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Excellent observations, thank you Lima.
Richard E. Uihlein maintains that he intends to invest more of his personal funds and invites investors to do so along with him. He says he intends to subscribe to $20,000,000 of a new offering to move the company forward. If so, I suppose that should be somewhat of a positive indication although $20,000,000 for him may not be that large of a percentage of his networth? I have not had time to study this to make a firm decision about whether I desire to invest more to account for the dilution in ownership that this may otherwise cause? However, that is what he invites existing investors to do.
Nidan: Just illustrating my cynicism relative to the drug approval and health care processes, which is sometimes motivated by self -interest as I believe the opioid fiasco is a prime example. As you probably know, the FDA approved a change in opioid labeling to provide for around the clock administration of opioids after holding private meetings with major pharmaceutical companies and without requiring clinical trials to demonstrate safety. The general public should be outraged, but I do not see evidence of that. In the meantime, badly needed and potentially beneficial drugs have demonstrated safety but remain bogged down in the FDA approval process. People should be asking why hold a private meeting at the FDA and approve more frequent opioid use without even requiring a safety study for those additional doses during each day. Moreover, we should demand to know why the FDA may be motivated to meet privately and expedite such a request for opioids when that sort of treatment is not available or extended for drugs that may treat Alzheimer’s and other serious CNS diseases that are becoming rampant in the United States and elsewhere.
The problem with AVXL 2-73 is you cannot obtain this because it is not an “approved” drug despite clinical trials that establish it is a safe drug. I think it will be approved outside the United States first.
In the mean time, load up on opiods around the clock to mask the pain says our dear old FDA without requiring any saftey clinical trials by big pharma here in the U.S. Never mind that we have become a nation of addicts because the good old government will authorize massive spending programs on injections and drugs like suboxone furnished by the same big pharma companies to manage the addictions. Now, I know I am considered crazy, and the process I just described in this paragraph is considered be be the sane approach. Therefore, I am so glad that I am crazy, and I plan to stay that way.
From all of the other extensive research I have done AVXL 2-73 is helpful for eliminating inflamation in the body, autophagy, etc, and should be useful for treating aging or age related diseases. Having said that, we may all have to suffer a lot before we will ever be allowed to get your hands on this “dangerous” drug. Anavex 2-73 is dangerous because it may damage the market for block buster drugs that only treat symptoms and do not treat or prevent disease. Also, it is dangerous because it may damage “health care professionals” by preventing diseases that they treat — not prevent or cure. So, you may be wasting your time reading about Anavex, inflamatory disease, autophagy and other crazy stuff.
Please, please, stick with your FDA approved pain pills. Take as much as you like around the clock. If you pass out from an overdose, hopefully you will not die before our police, medics, and emergency room personnel spend massive resources reviving you with our other “wonderful” drugs that have nothing to do with making you healthy, wealthy and wise - just keeping you alive so you can go back to taking more opiods. Of course, whether you die from overdosing opiods or you are revived, it continues to make for good news headlines that our nation looks forward to seeing/hearing each day.
Good luck and keep up the great work that supports our soaring increases in healthcare spending and provides our daily dose of shocking news headlines!
Great! I voted all my shares for all of management’s proposals as well. It is for the benefit of management, shareholders and society in general. We will prevail!
Re: Choline, see this:
Msg 15583 of 31285 at 6/27/2016 10:10:44 PM by
libertyhound
The following message was updated on 6/27/2016 10:12:45 PM.
In response to msg 15580 by Rob Cos view thread
Re: JMP last night- development- stage names that we believe offer compelling value for the biotech investor. Also rare opportunity to acquire large caps at < 1 x's growth....
"Alzheimers is one of the most intractable diseases known to medicine, and chipping away at this devastating illness could go a long way toward reinstituting confidence amongst investors (and hopefully, the generalist) that no problem is too large for current medical science to resolve or beat back. Further, the general consensus is that a successful Alzheimer’s disease drug could become the largest selling drug on the planet, outstripping sales of Ibrance (Pfizer, PFE, NC) and immune checkpoint inhibitors like Opdivo (Bristol-Myers Squibb, BMY, NC)."
*Considering the 'very' preliminary early indications of astounding efficacy, it is possible that AVXL (MC of ~ $250M), currently trialing their A2-73 in Australia, may be long-shot favorite to watch for Alzheimer's - they don't really appear to be pursuing the 'chipping away' (read incremental improvements) approach though.....seem more aligned with going for the Holy Grail approach; their approach is NOT a variation of the popular plaque reduction route.
From a 5/10/16 SA piece by Lane Simonian
"Moreover, science seems to back the early results. Alzheimer's is most likely a disease caused by oxidative stress which can probably be treated with certain antioxidants. Anavex 2-73 partially fits this bill as by impeding the interaction between PSD 95 and neuronal nitric oxide synthase, it reduces the formation of peroxynitrite (ONOO-). Peroxynitrite inhibits the uptake of choline, the enzyme choline acetyltransferase, and the release of acetylcholine through muscarinic acetylcholine receptors which prevents the retrieval of short-term memories and it activates caspase 3 causing the death of neurons. (Image one, Image two, and Study.)
If Anavex 2-73 reduces the formation of peroxynitrite sufficiently it would prevent the further decline in acetylcholine and the death of neurons. In short it would stop the progression of Alzheimer's disease. If it partially reverses the damage done by peroxynitrite, it would increase acetylcholine levels (and thus the retrieval of short-term memory) and the regeneration of neurons in the hippocampus. In short, it would partially reverse Alzheimer's disease. The early data suggests the latter is what is happening with Anavex 2-73."
*No idea whether his (Lane Simonian) interpretation of the 'apparent' mechanism of action is fully correct, but the very preliminary 'results' appear to indicate a trend for unheard of efficacy - their trial is for early Alzheimer's btw, and further 12 week and possibly 26 week results are expected at the upcoming late July AAIC Alzheimer's Conference.
BTW - A2-73 was recently awarded ODD for Infantile Spasms and Rett Syndrome, ODD to their A3-73 for Frontotemporal Dementia, and have reported astounding pre-clinical results for epilepsy.....M.J.Fox Foundation is also fully funding a pre-clinical (animal) study of A2-73 for Parkinson's.
Assuming the AAIC results further confirm efficacy of A2-73 in early Alzheimer's, my guess is BTD will likely follow within a few months.
https://www.investorvillage.com/smbd.asp?mb=17701&mn=15583&pt=msg&mid=16128001
See also: Should You Boost Your Choline
http://www.berkeleywellness.com/supplements/vitamins/article/should-you-boost-your-choline
CB, I wholeheartedly agree. I too am a longterm investor in this company for over 4 years now, and trust management. I think Missling is putting forth his best effort to make Anavex a success for all shareholders, himself included, and for the benefit of mankind as well.
Theodore Roosevelt was gifted in writing and speaking skills. I admire what he overcame in life, and what he accomplished dispite his afflictions. "Teddy" wrote this:
“It is not the critic who counts; not the man who points out how the strong man stumbles, or where the doer of deeds could have done them better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood; who strives valiantly; who errs, who comes short again and again, because there is no effort without error and shortcoming; but who does actually strive to do the deeds; who knows great enthusiasms, the great devotions; who spends himself in a worthy cause; who at the best knows in the end the triumph of high achievement, and who at the worst, if he fails, at least fails while daring greatly, so that his place shall never be with those cold and timid souls who neither know victory nor defeat.”
Christopher is striving. He dares to accomplish something great. Something that no person or entity has ever accomplished before. If he/Anavex fails at least they failed while daring greatly so that their "place shall never be with those cold and timid souls who neither know victory nor defeat".
Excellent! That and the clinical trial update we will get of Feb 7 (announced this morning) are hopefully both encouraging!
5G will begin to arrive in 2019/2020 although, like anything else, there will likely be obstacles and bumps along the way. Verizon, AT&T, Sprint have promised 5G devices for the first half of 2019, while T-Mobile says a nationwide network will launch in 2020. RESN technology, patent protected, is key to creating cost-efficient 5G phones. 5G will offer faster data and longer battery life. Network availability will be limited at first, but the world will demand 5G. Apple stumbled this past year. 5G’s ability to transmit huge of amounts of data, nearly instantaneously, will unlock many new technologies that humans have dreamt of for decades. Apple and others must get with the program or become extinct. Putting it all together, RESN will rise with the demand for 5G although not in a straight line.
The Right to Try Act or acts (STATE LAWS) is not that effective in my opinion. In some states companies are forbidden to charge for the drug (Texas for example). Small biotech companies with no sales are not in a position to give their drugs away. Also, companies are subject to accusations of peddling “snake oil”. Just think about attacks along those lines that may be made probably even by some people on this board. Anavex needs to concentrate on three clinical trials and more. Making AVXL 2-73 available now under this act could pose many problems for this small company and make it vulnerable to its competitors and enemies. Believe me, even though the approved AD drugs do not work, the companies producing them may go to great lengths to protect their billions and billions reaped from selling them. Sales people connected with these companies are motivated by sales bonuses - not curing patients. As much as I would like to see this drug available for you and others to exercise your right to try, I think the decision to not make it available now is the best under the circumstances. Making the drug available now may be its downfall.
My understanding is the Cognision system can easily measure ERP. There is no reason why Anavex will not do that. I suppose that Anavex may be able to submit this results as further evidence in support of an application for drug approval, but see this:
“Some scientists commented privately to Alzforum that they are unsure whether ERPs are ready for prime time as an efficacy biomarker for Alzheimer’s drug candidates, since little evidence exists yet that these signals change over time.”
https://www.alzforum.org/news/research-news/fda-has-cleared-new-cognitive-screening-tests
And this:
EVENT-RELATED POTENTIALS AND THE DIAGNOSIS OF ALZHEIMER’S DISEASE— THE COGNISION™ SYSTEM
David A Casey
US Neurology, 2010;6(2):34-36 DOI: http://doi.org/10.17925/USN.2010.06.02.34
Abstract: Alzheimer’s disease is a major cause of cognitive decline among older people. Current diagnostic approaches rely primarily on cognitive symptoms. Recently proposed changes in the definition of the disease place more emphasis on the use of biomarkers (such as neuroimaging or cerebrospinal fluid markers) in the hope of allowing earlier and more definitive diagnosis for research and, eventually, clinical purposes. Event-related potentials (ERP) represent another promising biomarker approach. Alzheimer’s disease has been demonstrated to have a recognizable ERP signature. Recent advances in ERP technology may make the process painless, non-invasive and portable. These advantages suggest that ERP should be further considered as a potential biomarker for Alzheimer’s disease.
Support: The publication of this article was funded by Neuronetrix Solutions. The views and opinions expressed are those of the author and not necessarily those of Neuronetrix Solutions.
Keywords: Alzheimer's, event-related potentials (ERP), bio-marker, COGNISION™
Disclosure: David A Casey, MD, is on the scientific advisory board of Neuronetrix Solutions.
Received: September 27, 2010 Accepted: November 29, 2010
Correspondence: David A Casey, MD, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, 401 E Chestnut St, Suite 610, Louisville, KY 40202. E: david.casey@louisville.edu
Alzheimer’s disease (AD) is a major source of disability and mortality among older people. AD prevalence is rapidly increasing with increasing lifespan and a larger absolute number of elders. Current treatments, such as cholinesterase inhibitors or N-methyl-D-aspartic acid antagonists are supportive or palliative in nature, and are based on optimizing neurotransmission, but do not alter the underlying disease process. Their effects are modest and not every patient responds positively. In recent years enormous efforts have been under way to improve understanding of the disease and develop improved treatments. This article examines new developments in the definition of the disease and the growing importance of biomarkers in diagnosis. It will focus on the possible use of event-related potentials (ERP), an electrophysiological parameter, as a cognitive AD biomarker.
Clinical Diagnosis of Alzheimer’s Disease
Clinical diagnostic criteria of AD rely primarily on cognitive parameters and are based on excluding other possible causes of cognitive deficit. Such parameters include:
progressive, disabling loss of memory (especially episodic memory);
loss of other cognitive skills, such as language and executive function; and
diminishing functional ability, such as the ability to carry out activities of daily living.
In clinical practice, laboratory testing and neuroimaging serve primarily to help rule out other potential conditions. One must have substantial loss of cognition to qualify for the diagnosis of AD.1
Pathological Characterization of Alzheimer’s Disease
AD is characterized pathologically by amyloid plaques and neurofibrillary tangles, which are comprised primarily of misfolded proteins, along with atrophy. Amyloid is widely believed to be central to the pathogenesis of AD, a point of view known as the ‘amyloid hypothesis’. Plaques are believed to evolve through a complex pathway, commencing years before clinical memory symptoms of AD. Plaques and tangles cannot be visualized or detected by standard clinical imaging or laboratory techniques.2 However, amyloid plaques can be visualized with advanced positron emission tomography (PET) imaging systems utilizing labeling compounds that can currently only be used in specialized research settings (although new approaches are under development).3,4
The recent failure of several amyloid-based clinical therapeutic trials has provoked a rethinking of treatment strategies in AD. Some researchers have become skeptical of the amyloid hypothesis.5Many others believe that memory symptoms are a relatively late development in AD and that a successful therapy, including an amyloid-based strategy, depends on intervening earlier in the disease process.
A New Definition of the Disease
In order to facilitate this strategy, a new and evolving definition of AD has been created that relies on biomarkers along with progressive cognitive decline. This approach defines AD more clearly as a brain disease of plaques and tangles, rather than strictly being a cognitive disorder or dementia. The three proposed categories include:
Alzheimer’s disease dementia;
mild cognitive impairment due to Alzheimer’s disease; and
pre-clinical Alzheimer’s disease.
This definition greatly expands the number of individuals counted as having the disease by including a large group of asymptomatic people. It is hoped that redefining AD in this way will facilitate a unified research program and prompt a search for earlier interventions. Under the old definition of AD that relies on clinical diagonsis, new drug development aimed at intervention at the earliest possible stage would be greatly hampered as the industry is reluctant to expend enormous resources on a condition that is not recognized as a disease.6
https://www.touchneurology.com/articles/event-related-potentials-and-diagnosis-alzheimer-s-disease-cognision-system
Mrplmer: Thank you for this link dated Jan 8th:
https://rettsyndromenews.com/2019/01/08/phase-2-trial-anavex-2-73-rett-syndrome/
Dr. Kaufmann’s prominence relative to Rett research and investigations of treatments for Rett Syndrome is indisputable. For example, this article says:
“Anavex recently appointed Walter E. Kaufmann, MD, as chief medical officer of the company. Kaufmann was the founder and leader of RettSearch, the international consortium of Rett syndrome clinical researchers, and co-author of the current diagnostic guidelines for the disorder.
He currently leads the Rett Syndrome Molecular Biomarkers Working Group for the International Rett Syndrome Foundation and the Rett Syndrome Behaviour Questionnaire Working Group.”
Bio -
I agree there are many reasons to explain the insider buying issue. What’s more, Anavex’s employees are based in New York. Up until recently, I made frequent trips to New York for business reasons, and I had close contact with people that lived and worked there. It is difficult to live comfortably in the City unless you have or make a lot of money, even more money than Missling’s salary. I remember too that when younger I knew about very good investment opportunities because of my position, but I simply did not have the funds to invest even though I made a decent salary.
The insider buying issue for this small developing biotech I view differently from that involving established companies that are are profitable, can afford to pay higher salaries and bonuses, and where the insiders may be in a position to employ leverage to purchase additional stock in their company. However, if I were a banker (and I once held shares in a closely held community bank), I would view any loan request by an employee of this biotech company very differently from a loan request from an employee of an established profitable company.
Therefore, I am not concerned about the lack of insider buying at this point. It may be another thing to watch as the trials progress though, but I think that tracking volume as I discussed yesterday may be an earlier indication of how the trials are proceeding. By the time you receive the reported insider buying/selling numbers, it is usually too late.
I am not worried or concerned about this issue.
Yes, you should watch volume, I think. Institutions/ hedge funds move markets (we don’t) although an individual investor that either buys or sells a few hundred thousand shares of stock in a small company like AVXL could move the share price for a day or so if that individual decided to purchase/sell all of those shares over a short period of time. Those of us here have our limits. So, try to follow the volume. It (large volume - unusually large volume % increases over time) may be a clue in the puzzle of attempting to decipher what is going with accumulation or distribution by larger players with access to information that eventually significantly moves share price. The % of volume increases may be a clue to whether clinical trials of a biotech are succeeding or failing. Of course, once this news is known is when you see the large moves either way, but larger than usual % of volume increases may demonstrate accumulation/distribution before the news is “known” by us lesser mortals.
However, it may turn out that we all get the big news at the same time. That is the way it is supposed to work, but quite often some get the word before others. Anavex is a small company with few employees, which you might say cuts down on the possibility of news leaking out. However, we are conducting three clinical trials at once with the same drug, and think about how many people total have access to information that could be “leaked” about how the trials are proceeding. Therefore, to those of us not in the know, larger than usual volume increases along with analyzing the price action may provide a clue that the larger players have some knowledge of what is going on and are making larger buys or sells accordingly.
I like Zena’s “dangerous” Compiled Due Diligence and the voluminous “dangerous” authorities cited in support of each item included in that due diligence.
The potential ANAVEX®2-73 to treat various Orphan diseases adds value to the company.
''Orphan drug companies have used with tremendous success as part of their drug life cycle management, the strategy to extend the life of their product by devising a succession of multiple discrete indications for the orphan drug. This strategy is critical to the continued financial success for orphan drug companies, especially when facing the challenges of generic competition and the demise of the traditional blockbuster drug strategy. The advantage of using multiple indications is that it allows a company to progressively expand the drug’s market.
This Blog Post presents several biotechnology companies that have used the multiple indication strategy for orphan drugs successfully:
• Alexion Pharmaceuticals’ Soliris
• Celgene’s Revlimid
• Novartis’ Gleevec.''
https://orphandruganaut.wordpress.com/2015/02/18/orphan-drugs-the-power-of-multiple-indications/
“I hope to bring expertise and experience to Anavex in order to succeed in the development of ANAVEX®2-73 ...’’
Hiring of a highly qualified Chief Medical Officer, use of the words“... to succeed in the development of ANAVEX®2-73 ...’’, and registration of the trademark. I like the words. I like the confidence. I like the science. I like the message. I like the PR.
Biogen - Anavex MTA
I have not found everything Bio posted about the Anavex - Biogen MTA as I mentioned earlier today. I am a bit rushed for now, but I provide some food for thought here, including some quotes from one of Bio's old posts.
Biogen made the agreement with Anavex in 2016. My recollection is that I concluded sometime since the agreement that Biogen was interested in Anavex's entire area of focus. I need to think more about this, but here is some background.
I went back to look at the announcement of that agreement Anavex signed with Biogen in 2016. It was a material transfer agreement with Biogen in September 2016 to conduct tests with AVXL 2-73 in relation to demyelinating diseases. The studies were to ”...examine the therapeutic role ANAVEX 2-73 may play in permitting remyelination in the brain..” https://www.anavex.com/anavex-compound-to-be-tested-in-biogen-neurological-protection-model/
Anavex's press release said: (It - Anavex) ..signed a material transfer agreement with Biogen (Cambridge, MA) under which Biogen will test Anavex’s lead drug candidate, ANAVEX 2-73 in an oligodendrocyte precursor cell (OPC) differentiation assay. A satisfactory result from the OPC assay study may lead to an in vivo remyelination study using a chemical demyelination model.
How does one fully study the role our drug plays ”in permitting remyelination in the brain” without performing work that may relate to other CNS diseases? Can this study be conducted without knowledge and understanding of how AVXL 2-73 works in relation to the Central nervous system? Was the Biogen study intended to simply be performed in a pitri dish, or was this MTA meant to lead to something more significant? Therefore, does the study by Biogen relate to the role AVXL 2-73 plays in treating CNS diseases in general as well as how AVXL 2-73 may relate to MS?
I think Biogen undoubtedly has and is studying AVXL 2-73 and how it may treat any CNS disease. Is Anavex using Biogen or is Biogen using Anavex?
Anavex appears sagacious in how it is going about protecting its IP. The latest patent most recently discussed here in depth adds a great deal to that protection.
What is a MTA and what does it accomplish? Here is a reference that shares some light about that:
"Use and Misuse of Material Transfer Agreements: Lessons in Proportionality from Research, Repositories, and Litigation
Abstract
Material transfer agreements exist to facilitate the exchange of materials and associated data between researchers as well as to protect the interests of the researchers and their institutions. But this dual mandate can be a source of frustration for researchers, creating administrative burdens and slowing down collaborations. We argue here that in most cases in pre-competitive research, a simple agreement would suffice; the more complex agreements and mechanisms for their negotiation should be reserved for cases where the risks posed to the institution and the potential commercial value of the research reagents is high."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315468/
Is the risk posed to Anavex in entering into a MTA with Biogen high? If so, I have to think that Anavex made a complex agreement with Biogen to protect itself. Additionally, Anavex has the IP protection as I alluded to above. Therefore, I have to think that Anavex has covered itself with adequate protection.
Next to last, I conclude with this quote from the below referenced article, which I am sure several posters on this board mentioned in the past:
First, I point out that the article said the Motley Fool and others were critical of Anavex, and in the article's opinion overlooked the implications of the MTA between Biogen and Anavex. The article went on to say:
"Anavex Life Sciences Corp (NASDAQ:AVXL) And Biogen Inc (NASDAQ:BIIB): A Perfect Match .....
'Biogen needs Anavex more than Anavex needs Biogen. Biogen has a $68 billion market cap, yet its share price is only up 2% YTD. This follows a dismal 2015 where Biogen fired 11% of its workforce and enacted cost-cutting programs. Furthermore, Biogen has bet a great deal on Aducanumab for the treatment of Alzheimer’s. Aducanumab is part of the amyloid hypothesis that the plaques are responsible for the pathology of Alzheimer’s disease. However, the data from Aducanumab has been rather unimpressive. From this article on Seeking Alpha:
'However, Biogen’s own data indicates that its drug is ineffective or minimally effective at slowing down the progression of the disease in its early stages. At 26 weeks there was no difference between placebo and the highest dose drug group (10 mg) using a cognitive staging test for Alzheimer’s disease (CDR-SB). At 54 weeks, there was a 1.44 difference between Aducanumab at 10mg and placebo using the same test. The high dose group seemed to show an incremental improvement between 26 and 54 weeks. The mini-mental state scores followed a similar pattern except at 26 weeks the 10mg group performed slightly better than the placebo group.'
Anavex’s approach is completely different and this is the key. It’s the science behind Anavex that will make the difference. ANAVEX 2-73 is the most promising drug being developed right now for Alzheimer’s. ANAVEX 2-73 is based on oxidation and nitration causing Alzheimer’s. Other drug companies have instead focused on the cause being amyloid. They have misdiagnosed the cause while we believe Anavex has the correct approach.''
https://insiderfinancial.com/anavex-life-sciences-corp-nasdaqavxl-and-biogen-inc-nasdaqbiib-a-perfect-match
Lastly, here is some of what Bio posted on Wednesday, 10/03/18 (Post # 167558) about the MS agreement:
''Here’s some DD which I investigated in an attempt to learn more about our MS Petri dish in vitro assays in conjunction with BIIB and how that particular process might be carried out from a practical standpoint. What turned up was not what I had intended to find. Still, I followed where the research led and I think what turned up sheds an awful lot of light on the entire process of CNS drug testing.
Bio went on to explain how the system was broken (the system should have focused on cognition as the end point instead of mere removal of plauque, etc., with no improvement in cognition) concluding:
"The good old government - us! And, contrary to some, the FDA could have determined at some point that clearing plaque was not a valid endpoint. They are allowed to look at the science that far! and based on previous failures say there is no connect and not approve a trial to go forward, just as they would not see any point in approving a trial for Alzheimer’s if a designated endpoint were to be able to sit long enough to have your blood drawn. It removes blood from the system and can be demonstrated to perform that but that has zero correlation to cognition. Same with removing other things from your body, like plaque. The endpoint should have been cognitive improvement or nothing and after 2-3 years of no gain with the A-b removal, they should have reviewed those trials very carefully before approving. You are right, nidan, egg is all over the FDA’s face now. But, if they were being paid off...just sayin’)
No tau tangles, you say? No problem. We took the closest thing we could get to work in mice to get their Amyloid to produce tau tangles...which happened to be a gene mutation from another CNS disease frontotemporal dementia, and injected the mutation into the already gene altered mice to get brains which contain plaque and tau. And it’s not even the same structure of tau as human brains diseased with Alzheimer’s. Mutated mice express only a 4-repeat tau variant whereas the human brain has a 4-repeat tau variant and a 3-repeat tau variant expressed in a 50:50 ratio.
It’s quite easy to see, as stated in the article, at this point one begins to question exactly what we are modeling. This sounds a lot like putting a bunch of stuff in which you know doesn’t belong in there just so you can take it out and say you show promise in curing the problem. It’s very bad science, if science at all. ''
....Here’s a summary of what is coming which is better than the past and supports our approach and what Anavex has done preclinically to make our results more meaningful. (with links after...this is becoming long-ish even by Bio’s standards, but it’s a complicated historical topic to delve into and do it justice without some substance).
None of this is a guarantee of success but when you look at the modeling we have, you will know why your money is in this company (I do!), and, you will wonder why the FDA hasn’t approved our trials yet (I will leave that to each of you, as well as why countries who want a cure DID approve our trials. And if and when a BP or 3 will drop the phony mouse model charade and buy the drug that treats the cause.) Those who say we just haven’t demonstrated enough with low double digit humans sample are guilty of looking out for themselves until there is nothing more to see and then looking away...we have demonstrated modeling in mice which is orders of magnitudes closer to human brains than anything else ever before seen. Maybe that’s why we have a person driving a car again? And a Nobel Scientist with the smarts joining our trial?)
Building a better mouse-model:
First, let’s agree that while other drugs claimed promise based upon the fact that they removed plaque and tau from the transgenic mouse brains (I keep trying to decide which is correct - mouse brains or mice brains?) , that was their objective, which, once met, justified using these to treat humans with Alzheimer’s and restore cognition. A jump to improved cognition was inferred by removal of plaque and tangles but never demonstrated.
Anavex A2-73 sigma 1 receptor agonist which was postulated to restore cellular homeostasis and correct mitochondrial dysfunction which our company’s science believed was the genesis of the disease, showed less in the area of plaque/tau clearing alone and initially, but demonstrated improved or regained cognition in the transgenic mice.
Here’s the A PLUS +++ takeaway: Even though these mice’s brains’ neurons and mitochondria and ER were damaged rather quickly and through a process altogether different from Alzheimer’s in humans (akin to just picking them up by their tails and traumatically smacking them down on the lab counters until they saw Tom and Jerry stars circling their heads - the equivalent of introducing mutations such that either way they never knew what him them), our approach STILL RESTORED COGNITION! That’s big! That suggests a lot: our S1r agonist can help with all types of brain problems be they Neurodegenerative or sudden concussion or due to hypoxia (X!), restoration appears to take place. That’s a bit huge, really!
Next, Anavex went further in their attempt to nail down the hypothesis. We took regular mice and removed their Sigma 1 receptors. These are called knock out mice. We knocked the S1r out. Then we crossbred them with the transgenically altered mice who have the Alzheimer’s hallmarks and cognitive impairment. Then we administered A2-73 to mice with no S1r to agonize. Know what? They never got better.
(Are you loving this, Nidan??? Bet if I were a gal, you’d kiss me right now lol!)
(Cite and quote at bottom: Anavex)
Finally,
“Rudy Tanzi, a neuroscientist at Harvard Medical School in Boston, Massachusetts, reported in 2014 that his lab had grown human neural stem cells containing APP and PSEN1 mutations in a 3D culture system supported by a gel matrix (S. H. Choi et al. Nature 515, 274–278; 2014). The results were startling: the tissue that developed contained neurons that deposited amyloid-ß into the gel, and plaques formed after 5 to 6 weeks. A week or two later, the elusive tau tangles also appeared” - the exact tau replica seen in humans with Alzheimer’s in the exact ratio. It’s remarkable. And lower cost, and much quicker...in fact, companies can test tons of compounds on these brain models in a very condensed period of time. Anyone want to speculate about the BIIB MTA Petri dish assays going on, now’s your chance! Someone posted it would require more A2-73 than they could get their hands on...au contraire, friend.
(Cite at bottom: Nature 2014)
Now, to dado’s post and the hope of all long investors reading (and not, for that matter):
“The race is on to add different cell types to organoids, so that they can better represent real brain tissue. Tanzi has already incorporated microglia into his model. Initially held in a reservoir outside the dish in which the organoids grow, the microglia travel down microfluidic channels into the main plate in response to the release of pro-inflammatory compounds by stressed neurons (J. Park et al. Nature Neurosci. 21, 941–951; 2018). The microglia then respond to any plaques by pruning the junctions between neurons — effectively trimming the connections that underpin memory. Tanzi thinks that this is how the immune system responds to plaques and tangles, and inflicts harm on the brain.” EMPHASIS MINE
(Cite at bottom: Nature)
Repeat for added emphasis:
In response to release of proflammatory compounds by stressed neurons, microglia travel down microfluidic channels then respond to any plaques by pruning the junctions between neurons - effectively trimming the connections that underpin memory.
Tanzi (Harvard) thinks this is how the immune system works and inflicts harm on the brain.
(Cite at bottom: Nature)
Nidan - cool (thumbs up)
Brain junctions are also referred to as gaps or synapses. (Google brain cell junctions)
“Neurotransmitter (NT) receptors are located on the surface of neuronal and glial cells. At a synapse, one neuron sends messages to the other neuron via neurotransmitters. Therefore, the postsynaptic neuron, the one receiving the message, clusters NT receptors at this specific place in its membrane.” (Google synapse)
“Microglial cells are responsible for clearing and maintaining the central nervous system (CNS) microenvironment. Upon brain damage, they move toward injuries to clear the area by engulfing dying neurons. However, in the context of many neurological disorders chronic microglial responses are responsible for neurodegeneration. Therefore, it is important to understand how these cells can be "switched-off" and regain their ramified state. Current research suggests that microglial inflammatory responses can be inhibited by sigma (s) receptor activation.”
2015 article.
https://www.ncbi.nlm.nih.gov/m/pubmed/25666889/
Nidan and all - the “How” this happened is, we had a really bad model. The “Why” is known to some as always. But, your gift today is to see that the broken model is being FIXED!!!! (And A2-73 passed with flying colors and even checked our math, using the knockout mice, BEFORE we turned in our test paper. We should get an A+ wink! Hell, we should be teacher’s pet! Lol!)
This should give some sense of how important the preclinical mouse work is and if we choose to laugh at “just another mouse model paper being presented” we can do so in context. These are very important when done correctly!
All this adds up to a great hope for our success and I didn’t even have to rely on painters, pianos, golfers, drivers...strong responders or genetic biomarkers. Imagine how we look once we add in those metrics. Yeah, baby! (Austin Powers)''
(End of Bio quotes)
Bio can correct me if I am wrong, but I see this MTA between Biogen and Anavex as revealing something more than a mere experiment is a pitri dish. Biogen is facing the realization that the tables are turning, and it cannot be assured that it can continue to develop CNS drugs under this broken system so well described by Bio and others on this board. Certainly, someone at Biogen decided that Biogen should put its foot in the door of the pursuit by Anavex. As I said before in my post entitled "The evolution of Anavex’s theory for treating Alzheimer’s and other CNS diseases" :
"AVXL 2-73 is a radical departure from mainstream science that believes that if we simply remove amyloid plaque all will be well with Alzheimer patients, except nothing is well as we all know. The Anavex approach is to correct the dysfunction within the body that causes the body to malfunction and prevents the body from clearing itself of waste, including amyloid plaque, and other offending matter resulting from a disconnect within the body’s central nervous system."
Bio and others have here have explained how the system is broken. Biogen must know the sytem is broken. Tiny Anavex's hypothesis has a sound scientific basis and its theory for treating has and is evolving as I and others have posted. Quoting Bio "We Got This". I think that at least someone at Biogen must be thinking that it needs to take another path that leads to to cognition as an end point instead of palque removal that has failed to produce a drug to treat AD or any other CNS disease. Simply put, the folks at Biogen are not stupid. They must know that at some point the pharmaceutical industry will no longer be able to reap billions from its failed plaque removal drugs. However, Biogen has not about to publicly admit that the AD plaque removal drugs that continue to reap billions are a failure and that it is time to pursue a different approach.
We do cannot know the actual terms and conditions of the MTA agreement because it is confidential, but we can analyze all facts and information that we have come to know to draw reasonable conclusions. My conclusion for now is that folks at Biogen must be thinking that maybe - just maybe Anavex has “got this”?
Yes, I agree. I wish we had access to the agreement between Anavex and Biogen, but my experience has been that due to confidentiality provisions that is not possible. However, as I remember, Bio has expressed ideas about the deal between Biogen and Anavex?
I believe it would be a mistake to attempt to license this drug, AVXL 2-73 (that includes its metabolite 19-144) for a single indication when it has potential for many indications. Remember too that such an attempt must also take into consideration the issue of off label prescribing that doctors are allowed to do. Instead, I believe that the multiple indications of Anavex’s drugs adds value that must be taken into consideration when negotiating a partnership for future development and marketing of Anavex’s drugs. Multiple indications are valuable. Additionally, Orphan drugs have value because Orphan drugs can be used with tremendous success in extending the life cycle of Anavex’s drugs. For example, see this:
''Orphan drug companies have used with tremendous success as part of their drug life cycle management, the strategy to extend the life of their product by devising a succession of multiple discrete indications for the orphan drug. This strategy is critical to the continued financial success for orphan drug companies, especially when facing the challenges of generic competition and the demise of the traditional blockbuster drug strategy. The advantage of using multiple indications is that it allows a company to progressively expand the drug’s market.
This Blog Post presents several biotechnology companies that have used the multiple indication strategy for orphan drugs successfully:
• Alexion Pharmaceuticals’ Soliris
• Celgene’s Revlimid
• Novartis’ Gleevec.''
https://orphandruganaut.wordpress.com/2015/02/18/orphan-drugs-the-power-of-multiple-indications/
Here are a few items (5 total) from the past that I believe may set AVXL 2-73 apart from other receptor agonist discussed on this board.
''Anavex 2-73 reportedly binds the sigma-1 receptor in the high nanomolar and the muscarinic receptor in the low micromolar range.'' SEE # 1 BELOW.
"Preclinical Data of ANAVEX 1-41 and ANAVEX 2-73, Show Highly Potent Anti-Amnesic and Neuroprotective Activity Against Amyloid Beta (25-35) Peptide Toxicity in Alzheimer's Disease (AD) Animal Mode." # 2 BELOW.
"ANAVEX2-73 is metabolized into the pharmacologically active metabolite, ANAVEX 19-144. The apparent elimination half-life of the metabolite (21.45hr) is approximately twice that of ANAVEX2-73 (10.71 hr) hence the active metabolite result in extended activation of the sigma-1 receptor." #3 BELOW.
An extended half-life implies an increased impact on patients.
"Preclinical data reveals that ANAVEX 2-73 and ANAVEX 19-144 exhibit significant anti-amnesic, neuroprotective and anticonvulsant properties in a variety of in vitro systems and specialized animal models. These activities involve sigma-1, muscarinic and NMDA receptors as well as ion channels, indicating a unique mode of action. In AD animal models, ANAVEX 2-73 has shown pharmacological, histological and behavioral evidence as a potential neuroprotective, anti-amnesic, anti-convulsive and anti-depressive therapeutic agent, due to its potent affinity to sigma-1 receptors and moderate affinities to M1-4 type muscarinic receptors. ANAVEX 2-73 has shown a potential dual mechanism which may impact both amyloid and tau pathology. ANAVEX 19-144 controls seizures and the epileptogenesis process in animal models. Moreover, its neuroprotective properties may prevent the process that causes long-term damage to tissue and cells as well as biochemical and physiological alterations to the brain from epileptic seizures." (10 K Part 1, ITEM 1. BUSINESS). #4
Orevko post (# 5 below) discussed patent rights on this board in the past and says this about AVXL 2-73 and 19-144: "I read through that new application last week and it's quite interesting. It gives some additional insight into the inner workings of Anavex 2-73 and Anavex PLUS. The metabolite (Anavex 19-144) really seems to be the secret sauce. ". Many excellent posts from the past by Orevko may be located on this board, and the patent Orveko refers to is something I or we all may review to learn more about the inner workings of Anavex’s drugs.
1. Chemical Name: Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Anavex Life Science Corp.
BACKGROUND
This compound is an agonist of the intracellular sigma-1 chaperone protein. Specifically, it is a mixed ligand for sigma1/muscarinic receptors. Expressed in most tissues and located at focal contacts between mitochondria and the endoplasmic reticulum, the sigma-1 receptor forms heterodimers with many other membrane receptors, and as such influences multiple cellular pathways and physiological processes. Anavex 2-73 reportedly binds the sigma-1 receptor in the high nanomolar and the muscarinic receptor in the low micromolar range.
The compound has been reported to have memory-preserving and neuroprotective effects in mice treated with the muscarinic receptor antagonist scopolamine, with synthetic Aß oligomer injection, or with the NMDA receptor agonist dizocilpine (Villard et al., 2011). A recent study suggested that Anavex 2-73 may block tau hyperphosphorylation (see Jan 2013 conference news and Lahmy et al., 2013).
https://www.alzforum.org/therapeutics/anavex-2-73
2. Preclinical Data of ANAVEX 1-41 and ANAVEX 2-73, Show Highly Potent Anti-Amnesic and Neuroprotective Activity Against Amyloid Beta (25-35) Peptide Toxicity in Alzheimer's Disease (AD) Animal Mode
http://www.marketwired.com/press-release/preclinical-data-anavex-1-41-anavex-2-73-show-highly-potent-anti-amnesic-neuroprotective-otc-bulletin-board-avxl-654103.htm
3. ANAVEX2-73 is metabolized into the pharmacologically active metabolite, ANAVEX 19-144.
The apparent elimination half-life of the metabolite (21.45hr) is approximately twice that of ANAVEX2-73 (10.71 hr) hence the active metabolite result in extended activation of the sigma-1 receptor.
https://anavex.com/wp-content/uploads/ANAVEX2-73-PKPD-Phase-2a-2017.pdf
4. "Preclinical data reveals that ANAVEX 2-73 and ANAVEX 19-144 exhibit significant anti-amnesic, neuroprotective and anticonvulsant properties in a variety of in vitro systems and specialized animal models. These activities involve sigma-1, muscarinic and NMDA receptors as well as ion channels, indicating a unique mode of action. In AD animal models, ANAVEX 2-73 has shown pharmacological, histological and behavioral evidence as a potential neuroprotective, anti-amnesic, anti-convulsive and anti-depressive therapeutic agent, due to its potent affinity to sigma-1 receptors and moderate affinities to M1-4 type muscarinic receptors. ANAVEX 2-73 has shown a potential dual mechanism which may impact both amyloid and tau pathology. ANAVEX 19-144 controls seizures and the epileptogenesis process in animal models. Moreover, its neuroprotective properties may prevent the process that causes long-term damage to tissue and cells as well as biochemical and physiological alterations to the brain from epileptic seizures." (10 K Part 1, ITEM 1. BUSINESS)
https://www.sec.gov/Archives/edgar/data/1314052/000106299311005004/form10k.htm
5. Orveko I-Hub post -Wednesday, 01/27/16 01:06:47 AM
Re: seventhwave post# 51618 0
Post # of 176791
Anavex 19-144 is the active metabolite of Anavex 2-73, i.e., when you ingest A2-73, your body metabolizes it into A19-144. A2-73 is therefore itself a drug and also a pro-drug for A19-144. One-two punch.
Dr. Vamvakides signed over Greek patent rights for A2-73 (AE 37), A19-144 (AE 37 MET), and other compounds per the following contract (effective January 29, 2007) - scroll down to the very end (Schedule A):
https://www.sec.gov/Archives/edgar/data/1314052/000108503707000289/super8k-exh10_1.htm
Most of the U.S. patent applications related to the original Greek patents are still pending, but all are either directly assigned to Anavex or are otherwise contractually owned by Anavex. I specifically asked IR about this new application and they say it is "contractually the property of Anavex."
Even though this new application (14/865862) was just published, it's priority date is March 28, 2013, same as 13/940352 and 14/395581. This is because they are all essentially "continuations" of the original Greek patent application GR2013000018 (WO2014155138). This Greek application (which is where Anavex PLUS comes from) was not part of the original contract with Vamvakides, but is still the contractual property of Anavex per the 2012 addendum to the original contract (effective January 11, 2013):
Quote:
1.1 (e) Inventions made during the term of the CONTRACT filed on or after January 29, 2007 and not falling under 1.1 (a) - (d) wherein Dr. Vamvakides is an inventor.
http://www.sec.gov/Archives/edgar/data/1314052/000106299313006497/exhibit10-81.htm
Anyway, I read through that new application last week and it's quite interesting. It gives some additional insight into the inner workings of Anavex 2-73 and Anavex PLUS. The metabolite (Anavex 19-144) really seems to be the secret sauce.
https://investorshub.advfn.com/boards/profilea.aspx?user=525667
Thank you, Xena.
CLEARLY, I BELIEVE THERE IS SCIENTIFIC SUPPORT FOR ANAVEX’S DRUGS, WHICH ACT AS MUSCARINIC AND SIGMA 1 RECEPTOR AGONIST. SIGMA 1 RECEPTORS PLAY A ROLE ON MITOCHONDRIAL FUNCTIONS RELEVANT TO NEURODEGENERATIVE DISEASES. THIS POST IS AN ATTEMPT TO SIMPLIFY THE DISCUSSION ABOUT WHETHER ANAVEX IS LEADING US DOWN A RABBIT TRAIL, WHICH I BELIEVE IS NOT THE CASE. THEREFORE, THIS IS A SIMPLE AND STRAIGHT FOWARD RESPONSE TO REFUTE A COUPLE OF CRITICS ON THIS BOARD THAT I BELIEVE ARE DEAD WRONG IN THEIR PERSISTENT EFFORTS TO CASTIGATE THE ANAVEX CLINICAL TRIALS BEFORE THE TRIALS ARE CONCLUDED TO ESTABLISH WHETHER ANAVEX’S DRUGS ARE BENEFICIAL IN TREATING CNS DISEASES. THESE CRITICS SEEM TO DOOM ANAVEX TO FAILURE EVEN BEFORE THE COMPANY HAS A CHANCE TO PROVE OR DISPROVE WHETHER ITS DRUGS ARE USEFUL TO TREAT CNS DISEASES. I BELIEVE THAT ANAVEX IS A BONA FIDE PIONEER IN SEARCHING FOR A TREATMENT FOR CNS DISEASES WHERE ALL OTHERS BEFORE HAVE FAILED. THERE IS A BASIS FOR THE PATH PURSUED BY ANAVEX, AND EVEN THE HARSHEST SKEPTICS NEED TO AT LEAST GIVE ANAVEX A CHANCE TO PROVE OR DISPROVE WHETHER ITS DRUGS ARE BENEFICIAL TO TREAT CNS DISEASES, WHICH HERETOFORE HAVE NO EFFECTIVE TREATMENT. HOWEVER, I DOUBT THIS OR ANY POST WILL DISSUADE THESE CLOSED MINDED CRITICS. AT LEAST, THIS POST MAY HELP TO ENCOURAGE OTHERS TO DO THEIR OWN DD AND DECIDE FOR THEMSELVES RATHER THAN BE INFLUENCED BY ME OR ANYONE ELSE (INCLUDING THE SINGLE-MINDED CRITICS).
Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases
Tzu-Yu Weng, Shang-Yi Anne Tsai, and Tsung-Ping Su
Additional article information
Associated Data
Data Availability Statement
All data in this review are already published and are available in public domains.
Abstract
The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca2+ signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca2+ transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed.
Keywords: Sigma-1 receptor, Mitochondria, Mitochondrion-associated ER membrane (MAM), Neurodegenerative disorders
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603014/
ANAVEX2-73 is a sigma-1 receptor agonist with muscarinic receptor activity...
https://onlinelibrary.wiley.com/doi/full/10.1111/jch.13197
THE FOLLOWING IS FROM WIKIPEDIA AND INCLUDES REFERENCES:
ANAVEX2-73 is an experimental drug is in Phase II trials for Alzheimer's disease, phase I trials for epilepsy, and in preclinical trials for amyotrophic lateral sclerosis, Parkinson's disease, Rett syndrome, stroke.[1][2] ANAVEX2-73 acts as a muscarinic receptor and a moderate sigma1 receptor agonist.[1] ANAVEX2-73 may function as a pro-drug for ANAVEX19-144 as well as a drug itself. ANAVEX19-144 is the active metabolite of ANAVEX 1-41, which is similar to ANAVEX2-73 but it is not as selective for sigma receptor.[2]
ANAVEX2-73
ANAVEX2-73.svg
Legal status
Legal status
Investigational
Identifiers
IUPAC name
1-(2,2-Diphenyltetrahydro-3-furanyl)-N,N-dimethylmethanamine
CAS Number
195615-83-9
ChemSpider
8057864
UNII
9T210MMZ3F
Chemical and physical data
Formula
C19H23NO
Molar mass
281.40 g·mol-1
3D model (JSmol)
Interactive image
SMILES
O3C(c1ccccc1)(c2ccccc2)C(CN(C)C)CC3
InChI
InChI=1S/C19H23NO/c1-20(2)15-18-13-14-21-19(18,16-9-5-3-6-10-16)17-11-7-4-8-12-17/h3-12,18H,13-15H2,1-2H3
Key:BOTHKNZTGGXFEQ-UHFFFAOYSA-N
Properties and usesEdit Edit
ANAVEX2-73 has an inhibitory constant (ki) lower than 500 nM for all M1–M4 muscarinic acetylcholine receptor subtypes, demonstrating that it acts as a powerful antimuscarinic compound.[2] ANAVEX2-73 was originally tested in mice against the effect of the muscarinic receptor antagonist scopolamine, which induces learning impairment.[1] M1 receptor agonists are known to reverse the amnesia caused by scopolamine.[3] Scopolamine is used in the treatment of Parkinson's disease and motion sickness by reducing the secretions of the stomach and intestines and can also decreases nerve signals to the stomach.[3] This is via competitive inhibition of muscarinic receptors.[3] Muscarinic receptors are involved in the formation of both short term and long term memories.[1] Experiments in mice have found that M1 and M3 receptor agonists inhibit the formation of amyloid-beta and target GSK-3B.[clarification needed]Furthermore, stimulation of the M1 receptor activates AF267B, which in turn blocks ß-secretase, which cleaves the amyloid precursor protein to produce the amyloid-beta peptide. These amyloid-beta peptides aggregate together to form plaques. This enzyme[clarification needed] is involved in the formation of Tau plaques, which are common in Alzheimer's disease.[clarification needed][4] Therefore. M1 receptor activation appears to decreases tau hyperphosphorylation and amyloid-beta accumulation.[4]
Sigma1 activation appears to be only involved in long-term memory processes. This partly explains why ANAVEX2-73 seems to be more effective in reversing scopolamine-induced long-term memory problems compared to short-term memory deficits.[1] The sigma-1 receptor is located on mitochondria-associated endoplasmic reticulum membranes and modulates the ER stress response and local calcium exchanges with the mitochondria. ANAVEX2-73 prevented Aß25-35-induced increases in lipid peroxidation levels, Bax/Bcl-2 ratio and cytochrome c release into the cytosol, which are indicative of elevated toxicity.[clarification needed] ANAVEX2-73 inhibits mitochondrial respiratory dysfunction and therefore prevents against oxidative stress and apoptosis. This drug prevented the appearance of oxidative stress. ANAVEX2-73 also exhibits anti-apoptotic and anti-oxidant activity. This is due in part because sigma-1 agonists stimulate the anti-apoptoic factor Bcl-2 due to reactive oxygen species dependent transcriptional activation of nuclear factor kB.[5]Results from Marice (2016) demonstrate that sigma1 compounds offer a protective potential, both alone and possibly with other agents like donepezil, an acetylcholinesterase inhibitor, or the memantine, a NMDA receptor antagonist.[6]
References Edit
^ a b c d e "Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma" (PDF). Journal of Psychopharmacology. Archived from the original(PDF) on 2015-11-12. Retrieved 2016-05-25.
^ a b c "ANAVEX 2-73 - AdisInsight". Adisinsight.springer.com. Retrieved 2016-05-25.
^ a b c Malviya, M; Kumar, YC; Asha, D; Chandra, JN; Subhash, MN; Rangappa, KS (2008). "Muscarinic receptor 1 agonist activity of novel N-arylthioureas substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models". Bioorg Med Chem. 16: 7095–7101. doi:10.1016/j.bmc.2008.06.053.
^ a b Leal, NS; Schreiner, B; Pinho, CM; Filadi, R; Wiehager, B; Karlström, H; Pizzo, P; Ankarcrona, M (2016). "Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid ß-peptide production". J Cell Mol Med. 20: 1686–1695. doi:10.1111/jcmm.12863. PMID 27203684.
^ Lahmy, V; Long, R; Morin, D; Villard, V; Maurice, T (2015-09-28). "Mitochondrial protection by the mixed muscarinic/s1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aß25-35 peptide-injected mice, a nontransgenic Alzheimer's disease model". Front Cell Neurosci. 8: 463. doi:10.3389/fncel.2014.00463. PMC 4299448. PMID 25653589.
^ Maurice, T (2015-09-28). "Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments". Behav. Brain Res. 296: 270–8. doi:10.1016/j.bbr.2015.09.020. PMID 26386305.
https://en.m.wikipedia.org/wiki/ANAVEX2-73
LOUISVILLE, KY (NOVEMBER 7, 2014)
Louisville, KY — Neuronetrix has been selected by AnavexLife Sciences Corp. (OTCQB: AVXL) to support the upcoming Phase 2a clinical trial for ANAVEX 2-73, a symptomatic and potentially disease-modifying treatment for Alzheimer’s disease. Neuronetrix will be utilizing their COGNISION®™ System to measure and analyze cognitive biomarkers in study participants. The ANAVEX 2-73 study incorporates an adaptive design, with an enrollment of 32 mild to moderate Alzheimer’s disease patients.
http://www.cognision.com/neuronetrix-has-been-selected-by-anavex-life-sciences-corp-to-support-the-upcoming-phase-2a-clinical-trial-for-anavex-2-73/
What Falconer says MIGHT happen is backed by scientific studies some of which I reference below. However, as Investor points out and as most everyone here recognizes, the evidence is playing out in the clinical trials. The hypothesis for these clinical trials is shared by a number of scientists and studies. Granted many scientists disagree and have different theories for treating AD, PD and RS, but no one has any real success so far. However, the basis for these Anavex trials is sound. I believe what Falconer has published is reasonable based on the DD/research I have done, and based on what others on this board have found and shared. Therefore, my speculation is that OFP is dead wrong, and Anavex may likely prove some CNS benefit from AVXL 2-73 or from some of its other drugs. In any event, I hope this is how it plays out, and I am not at all deterred by anyone that attempts to rub my nose in the sand or dirt. Hope, I think is a good thing. Nothing can be accomplished without someone having some hope for what they are attempting to achieve. As Teddy Roosevelt said when he was restoring hope in America:
“It is not the critic who counts; not the man who points out how the strong man stumbles, or where the doer of deeds could have done them better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood; who strives valiantly; who errs, who comes short again and again, because there is no effort without error and shortcoming; but who does actually strive to do the deeds; who knows great enthusiasms, the great devotions; who spends himself in a worthy cause; who at the best knows in the end the triumph of high achievement, and who at the worst, if he fails, at least fails while daring greatly, so that his place shall never be with those cold and timid souls who neither know victory nor defeat.”
Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection.
Review article
Nguyen L, et al. Adv Exp Med Biol. 2017.
Show full citation
Abstract
Sigma-1 receptors are molecular chaperones that may act as pathological mediators and targets for novel therapeutic applications in neurodegenerative diseases. Accumulating evidence indicates that sigma-1 ligands can either directly or indirectly modulate multiple neurodegenerative processes, including excitotoxicity, calcium dysregulation, mitochondrial and endoplasmic reticulum dysfunction, inflammation, and astrogliosis. In addition, sigma-1 ligands may act as disease-modifying agents in the treatment for central nervous system (CNS) diseases by promoting the activity of neurotrophic factors and neural plasticity. Here, we summarize their neuroprotective and neurorestorative effects in different animal models of acute brain injury and chronic neurodegenerative diseases, and highlight their potential role in mitigating disease. Notably, current data suggest that sigma-1 receptor dysfunction worsens disease progression, whereas enhancement amplifies pre-existing functional mechanisms of neuroprotection and/or restoration to slow disease progression. Collectively, the data support a model of the sigma-1 receptor as an amplifier of intracellular signaling, and suggest future clinical applications of sigma-1 ligands as part of multi-therapy approaches to treat neurodegenerative diseases.
PMID 28315269 [Indexed for MEDLINE] PMCID PMC5500918
https://www.ncbi.nlm.nih.gov/m/pubmed/28315269/
Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regulate Ca2+ Signaling and Cell Survival
Summary
Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca2+ 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 Ca2+-sensitive and ligand-operated receptor chaperone at MAM. Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca2+ depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca2+ 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 Ca2+ concentrations, regulates ER-mitochondrial interorganellar Ca2+ signaling and cell survival.
https://www.sciencedirect.com/science/article/pii/S0092867407010999
Mitochondrial dysfunction has been consistently reported as an early cause of Alzheimer’s disease and the treatment and cure for Alzheimer’s disease may be very connected to the cure for mitochondrial disease.
In a scientific study conducted in France at the University of Montpellier and INSERM, ANAVEX 2-73 demonstrated disease-modifying effects, including the ability to repair normal mitochondrial functionality in the hippocampus, the part of the brain involved with learning, memory and emotions.
http://mitochondrialdiseases.org/anavex-2-73-linking-mitochondrial-functionality-to-alzheimers/
http://www.anavex.com/files/1303_ADPD_Valentine.pdfeenous Neuroprotection in Neurodegenerative Diseases', at the University of Montpellier and INSERM. "Mitochondrial dysfunction and resulting oxidative stress are critical hallmarks of Alzheimer's disease pathology and believed responsible for increased amyloid-beta production and Tau hyperphosphorylation."
"The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) protein that resides specifically in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), an interface between ER and mitochondria. In addition to being able to translocate to the plasma membrane (PM) to interact with ion channels and other receptors, Sig-1R also occurs at the nuclear envelope, where it recruits chromatin-remodeling factors to affect the transcription of genes. Sig-1Rs have also been reported to interact with other membranous or soluble proteins at other loci, including the cytosol, and to be involved in several central nervous system (CNS) diseases. Here, we propose that Sig-1R is a pluripotent modulator with resultant multiple functional manifestations in living systems.”
Cite
https://www.ncbi.nlm.nih.gov/m/pubmed/26869505/
Mitochondrial dysfunction has been consistently reported as an early cause of Alzheimer’s disease and the treatment and cure for Alzheimer’s disease may be very connected to the cure for mitochondrial disease.
In a scientific study conducted in France at the University of Montpellier and INSERM, ANAVEX 2-73 demonstrated disease-modifying effects, including the ability to repair normal mitochondrial functionality in the hippocampus, the part of the brain involved with learning, memory and emotions.
http://mitochondrialdiseases.org/anavex-2-73-linking-mitochondrial-functionality-to-alzheimers/
http://www.anavex.com/files/1303_ADPD_Valentine.pdf
”Anavex focuses on restoring cellular homeostasis: Alzheimer's is a complex disease potentially driven by amyloid beta, tau hyperphosphorylation, calcium ion imbalance, inflammation and mitochondrial dysfunction. Anavex is targeting treatment of Alzheimer's disease using a mixed muscarinic receptor and the sigma-1 agonist to restore cellular homeostasis by reducing chronic stress and protein misfolding. The sigma-1 receptor agonist activity is seen only under pathological condition and does not impact normal physiological activity reducing the potential for adverse effects.”
http://nobleresearch.com/reports/AVXL_20170206_9669.pdf
"Goguadze N et al presented preclinical data indicating that in addition to reducing oxidative stress, ANAVEX 2-73, ANAVEX 3-71 and ANAVEX 1-41 also demonstrated protective effects of the mitochondrial enzyme complexes I and IV during pathological conditions. The mitochondrial enzyme complex IV is directly involved in the synthesis of ATP, which provides energy within cells for metabolism. It is believed that energy production impairment and mitochondrial dysfunction play a role in the pathogenesis of neurodegenerative disorders and neurodevelopmental diseases."
https://www.anavex.com/anavex-life-sciences-reports-new-mechanism-action-data-related-anavex-compounds-targeting-sigma-1-receptor/
”Restoring 'cellular balance'
Dr. Harald Hampel, a professor at Sorbonne University in Paris, explained that the experimental drug, Anavex 2-73, a precision medicine candidate from specialty pharmaceutical company Anavex Life Sciences Corp., activates the Sigma-1 receptor.
A worthy target for precision medicine, the Sigma-1 receptor "is involved in several important pathways related to Alzheimer's disease," Hampel said. It reduces beta amyloid (the signature plaque deposits seen in the brains of deceased Alzheimer's patients) and hyperphosphorylated tau (the signature protein tangles also seen in patients' brains), he said. It also lessens oxidative stress and inflammation in the brain, both of which have been linked to aging and age-related diseases.
The advantage of targeting the Sigma-1 receptor is that it "activates the body's own defense mechanism to restore cellular balance," Hampel said.”
Alzheimer's disease is a complex disease," he said. "The newest weapon in the fight against Alzheimer's disease might be your own body."
Lundbeck, a global pharmaceutical company focused on psychiatric and neurological disorders, also subscribes to this philosophy as it works to develop an immunotherapy for Alzheimer's patients.”
’...The good news is that once a link has been established between changes in biomarkers and a beneficial change in a patient's cognitive abilities, the FDA has indicated it will no longer require drug developers to prove that each potential new drug can modify Alzheimer's disease, Williamson said.
Once a firm connection is established, drug developers will need only to show their candidate drugs affect the biomarkers.
"An analogy to this would be cholesterol-lowering drugs and heart disease," Williamson said. Once the link between lowering cholesterol and heart disease was established, scientists no longer needed to conduct thousands of patient studies to show that a drug reduced heart disease. "You just needed to show you could reduce cholesterol.’
https://www.cnn.com/2018/07/30/health/alzheimers-treatment-precision-medicine-immunotherapy/index.html?no-st=1535202492
Bio: You deserve the NUMBER ONE best all time post award. Thank you.
If institutions “dump” a stock, you see really heavy selling. I think we are experiencing tax loss selling and not “dumping” for fundamental reasons. Certainly, there has been year end tax loss selling of this stock. This tax loss selling is occurring during a news void meaning there is no news to be reported from the three clinical trials that are ramping up. Although there are signs of some selling exhaustion, selling pressure may continue toward year end. Probably most tax motivated selling is behind us, but we may very well see more during this brief period left before year end. Therefore, the stock may not see a recovery for another three weeks or so unless the selling exhausts itself earlier. In the meantime, if you have something in reserve and willing to speculate on a recovery next year, this may be the ideal time to buy — not sell.
Yes, we should get a move up from today’s close. The question is, how much assuming it has bottomed for now as I believe it has. Barring some unexpected positive development from any of the three clinical trials, which I think is premature, I believe it will most likely be a modest move up along the lines you indicate.
Me too. It may dip below $1.90, but it should bottom today.
Results from the Alzheimer’s trial seems to be pretty far away, but wait! The PDD trial in Spain is a 14 week dementia trial involving 120 patients —34 weeks shorter and 330 fewer patients. We may be getting PDD trial news of results on a rolling basis. In any event, If we receive significantly positive news about dementia and motor skills, we should generate interests for Alzheimer’s, Parkinson's and Rett.
Remember, donepezil was marketed on something like a 3-4 ADAS-Cog point benefit over placebo over about 6 months. If the PDD trial confirms ADAS-Cog benefit demonstrated for 148 weeks and indicates a ADAS-Cog more than a 3-4 point benefit over the placebo, Anavex should generate serious interests.
The PDD trial news, unlike the AD trial news, is not that far away.
How wrong AD "experts" may be? Here I post parts of a report from an Alzheimer"s conference that occurred in March 2016. AVXL 2-73 is briefly mentioned under the Emerging Therapeutic Targets section where it is said that: "5-HT6 receptor antagonists are likely the next treatments off the block." Axovant's drug and Lundbeck's drug fall within the latter category and are seemingly mentioned favorably. Near the end of what I quote below the author says this "His prediction is that within a few years we are likely to be using one or more of 5HT6 antagonists, LMTN (methylene blue derivatives), solanezumab and still recommending Souvenaid- and here the author is in agreement." Of course, we now know that both Axovant's and Lundbeck's clinicial trials failed, and it has been a few years without, to my knowledge, any use of methylene blue derivatives, etc. There is much more to this report than I comment about, and you can read it for yourself for other interesting things such as how much of an improvement may need to be shown for approval of a new AD drug. Read this and answer this question: How much, if any, of an improvement over a placebo may be need for any approval of AVXL 3-73?
http://www.drphilipmorris.com/new-developments-in-alzheimers-disease-research/
New developments in Alzheimer’s disease research Leave a comment »
The following article is from my senior colleague, A/Prof Michael Woodward, geriatrician at the Austin Medical Centre, Heidelberg Victoria. I wish to thank Michael for allowing me to post it on my website.
Springfield Advances in Alzheimer’s Treatment conference
Athens, March 2016
Conference report- Associate Professor Michael Woodward AM
........
Emerging Therapeutic Targets
5-HT6 receptor antagonists are likely the next treatments off the block. The closest to trial completion is the Lundbeck drug idalopridine, with three 6 month duration Phase III trials near recruitment closure. The Axovant drug, RVT-101, purchased from GSK, is moving ahead at breakneck speed. There is also a third drug in this class being developed by a small biotech company in India.
Inge de Jong presented the scientific rationale for this treatment approach, and likely underlying the very encouraging Phase II results of idalopridine. She showed that idalopridine potentiates the effect of donepezil on desirable gamma oscillation in regions of the brain important to cognition. This drug also affects other neurotransmitter systems, including glutamate and GABA and these are likely to contribute to its effects- ie the drug is not just working through 5HT6 and potentiating AChEI actions on cholinergic systems. Functional MRI also shows that when idalopridine is used with donepezil there is increased brain activity in regions of the brain underpinning cognition, including the hippocampi, amygdala and striatopallidal regions. These are actions not seen with donepezil alone and suggest that the combination has a unique and hopefully effective mode of action.
The Axovant drug , because it has cholinergic actions, may well work alone- ie not requiring co-administration of a cholinesterase inhibitor. Geetha Ramaswamy, from the company, presented the phase II results from the GSK trial and it is encouraging that both this and idalopridine have positive results in their phase II RCTs. As their drug has cholinergic activity it is also being trialled in DLB where there is a profound cholinergic deficit. It has 5HT2A activity and this receptor may underpin visual hallucinations, further supporting the potential benefit of RVT-101 in DLB. Only the data will tell though.
Souvenaid’s phase III trial in prodromal AD, the LipiDiDiet study, is now completed and the results were released at the conference. Tobias Hartmann from Hamburg presented the rationale for multi-nutrient intervention in prodromal AD- a condition where the brain is under amyloid/tau “attack” and rapidly runs out of the neuronal membrane/ synaptic precursors, exacerbated by the common dietary deficiencies of these in AD patients. Fortasyn Connect, which is the only component of Souvenaid, supplies these polyunsaturated fatty acids, uridine and other nutrients to enable the neurones to form synapses to potentially slow down the effects of the neurodegenerative process. Hikka Soininen from Kupio presented the trial results-this 2 year EU- funded RCT had approximately 300 randomized patients and is one of the first completed treatment trials in prodromal AD, using Dubois criteria. Disappointingly it was negative on the combined neuropsychological endpoint (the NTB) but there were positive secondary endpoints including memory and an almost significant CDR-SB (p= 0.051). The results were more positive in those with higher MMSE scores at baseline, but the numbers were becoming small when one added this subgroup analysis. There was a statistically significant reduction in the rate of hippocampal atrophy in the treatment group, supporting a biological rationale for the cognitive and functional improvements. Reassuringly the placebo and treatment curves seemed to be separating at 2 years on the functional and cognitive endpoints and as the study remains blinded, 3 and even 4 year results will be most interesting- especially to see if the original primary, the NTB, becomes positive. The preparation seemed entirely safe although there were, in absolute rather than percentage terms, a slightly higher number of strokes and other cardiovascular endpoints in the treatment arm. So, the doubters will feel vindicated by the primary but other folk will feel that the encouraging secondaries and the 2 year trend suggest the treatment will be a major step in prodromal AD management.
Other targets that have been subject to the harsh light of clinical research include the pyroglutamate modification of Aß and animal studies have used inhibitors of glutaminyl cyclase or monoclonal antibodies against this. Amyloid aggregation remains a target using tramiprosate- sadly the phase III trial results were negative but in Apo E4 heterozygotes the results are more encouraging. Iinflammation remains a robust target and masitinib has been used as another approach here. Anavex’s drug, targeting the sigmoid 1 mu- receptor, continues its non-blinded Phase IIa trial with a 52 week open label extension. Preliminary results demonstrate a favourable safety, bioavailability, dose-response curve and tolerability/risk profile. Analysis seems to indicate a cognitive benefit associated with ANAVEX 2-73. Cogstate, MMSE and EEG/ERP improved significantly at 5 weeks of treatment. The effect of changing from low to high dose was statistically significant with MMSE-? (p=0.0285) and ERP-? (p=0.0168) respectively.
Stem cells
These were darling of earlier AAIC meetings but seem to have dropped off the radar. However at this meeting Tristan Bolmont from Lausanne reinvigorated some enthusiasm, presenting results of trials where mesenchymal stem cells were given into transgenic mice bred to over-express amyloid. There was a clear reduction of Aß42 deposition. But mouse dementia seems a much easier condition to treat than human AD so watch this space and do not encourage your patients to seek unproven stem cell therapies just yet, despite the current interest and unprofessional promotion of such approaches.
What will be the Best Treatment for AD?
........
Lon Schneider returned and to this author’s mind had the final say. He began by simply saying the best treatment will be the one that works. But how well does it need to work? It is noteworthy that trials are being constructed, and reconstructed, to be statistically significant, and thus get a drug to market, even with small and potentially clinically insignificant effect sizes. Indeed the Lilly EXPEDITION 3 solanezumab trial, to be completed in November this year, has just dropped one of its 2 primary endpoints and one could somewhat cynically argue that this is to give it a greater chance of success- easier to improve one than two primary endpoints, as many other completed trials that only hit one endpoint have shown. But Lon would always see himself as a realist, and is no doubt visionary, rather than a cynic. He noted that we now have 390 AD therapy trials completed, in progress or about to commence, testing some 200 agents, and the trend is to design them to show the smallest possible benefit. Back to Lilly- he believes they have secured an undertaking that a 2 year ADAS-Cog improvement of 1.5 points, over placebo, would be sufficient for them to file for listing of solanezumab as an AD- disease modifying drug. Remember the AChEIs, including donepezil, were marketed on a 3-4 point benefit over placebo over 6 months. But they were far more progressed subjects. In question time Ezio Giacobini, the co-founder of this meeting, felt new drugs should be aiming at a 6 point ADAS-Cog benefit over placebo, and he felt that was imminent. In his opinion, the best drug would be better than donepezil and would simply be the first drug next approved by the regulatory authorities.
Lon noted that over 100 Phase IIb/III trials have proceeded on the basis of a negative Phase IIa trial albeit with a post-hoc rationale for the failed trial, and with no clear understanding of the drug mechanism of action- this somewhat gun-ho approach to trial progression is almost unique to this clinical research area. Again, EXPEDITION 3 follows failed EXPEDITION 1 and 2 trials. But this is his view, and not necessarily the author’s! His prediction is that within a few years we are likely to be using one or more of 5HT6 antagonists, LMTN (methylene blue derivatives), solanezumab and still recommending Souvenaid- and here the author is in agreement. He does believe we can develop drugs with large clinically significant effects if we better design trials (which need to be shorter, but better select subjects), pool data (as placebo data is currently being pooled between 6 large pharma and 9 regulatory agencies in an exciting initiative) and of course design better drugs that strongly engage their target. He notes that AD is not a single disease and is too mixed with normal ageing- we need to define the appropriate target/s in an individual and use drugs that engage these targets, probably in combination. He feels we can develop drugs that reduce AD risk in Aß/tau positive preclinical individuals by 25-30% and that this would be clearly clinically important. He fears that we may lurch away from amyloid as the target, to again waste years on tau as the new target- we need to learn from our amyloid experience if it does indeed disappoint us.
Conclusion
Again an exciting and rich Springfield- albeit the last (in future it will be combined with ADPD). I strongly believe that in the next 5 years these meetings will be focussing on bettering current disease-modifying drugs, and new symptomatic therapies- and will move away from the tau versus amyloid debate that to date has been fuelled by the lack of any effective preventative therapy for this most devastating disease. As one of Bengt Winblad’s patients said, what a shame Alzheimer himself died at 51- if he’d lived a few decades longer he may have cured the disease that was first described by him. Hope springs eternal.
Sixteen out of twenty one PDD clinical trial sites in Spain are now reported active. I believe it is likely Anavex stock will trade “in the box” until we hear news from Spain that confirms or disaffirms the 148 weeks result. If we obtain positive news from the Spanish PDD trial, it will help pave the way for an licensing early approval of AVXL 2-73 for treatment of dementia in Australia and the European Union. Australia and the European Union have regulations that make this possible as I have posted before.
Organizations within Australia and the European Union are keenly aware of the Spanish PDD trial. For example, I received a response from the European Parkinson’s Disease Association that says “thank you for contacting the EPDA and for sending us these interesting news – we are already aware of the Anavex clinical trial which we hope will lead to concrete improvements in the treatment of Parkinson’s.” If our news from Spain leads to any improvement in treatment of PD, European Organizations and Dag Aarsland, MD, PhD (see today's announcement) will help with licensing and approval of AVXL 2-73.
We may do a licensing agreement with a partner pre-approval. Aarsland Played a role in the licensing of rivastigmine for Parkinsonian dementia as announced today.
My guess is that the good or bad news that moves the share price out of the box will occur in early 2019. In the meantime, the PDD trial is moving along because we have gone from twelve to sixteen active sites within the last week or so.
I contacted, among others, the European Parkinson’s Disease Association about Anavex. Below is the response:
“thank you for contacting the EPDA and for sending us these interesting news – we are already aware of the Anavex clinical trial which we hope will lead to concrete improvements in the treatment of Parkinson’s.
If you are interested in more information about clinical trials for Parkinson’s, please check out the Clinical Trials page on the EPDA website: https://epda.eu.com/about-parkinsons/treatments/clinical-trials/
On a final note, since you have a keen interest on Parkinson’s, we would be pleased to share with you other information that you may find interesting and relevant.
However, due to the recent new EU legislative changes in relation to General Data Protection Regulation (GDPR), it is now necessary for individuals to subscribe (or ‘opt-in’) to each mailing individually. Therefore, if you wish to receive information from the EPDA, please click on the relevant opt-in link on the links below to subscribe.
· Parkinson’s Life (www.parkinsonslife.eu): Our weekly, free online lifestyle magazine. I think you will find this very useful. Opt-in here: http://eepurl.com/bg0Dm1
· The EPDA's general mailings. By subscribing, you will be kept updated (on an ad-hoc basis) on all our projects, ranging from the #UniteForParkinsons global awareness campaign, The Parky Challenge (our fundraising campaign) and other EPDA projects (including new resources, surveys, news stories etc). Opt-in here: http://eepurl.com/dz69Hv
Please be assured that you can very easily unsubscribe to any mailings at any time. For further information, please visit the EPDA's privacy policy.
Thank you again for contacting us, and please do not hesitate to get back in touch if you have any questions.
Kindest regards,
EPDA
Francesco De Renzis
Subscribe to our online magazine - Parkinson's Life/ www.epda.eu.com / facebook / twitter / YouTube
The EPDA is a not-for-profit European Parkinson's disease umbrella organisation. An AISBL registered in Bruxelles (Numéro de l'association: 8727/2000, No. d'entreprise: 465299201). A charity registered in England and Wales (1163211) ::: DISCLAIMER >:::”
A superb collection of Anavex AVXL 2-73 research. Thank you for all of your efforts.
Thank you all for your informative posts. I have been absent posting here because of personal commitments. I do, however, have one comment to offer about the observation that Missling is ”hiding our light” (for a good reason) as Bio put it in a post today, but first I must say that I am very sad about the tragedy that occurred in Bio’s city.
I am convinced Anavex is purposefully not seeking publicity, and that is a good thing for the following reasons.
It is a waste of time for Anavex to attempt to convince the major pharmaceutical companies and the financial media that AVXL 2-73 may be useful in the treatment of AD. AVXL 2-73 is a radical departure from the mainstream theory of treatment of AD. Anavex is developing drugs that are an insult to the establishment, which has made an enormous mistake of investing countless resources and funds in pursuing the wrong path for a treatment or cure of AD, i.e., by merely removing amyloid plaque.
Virtually no one, besides people on this board, is likely to believe that Anavex may be right and all of the major pharmaceutical companies have been wrong all along? What scientist or scientific committee with any major drug company is going to admit that their companies, based on their recommendations, have spent the last decade and enormous sums of money in pursuing the wrong theory. What management of what company is willing to admit to their investors that their amyloid plaque removal drugs do not work? What would happen if they did?
The major drug companies face the necessity of making presentations about their AD drugs at conferences each year. They have no choice but to appear and present the best case they can at conferences like the AAIC and CTAD. What would happen if they did otherwise? So, what do they do? Dress up their pig, apply the best lipstick available, wine and dine the press and the "experts," overwhelm tiny Anavex at these conferences, and kick the can down the road.
What is best for Anavex to do? I think the answer is it is best for Anavex to follow the path of least resistance. Do not fight an uphill battle in the United States. Be fluid and go elsewhere, and that is what Anavex is doing. Australia and Spain are excellent choices for Anavex Trials. Why should Anavex wear itself down taking on the giant pharmaceutical industry in the United States? Here is a portion of my older post about Anavex trials in Australia and Spain:
"Australia and Spain - Excellent Choices for Anavex Trials.
Spain encourages clinical trials to be conducted in country, and Spain passed new regulations on clinical trials to increase transparency and simplify procedures. See: http://www.barcelonaclinicaltrials.org/en/spain-passes-new-regulations-clinical-trials-increase-transparency-and-simplify-procedures.
It seems that recruitment of patients for clinical trials in Spain with its National Healthcare system is likely to move along more quickly than in many other countries. http://www.farmaindustria.es/web_en/documents/press-releases/2017/03/09/clinical-trials-early-stages-growing-steadily-spain-already-make-51-total/....
The Spanish healthcare system is one of the best in the world.
https://www.expatica.com/new/es/healthcare/general-healthcare/healthcare-system-101467/
Life expectancy in Spain ranks number 3 in the world
http://www.worldlifeexpectancy.com/spain-life-expectancy
Spanish have the highest healthy life expectancy in Europe
https://www.theguardian.com/world/2013/mar/05/spanish-highest-life-expectancy-europe
Australia is an ideal country for Alzheimer’s clinical trials because it offers more support for the trials, including funds for our trials.
It has also launched the world-first dementia network to fast-track treatment and research.
https://www.9news.com.au/national/2018/07/02/20/06/australian-dementia-network-launched-to-track-diagnosis-and-care-of-patients”
We now have three clinical trials in progress, and that is where Anavex needs to spend its time and energy. I think Anavex's strategy is to proceed quietly and not make a big fuss about its CNS science and theories that fly in the face of major drug companies. It is best that it go about letting its clinical trials in Australia and Spain proceed and do the speaking instead of wearing itself down fighting against the odds in the United States drug regulatory environment that is dominated by major pharma. Like water, Anavex is seeking the path of least resistance by conducting its clinical trials elsewhere.
“Water is fluid, soft, and yielding. But water will wear away rock, which is rigid and cannot yield. As a rule, whatever is fluid, soft, and yielding will overcome whatever is rigid and hard. This is another paradox: what is soft is strong.”
? Lao Tzu
Anavex is yielding the home court to the pharmaceutical interest in the United States, which they dominate anyway, to avoid powerful forces that may otherwise delay and defeat Anavex. Going to Australia and Spain and sliding under the radar is the softer and stronger approach.
Following up: This is from an Elliott Wave analysis I read tonight:
“And, boy do market analysts and participants love to discuss these fundamentals to explain why one will exert more pressure on the market than the other, depending upon their initial bias.
As for me, price means everything. If the price structure of the market is bullish, then I will be bullish. If the price structure of the market is bearish, then I will be bearish.”
So, I now understand better what you are saying, I think.
Yes, I see and agree.
Well, since the double tops in June and July, the market is saying NFLX is worth less and less. After the parabolic move up to the double tops earlier this year, rallies have not been able to break the neckline of the double top. In otherwords, the market has rejected higher prices resulting from those rallies to the extent that share price is now below the 50 day and 200 day moving average. Therefore, one may very well say that the market is in the process of adjusting (for whatever reason) the value of the company to be worth less -- not more.
Bio: Brilliant post! Thank you.
Thanks to everyone for their posts. Most posts here are informative. I read them all, and I check every one -- every thing -- against what I know or do more DD if I am unsure/do not know. But, of course, there is the ultimate unknown as there is with any clinical trial for any new drug. That said, I remain very encouraged even though I keep trying to find fault with the direction Anavex is headed. Bio and others say Anavex is on the right path, and they provide good support for what they say. Therefore, I agree with them.
I wish I had more time to post, but duty calls and time is limited. I will post more when time permits, but my rule or principle is to provide corroboration for what I post as most posters on this board do. That takes time, and regrettably I do not have the time for now. More later!