R) agonists on neuroinflammation, including with ANAVEX®2-735. The effect might potentially be reversal of the microbiota imbalances and might have a homeostatic effect on the brain-gut-microbiota axis."
So, what he means is that reduced inflammation even in the brain improves gut microbiota.
This hypothesis is reasonable because if for example you have some inflamed wound - such as an infected tooth. The inflammation markers in your blood such as but not only white blood counts, if you get a second wound, it will become more inflamed than it would have had you not had the infected tooth.
Or in this case, the authors hypothesis is that the reduced brain inflammation results in overall lower inflammation level which in the gut means that that fewer bacteria in the gut are under attack by the immune system of the gut. Which in turn results in less of a microbiota imbalance.
Hi N2deep1, the thing about biotechs like AVXL is that they really are not a get rich quick kind of thing unless the investor is luckier than I am.
You can trade them as a short term trade - when there is news. Or you can invest in them as a longer term play. But keep the investment small enough that it won't kill you to lose the money or part of the money. Maybe increase the investment if the news is positive and decrease it if it isn't. And be ready to sell.
I have AVXL as a long term play. It started out as 2% of my portfolio and is now at 3% - I did buy more early in 2019.
The recent news that they have is very positive. The findings for the SIGMAR1 WT structure seem to me to be very important as they explain how some patients had a much different response to the drug. Luckily, 80% of the population should respond well to Anavex 2-73. And it is something that can be screened for.
I give AVXL about a 30% to 50% chance to do well. Whether it does or not, I give myself about an 50% chance of making money on it and 30% chance of losing most of my investment. I think pending trial news the stock will gradually move up. If the drugs prove out, the stock should be more than a 10 bagger as they get purchased.
Given your logic, life is obsolete because we all eventually die. In fact, after our mid to late 20s, we all begin a slow decline. Our body declines. Our brain and memory decline. Our energy declines.
Imagine if there were a drug to slow this decline due to aging by 40%?
Would it be valuable to our aging population? Would anyone even buy it knowing that it only slows the decline?
For those who think that yes, people would buy it, then it is clear that they would also buy Anavex 2-73. Even if it only slows the decline of diseases like AH.
s
Hopefully, Anavex can get funding from the 21st century cures act.
Large companies usually get the lions share of government funding even for US farm subsidies. The large companies have the connections, pay the lobbyists and get the money.
However, with all the recent Alzheimer's disease trial failures, anything is possible. Maybe they can get a grant. I just would not count on it.
Thanks, I should have looked for the "subsequent" post prior to posting.
What does Anavex say about the mechanism of action for Anavex 2-73?
I don't mind you copying my post from IV, but you should post the link or credit me with it.
http://www.investorvillage.com/smbd.asp?mb=9414&mn=649&pt=msg&mid=16967059
Alzheimer’s disease, Amyloid Precursor Protein and Amyloid Beta
One of the few things that is known for sure about Amyloid Precursor Protein (APP) is that it is a “highly conserved” protein in nature. Meaning, that some form of APP is found in many animals. In fact, APP is often studied in mice or rats.
In nature, if something is “highly conserved” across many lifeforms and animals, this typically means that whatever is conserved is not only critical but that nothing better has been discovered in the evolutionary process. It must be critical because animals that have mutations that don't pass on the "highly conserved" trait are not currently around. Which means that not having the trait is a severe disadvantage.
Some known functions of APP have been found. It has a role in the differentiation of neurons. It has a role in repair of neural injuries. It has some impact on cell signaling. APP has an effect on neuronal transport of iron and in transport of some molecules to synapses that may be located quite a way from the cell center. These are only the known or suspected functions of APP. There are probably a few others.
APP breaks down into smaller molecules called Amyloid Beta (Aß). APP can be broken down by the body in various ways. The most common Aß form in healthy cells is for it to be broken down into a peptide of length 40 (Aß40). This is done in an “organelle” of the cell called the trans-Golgi network. Another more toxic form is Aß42. This is mainly formed on the endoplasmic reticulum. Several other Aß forms are also created in various ways in the cells usually in lesser amounts than Aß40 or Aß42. Some of them result in Aß that is fairly “toxic” to cells. Larger amounts of Aß42 tends to be found in diseased cells.
In healthy persons, the various forms of Aß are usually broken down further by various enzymes that specifically target Aß. These enzymes are typically called amyloid degrading enzymes. In healthy brains, excess amounts of Aß do not continue to accumulate and Aß is not continually excreted from the cells in large amounts such that it forms Aß plaques between cells.
Aß is often linked with the term “misfolded proteins”. In reality, Aß is not a protein. Nor does the typical “misfolded” protein description strictly apply. Aß is a fragment of a protein which is too small to be called a protein. Aß is a “peptide”. Excess amounts of certain forms of Aß tend to aggregate together and can do so in “forms” that appear to poison cells. In some of the aggregations of Aß, the peptide is folded in ways that make it more toxic. The reason that the misfolded protein description does not strictly apply in the sense it normally does is first of all Aß is not a protein. Second after ribosomes in the cells build proteins, they are “folded” in parts of the endoplasmic reticulum so that the protein can perform its biological function. In Aß, the “folding” problem happens after the protein APP is “cleaved” into smaller sections forming Aß.
On the other hand, there are several “mysteries” surrounding Aß. The various peptide forms of Aß may indeed have cellular functions. The reason to think this is because Aß is formed by “cleaving” APP in very specific ways by types of enzymes that are also highly conserved. In other words, the enzymes that cut up or breaks apart the APP protein into smaller Aß peptides are something that is widely present in similar form in a wide range of animals and life forms. Thus, the structure of the enzymes that cuts APP must be critical. And it would follow, that it is cutting them into various types of Aß with varying lengths for specific biological functions even if we don’t know what all of those functions may be. Lending some additional insight into why this might be so is a recent study on one function of Aß working as an antibiotic:
“A new study from Massachusetts General Hospital (MGH) investigators provides additional evidence that amyloid-beta protein -- which is deposited in the form of beta-amyloid plaques in the brains of patients with Alzheimer's disease -- is a normal part of the innate immune system, the body's first-line defense against infection. Their study published in Science Translational Medicine finds that expression of human amyloid-beta (A-beta or Aß) was protective against potentially lethal infections in mice, in roundworms and in cultured human brain cells. The findings may lead to potential new therapeutic strategies and suggest limitations to therapies designed to eliminate amyloid plaques from patient's brains.”
https://www.sciencedaily.com/releases/2016/05/160525161351.htm
Why is this important? I believe that the formation of Aß is something “regulated” by the cells and by various organisms from humans to roundworms. Given how conserved the function of the enzymes are for cutting apart APP into small peptides, it seems logical that not only does APP have many roles in the cell, but that Aß must also. The recent study that Aß helps fight certain disease leads credence to this.
Therefore it is possible that the accumulation of Aß may be a consequence of cellular misregulation or due to inflammation processes. If a cell is “inflamed”, it may be undergoing an immune reaction where the cell is reacting to what it believes is an infection or attack. A younger healthier person has more robust regulation of cellular mechanisms due to producing higher concentrations of regulatory, hormones, having better circulation, having better metabolic regulation and better overall health. Therefore, the brains of younger people recover from such inflammation processes while the brains of older people sometime don't. Instead, the inflammation triggers other problems causing the cascade of issues ultimately leading to full blown Alzheimer’s disease.
Drugs that target Aß have not been effective because the misregulation of cellular mechanisms is not corrected by drugs that target Aß. And in fact, targeting Aß may make the misregulation issues worse. Just as too much Aß is a problem, too little may also be a problem.
Anavex2-73 does not target Aß directly. Rather, the impact is to signal the cell that it is under “stress” and should change cellular behavior in ways to reduce the stress and help the cell return to homeostasis.
The way it does this is mainly as a sigma-1 receptor agonist and mixed muscarinic receptor agonist. The most widely known of those is the sigma-1 receptor which is what is called a receptor chaperone. For example, one of several functions is to modulate calcium signaling in the cell. Other changes in the receptor can signal the cell to die via programmed cell death (apoptosis) or signal it to try to recover and fight disease processes leading towards homeostasis.
For a person with diabetes, insulin brings the blood sugar levels back to healthy homeostatic levels which allow diabetics to function normally. For Alzheimer's patients, Anavex2-73 may help to similarly bring cellular metabolic processes back towards homeostasis which is exactly what the lab results and human trial results suggest.
My view of this is that the generation of Aß species that lead to senile plaques is normal. What is not normal is the generation of an excess amount of the Aß species such that senile plaques are formed instead of the Aß being metabolized/removed from the body. Any drug that targets Aß specifically with any kind of immune response will cause similar problems to Alzheimer's disease.
APP and consequently, Aß creation is likely something cells have been forming prior to advanced life evolving. It is not something that should be attacked - but rather, it should be regulated or better yet, the cells need to be brought back to homeostasis so that excess Aß is not formed.
The holy grail here in my opinion is simply to restore homeostasis. If homeostasis is restored, then the cells take care of themselves.
Given that we don't have the knowledge to put into production drugs that can target brain cells in many ways such that the drugs themselves bring the cells into homeostasis, the best we can do is regulate the cells in ways that tell them that they are under a specific kind of stress and that they should react in specific ways. Luckily, there are various cellular signaling mechanisms that scientists are becoming aware of. The ones we are interested in as Anavex investors are those targeted by Anavex drugs.
Cells have many regulatory paths in them - many which have been around for hundreds of millions of years. For example, if radiation increases in the environment, cells turn on mechanisms that "harden" the cell to radiation damage and cause damage to be repaired more quickly. This mechanism has disadvantages when radiation levels are lower so it does not make sense for it to always be turned on.
Likewise, cells have many other stress related pathways that can be turned on. The problem in Alzheimer's disease is that for people who get it, the appropriate mechanisms are not turned on and people get sicker.
The Anavex2-73 Alzheimer's drug works by turning on signaling paths that cause the brain cells to recognize that they are under a certain type of stress and to turn on innate mechanisms that deal with the stress to bring the cells back towards normalcy.
It is a good question, "does Anavex2-73 cure insomnia for non Alzheimer's patients?"
That question depends in part on whether or not the insomnia that Alzheimer's patients have is more related to Alzheimer's disease or it is just normal insomnia.
What I first though was likely is that insomnia is cured in the same way the ERP P300 amplitude issue is fixed. The ERP amplitude returns to normal by around week 48. However, given insomnia was gone by around week 12, that means that something else is at work.
Several other sigma 1 receptor agonists including the sigma-1 receptor agonist aspect of the donepezil (the most widely used Alzheimer's drug) don't help with insomnia. It is possible that the mixed muscarinic receptor aspect of Anavex2-73 is linked to this given the pharmacology of drugs like Doxepin which is sometimes used for depression an insomnia that have a muxcaninic aspect. Anavex2-73 is mainly a sigma-1 receptor and a mixed muscarinic agonist. On the other hand, it is possible that the sigma-1 receptor agonism of Anavex2-73 is different from other sigma-1 receptor agonists in the right way to help with insomnia.
At this point, I think more likely it is the mixed muscarinic aspect that is working to reduce insomnia. If it reduces insomnia the same way other muscarinic receptors work, then it might also help slightly with depression which is good given that having Alzheimer's is going to be depressing for anyone.
Funny, because it really seemed like you were the one that didn't read your own reference.
LOL. The problem is a comprehension issue on your part.
I'm going to give up on this topic given you can't seem to comprehend that there are more than one type of chaperones and that the sigma-1 receptor is not a protein chaperone. Therefore, it does not chaperone proteins.
Protein chaperones chaperone proteins in order to try to prevent misfolding.
And that IS a very critical distinction.
The answer given by MycroftHolmes matches most published sources:
"...the Sigma Receptor does not impact protein folding directly by chaperoning but rather indirectly but modulating PERK, IRE1a, and ATF6 and thus the UPR (Unfolded Protein Response) ..."
OFP's quote: "If you recall, one of the main chaperone functions of S1R is correct protein folding."
That comment is still not correct. It is not a "chaperone function".
Why is this important? The "protein chaperone" topic is a very complex and large topic.
https://www.researchgate.net/publication/51508608_Molecular_chaperones_in_protein_folding_and_proteostasis
The comment that, "...one of the main chaperone functions of S1R is correct protein folding." implies incorrectly that the sigma-1 receptor is a protein chaperone. It is not. The sigma-1 receptor is a "receptor chaperone". Something totally different.
"The sigma-1 receptor is a receptor chaperone whose activity can be activated/deactivated by specific ligands. Under physiological conditions, the sigma-1 receptor chaperones the functional IP3 receptor at the endoplasmic reticulum and mitochondrion interface to ensure proper Ca(2+) signaling from endoplasmic reticulum into mitochondrion. However, under pathological conditions whereby cells encounter enormous stress that results in the endoplasmic reticulum losing its global Ca(2+) homeostasis, the sigma-1 receptor translocates and counteracts the arising apoptosis. Thus, the sigma-1 receptor is a receptor chaperone essential for the metabotropic receptor signaling and for the survival against cellular stress."
Or:
"Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca(2+) directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which is implicated in neuroprotection, carcinogenesis, and neuroplasticity, is a Ca(2+)-sensitive and ligand-operated receptor chaperone at MAM. Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca(2+) depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca(2+) signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis. These results reveal that the orchestrated ER chaperone machinery at MAM, by sensing ER Ca(2+) concentrations, regulates ER-mitochondrial interorganellar Ca(2+) signaling and cell survival. "
https://www.researchgate.net/publication/5865783_Sigma-1_Receptor_Chaperones_at_the_ER-_Mitochondrion_Interface_Regulate_Ca2_Signaling_and_Cell_Survival
Returning cells to homeostasis won't help very much with slowing of the aging process. Aging is due to several things - the one that seems hardest to overcome is telomere shortening.
Telomeres are at the ends of chromosomes. When a "normal" cell divides, the telomere is shortened. As it becomes shorter, the cell responds differently and eventually will no longer divide and is more likely to die. The telomere functions as a kind of biological clock.
A cell that is constantly under stress due and is not in homeostasis is more likely to die via apoptosis. This can cause more cellular divisions than there otherwise would be to repair the damage. Which in turn causes more rapid aging of that tissue.
Returning cells to homeostasis on the other hand, will help people age better.