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This is a nice interesting site.
Funds holding AVXL:
https://www.holdingschannel.com/funds/holding-avxl/
Holdings changes:
https://www.holdingschannel.com/holdings-changes/avxl/
Also check out the "Long Only" link.
Informative.
re: "I hate when I do things like that..."
Yeah. Me too. I reached for the wrong brush again this morning. Not too bad yet, but, still... :)
The availability of Anavex 2-73 can't come too soon imo.
Sales license should be real soon now...
re: "Something just doesn't ring true on the whole Neurotrop/Bryostatin operation. "
Agreed.
re:"I don't even see the two drugs as competitors. The NTRP drug is dosed IV in intermittent doses to avoid toxicity. At best it could "jump start" moderate to severe cases and enable them to benefit from 2-73."
Bryostatin is also pretty expensive.
10 micrograms @ $166.00
( $166 x 100,000) = $16.6 million per gram
http://www.sigmaaldrich.com/catalog/product/sigma/b7431?lang=en®ion=US
The proof is out there. :)
Thanks. Looks like I should have waited an extra day or two, but that's all right. With all the sabre rattling with N. Korea, we may see some "flight to safety" buying at some point. Otherwise, it looks like the long pm/commodity cycle is starting to turn back up again. And one learns to be patient with mining stocks.
Here is some new research on micro-tubules that I found quite interesting.
Bear in mind that this is being approached from an electrical / physics standpoint to gain insights into the internal complexities that underpin cognitive function i.e. consciousness and memory.
I would cut the guy at the end some slack who wants to try ultrasound. As I've commented in the past, it appears problematic, and even if it did help, at best, the effect would be temporary, if the biochemistry isn't fixed. Besides, AZ isn't caused by a lack of ultrasound. It's only natural that a physicist is going to try to think of a physical solution instead of pharmo-kinetics. The work is nevertheless brilliant.
Perhaps needless to say, I am a rather avid supporter of the EU/ Thunderbolts Project (maybe be forgiven because of my EE background). Mind boggling stuff, especially in the new field of plasma cosmology, new theories that explain many "mysteries", supported by new scientific evidence, but still largely ignored by the modern day equivalent of the 17th century Royal Astronomers Society. (ref the movie "Longitude").
Water plays a remarkable role and considering how brain shrinkage occurs if the disease progresses unabated, that would seem to indicate a water imbalancee/loss. If so, it would then seem likely to straighten itself out, once healthy cell functioning / homeostasis is restored (via Anavex 2-73).
Note also the vital role of tau proteins (part way into the video). One competitor of Anavex is aiming to inhibit tau formation inside the cell. Bad idea, imo.
re: "...they just ACT stupid to deceive uninformed retail investors. MF is well aware of Anavex's groundbreaking science ..."
I just noticed. Both MF's have the same initials. As well as a certain pejorative vulgarity. :)
Another one in the space to look at, though not as pure a play as ATVVF, is:
Golden Share GLDMF
At least it's trading, The chart doesn't look too bad, been on a steady climb. So it's already up quite a bit. They are basically gold/silver and don't have any vanadium of their own, but will market Chinese vanadium electrolyte, on the side, as it were.
Actually would be good to take a closer look while we're waiting. Compare the two as to relative merits.
After all this (setting up board), OTC MM seems to have fizzled out. Showing 0.00 bid/ask etc , not updating. The primary stock to ATVVF, AVL traded 1.5 million shares on the ASX last night (well, day for them). So it's not like it's not trading anywhere.
'
I just sent the company an email to see what's up with their market maker.
Those interested may yet have a chance to have a little fling at this. :)
This happens sometimes with foreign stocks that don't trade at the same hours as over here. It's annoying.
Another word of caution: When / if it starts trading again, it's a good idea to check the ASX to check where it's actually trading at, then multiply by the currency exchange rate, (currently .76) as a reference in deciding your price.
OK. This is an interesting little resource play but there are pros and cons. It's a nice story and shares are currently trading around 2 cents Australian ( $ 0.015 US). The company has been on an equity financed spending spree and has run up about a billion shares. That gives us a current market cap of around $15 million, right?
On the other hand, the assets they've acquired seem likely to prove out to provide future value to justify it.
There are signs that the bear market for resource stocks may be easing. I'm making a guess here that Vanadium Redox batteries may finally start to catch on as a preferred energy storage medium for land based solar. Solar is getting economically feasible due to advances in manufacturing technology. Wind needs reliable storage as well. The compactness of lithium isn't needed for fixed installations and lithium batteries wear out after a few years. Vanadium redox batteries have liquid electrodes that don't wear out and stay functional for 20+ years. They're also easily scalable, to increase capacity you just add more electrolyte / tanks. The electrolyte also changes color when it's charged which is handy for monitoring. Much safer, fire hazard wise than lithium, simpler. Quite a list of advantages.
The funny thing is, a few years ago, there was a company called American Vanadium with an almost identical story. They just went bankrupt recently. Certain conditions are different now and the timing seems more favorable. So, these guys may do better. They have their foot in the door as a Vanadium battery reseller - the Australian outback looks to be a good market. Supposedly, they've made a sale and have 70 more prospects lined up. If they can get revenues going that way hopefully they won't go broke.
They plan on using their high quality vanadium to make and market vanadium electrolyte. Then make batteries.
I'm not too happy about their wild and crazy lithium/tantalum acquisition but it could turn out to be a bargain if it doesn't put them under. Tantalum is useful and rare to begin with. A leading tantalum producer just had a fire, likely reducing production by 50% for the next year. Normally, brine is more economical for lithium but the hard rock deposits in question look to be very rich grade, so, hard to say. Maybe not a completely reckless move...
It's a somewhat dicey gamble but I plan on trying to open a small position at these prices just to see what happens. It gives one an excuse to keep watching it.
Currently it's listed but not trading (0.00 bid/ask). Maybe stirring up a little interest here will wake up the Market Maker. Here again, I would caution buying a stock like this. I wouldn't risk more than a couple hundred bucks or so, money you figure that you could afford to lose if things don't pan out.
For those of us investing in the cannabis sector, certain comments coming out of the new DOJ have caused concern since they, obviously, have had a negative impact on share prices. It has even spilled over to Supreme.
At least, one remark by the new attorney general that I do not find deeply disturbing is:
"If you don't like the law, then change it."
OK.
It was a liitle hard to find at first, but contacting one's Congress-person to support this, would seem to be be a good way to help protect one's investment.
the “Respect State Marijuana Laws Act of 2017”.
https://www.congress.gov/bill/115th-congress/house-bill/975/text
re: 47% better cash flow.
Nice all the way around. Just opened a position.
The tabloid press sure has had a field day with David M. , he seems reminiscent of the flamboyant Howard Hughes, however seems to be likely to continue keeping his wits about him unlike the unfortunate Howard.
The people he has in place running operations seem very competent.
re: " the treated ones could get a very large placebo-effect boost, while the placebo group gets the opposite—an adverse “nocebo” effect from the expectation that their disease will worsen unabated. "
re: "The IVIg-treated patients also showed less evidence of Alzheimer’s-related brain shrinkage. Yet in a more recent, larger trial, IVIg-treated patients on the whole fared no better than a placebo group..."
Now I keep thinking about this mysterious thing called "placebo effect". Maybe because it keeps popping up in discussion around here like a cowlick that won't stay combed down. It still gets mostly dismissed as chance or psychological, but here, in your example, it looks like we're seeing some actual physical effect.
So, although not reliably repeatable, placebo effect, and directed positive thinking like prayer, are recognized as real phenomena that can cause improvement and even "spontaneous remission" of disease, e.g. cancer. Maybe even Alzheimers?
Here's a radical thought: What if, in some cases, people are able to reach their S1 receptors as a mental response, considering that thought patterns, good or bad, take place in the CNS which pretty much connects everywhere in the body?
We've all heard the sad expression about someone "dying of a broken hearr". Maybe it's not necessarily imaginary in every case? What if their mental/emotional state is modulating S1 the wrong way, triggering anti-survival (i.e. adverse “nocebo” effect).
You know how some people, like, certain Buddhist monks, by practicing advanced meditation techniques or whatever, can mentally control their own body temperature?
http://www.snopes.com/harvard-study-confirms-tibetan-monks-can-raise-body-temperature-with-their-minds/
Although those would be different receptors, it does provide a sort of proof of concept for the general notion.
The exact internal mechanism modulating the S-1 in the body "is not completely understood'.
"...A variety of specific physiological functions have been attributed to the s1 receptor. Chief among these are modulation of Ca2+ release, modulation of cardiac myocyte contractility, and inhibition of voltage gated K+ channels.[16] The reasons for these effects are not well understood, even though s1 receptors have been linked circumstantially to a wide variety of signal transduction pathways. ..."
https://en.wikipedia.org/wiki/Sigma-1_receptor
It's pretty hard to maintain a directed or positive attitude over a long period of time. Seems like there's always some killjoy or buzz-kill around the next corner, or you just tire out. So placebo effect peters out, even when it is a real phenomona with real physiological effects.
What if it is connected to S-1 modulation somehow? The radical notion here is that Anavex 2-73 could be taking the load off of maintaining a positive S1 by mental power alone (among other beneficial things). In such a case, "placebo effect" isn't a bad thing, no need to contest it, after all it results in improvement. Maybe we've just found a way to keep it going and make it permanent. :)
re: "Lectins: "Tomatoes are loaded, along with peppers, eggplant, ...and all grains." Makes it sound as if Italians should all be dead...yet the Mediterranean diet is actually healthy and promotes longer life. "
You make a good point. In fact, a guy sharing some credible personal research on u-tube found that Alzheimers is not present in many old Mediterranean towns and is completely non-existant in Arctic Inuit populations. He thought is was because of the olive oil and fish oil, respectively, but, I'm thinking, maybe not.
I watched a cooking show about preparing old fashioned, traditional spagetti sauce. They use roma tomatoes, which are quite fleshy, and notably, remove the skins and squeeze out all the seeds, prior to cooking. This effectively eliminates, probably 99.9 % of the lectins. I suspect that all the other associated old world Mediterranean foods and preparation methods result in a very low lectin loading factor.
The Inuit situation is even more interesting. There's a movie out called "Into Greenland". It's a kind-of semi-professional u-tube style account of a guy who goes with his friend to visit his father who, years ealier, decided to leave France and take up residence in a remote Inuit village.
Nothing grows in the arctic. So they eat meat and fish. Not too big on cooking either, apparently. The welcoming party feast consisted of a slab of raw seal's liver. Table etiquette involves carving off bite-size bits. Later they go on a seal hunt and bag a seal. It's a bit excruciating to watch the poor young French fellow straining to show appreciation, poltely eating the treat gifted by the hunter, which consisted of the seal's eye. The town people also eat polar bear and whale blubber, but whales have been scarce in recent years. And, contrary to what one might suspect, there were old people too, pretty spry, actually. And no lectins in sight.
At the end, as a parting gift. the Frenchmen make pancakes for the townspeople. Not sure they were doing them a favor, though, considering. It's a bit funny, one old guy looked like he was eating his pancake, more to be polite, than actually enjoying the strange food.
I just saw that deplorably clueless Alzheimer's article in what, NewsWeek, about "early prevention". Didn't they get the memo on amyloid? Monthly intravenous infusions? Did I read that right? Sheesh! Throughout history, circles of institutional scowlers focus on protecting their calcified theories from being threatened by contravening facts rather than even recognize their existance. Are the Dark Ages over yet? Shall we give leeches a go at sucking out the "bad humours"? They're scarcely that up to date.
Maybe it hasn't been explicitely proposed yet, but taking a nice little Anavex 2-73 pill as a preventive measure for people at risk is easily implied. Is there such a thing as a conspiracy of organized ignorance? I'm beginning to wonder.
What if the rising prevalence of Alzheimers is caused by something that we can't do without, like, say, our food?
There was this info-mercial that started by showing a dead bug on its back. Nature's insecticide. Ever heard of lectins? Natural defense mechanism in plants, tend to be concentrated in the skins and seeds. Worse for bugs, but maybe not so good for humans either. Guess what? Lectins are present in all our favorite foods. Of course they are. Somehow that doesn't seem too surprising. "Everything's bad for you" is kind of a joke. But now it's starting to look like, maybe not so much.
I did a little further lectin research. Sticky small molecules. Helps hold cells together, yada yada... also plays a role in programmed cell death... Huh? Wait a minute. That's the evil twin mode of the sigma-1 receptor, isn't it, if something happens to antagonize it. That mode is available to provide the means for seperating out things like fingers during pre-natal development, but, otherwise, tapping the "elevator down" button for, next stop, programmed cell death, is not what we want, normally. Considering that lectins can penetrate the brain blood barrior, there doesn't seem to be any reason that they couldn't create a negative anti-survival bias on the S1 over time.
While there has been some testing to determine what contains lectins (almost everything), analysis of how much and what kind, has only been done for relatively few foods. Tomatoes are loaded, along with peppers, eggplant, potatoes, legumes like beans, peas, also peanuts and all grains. Eating a handful of raw kidney beans will make you deathly ill due to their high lectin content. I always wondered about, why the soaking and rinsing instructions for dry beans. Ok then. That's why. Cooking, also tends to reduce lectins.
Theoretically, meat is ok, except we're screwed there, because pretty much all livestock in this country is raised by feeding them lectin laden grain. Lectins tend to stick around in the system so we might expect them to build up in an animal after eating the, for example, 3200 lbs of corn needed to raise an average steer. Due to concerns about mad cow disease, the practice of feeding cows ground-up leftover parts of other cows mixed in with their feed has ostensibly been discontinued. But not due to concern about lectins. The modification was to prevent prion buildup. They also slaughter them now before they get old enough to develop the disease, which is somehow, not terribly reassuring.
What if, under cartain conditions, neural cells start churning out prions due to the influence of lectins? Prions are, after all, misfolded proteins. Wouldn't "programmed cell death" basically be throwing a wrench into the mitochondrial gears, so to speak?
It gets a bit worse. There are something like 9 trillion microbes in the human gut, among them, the good symbiotic ones which we need to help digest a range of vital nutrients.These are at war with the bad ones which only want carbohydrate (i.e. sugar). Weirdly, some of the bad ones secrete compounds that travel to the brain and bind to receptors that trigger sugar cravings. Unfortuneately, lectins tend to kill off the good ones and also mess up the intestinal lining causing leakage of who-knows-what other toxins into the bloodsteam.
According to a "60-Minutes" episode from a few years ago, big agri e.g. Archer-Daniels Midland contributed $100 million to political campaigns, of both parties, we might suppose, so that neither side would feel left out. Although the government, along with big agri have helpfully established "acceptable" human dose levels for residual Glyphosate ("Monsanto's highly popular Roundup") herbicide in food, there hasn't been much, if any, major money interest in investigating lectins in food, so far.
There are supplements out there to help out one's friendly gut microbes, as well as advocates for the "Paleo Diet". "Paleo" from "Paleolithic" i.e. the prehistoric "cave-man" era. The idea is that our pre-agriculture ancestors hunted and ate animals for food and very little else, perhaps some mushrooms as a side dish, which incidently, are ok, lectin-wise. Likely they also ate a few nuts and berries, which would explain why we have some tolerance, but cave-people probably tended to skip dessert. Humans haven't had time to evolve and properly adapt to the "new" lectin containg diet.
The Paleo Diet may be ok for a few, but, as a general solution, that's really not practical. There's no way to feed 7 billion people without grains and so forth. There's just not enough chinese cabbage, mushrooms and dark chocolate (thank goodness that's ok) to go around. Sorry, I'm not about to give up my pizza, cereal, burger and fries.
What we need is an antidote. Something to protect our S1 receptors from flickering into "system crash" mode. I think we may have found that with Anavex 2-73.
re: "Neah Auction"
Were they just being prudent or, getting ready to leave town? :)
re: "The question it might be good to ask yourself... if you were brand new to NPWZ and you did your research would you invest now?"
Just started looking at this. Nice story with the battery tech, but the company itself seems pretty dicey. The question is, how dicey?
re: "Through the SBV Pilot, the company will utilize Argonne National Laboratory staff and expertise to determine the optimal metallization scheme for porous silicon as well as reliable and reproducible processes and insights into possible causes of degradation, capacity fade and dendrite growth."
As I recall, degradation, capacity fade and dendrite growth were severe problems with the original lithium battery. It took a lot of experimentation, design tweaking and lastly, pure luck, to finally stumble on the right combination of additives to get it working good enough for commercialization. Since this is a new design, will the same fixes apply? The wording seems carefully chosen to avoid sounding negative but doesn't really rule out that there may be some bugs yet to be worked out.
re: "Allergan with its potential $3 Bil USD licensing deal with Heptares for its Sigma One Phase 1 drug platform "
Heptares pipeline is only targetting muscarinic receptors M1 in clinical 1b and M4 in pre-clinical. (Not Sigma-1)
http://www.heptares.com/pipeline/
Hey. Where's Supreme? They have a license to produce.
Ah yes, HC - Your tax dollars, in action.
Or should I say "inaction"? :)
Actually I agree in that alternative combo-therapy candidates should be looked for. From my previous posts you may gather that I am not very keen on donepezil (to say the least).
Role of Anatabine (RCP006 from Rock Creek Pharmaceuticals) as an anti-inflammatory agent
http://www.roskamps.com/inflammaging.html
Patience pays off. It's been a tough wait these couple years ( has it been even longer?).
Decided to trim a bit after being up 384%. Now staying the course. It's likely history will repeat itself. (more upside in the future).
re: "...long-term lowers mental function"
Obviously, one would be surprised if someone scored higher on an IQ test as a result of being in a constant state of inebriation spanning many years. We would expect their scores to go down. So moderation could be argued in any case. Various myths and belief systems aside, consider the following:
Cannibanoid receptor signalling is temporary and wears off after a while as the additional cannibinoid leaves the system and receptor sites resume mundane interaction with cannibanoids naturally produced in the body.Cannabinoids found naturally in the body are called endocannabinoids. ‘Endo’ stands for endogenous, meaning within the body. They are non-toxic.
( http://www.leafscience.com/endocannabinoid-system/works/cannabinoids/ )
Alcohol (for example, Bourbon) is proven to kill brain cells and proceeds to destroy your liver in the process of lowering your mental function. There are no alcohol receptors. Alcohol works by paralyzing the outer layer of brains cells where mental inhibitions reside, then the paralysis spreads inward as it soaks into the interior of the brain. If consumption continues, it finally reaches the autonomic area, resulting in death. A certain percentage of the paralyzed brain cells never recover each time. It is a poison.
There is nevertheless a strong cultural bias toward consuming alcohol to "feel good" though it is better suited as a fuel or industrial solvent.
I notice a similar bias to downplay toxicity in pharmaceuticals. Many of these huge clinical trials seem designed to try to find some evidence of efficacy no matter what. It's almost as if there is an unstated belief "how can it have any effect if it isn't toxic?"
Anavex 2-73 isn't toxic.
The fact that there have been no challenges or counter claims indicates that all patent and exclusivity avenues continue to be covered by Anavex's top notch IP expertise.
And wouldn't it be cool if it also worked on cancer? We don't know that it doesn't.
"Anavex Receives Notice of Allowance for U.S. Patent Application Related to ANAVEX 2-73
NEW YORK, Aug. 12, 2015 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (OTCQX:AVXL), a clinical-stage biopharmaceutical company developing drug candidates to treat Alzheimer’s disease, other central nervous system (CNS) diseases, pain, and various types of cancer, today announced that it has received a Notice of Allowance from the U.S. Patent and Trademark Office (USPTO) for U.S. Pat. App. No. 14/205,637 related to ANAVEX 2-73. Upon issuance, the patent will provide intellectual property (IP) protection until at least 2035. ANAVEX2-73 is the subject of an ongoing Phase 2a clinical trial for the treatment of Alzheimer’s disease. [...]"
https://globenewswire.com/news-release/2015/08/12/760035/0/en/Anavex-Receives-Notice-of-Allowance-for-U-S-Patent-Application-Related-to-ANAVEX-2-73.html
Allowance is 99% of the way there. It makes sense to try to hold off issuance until FDA requirements are completed, until commercial production and distribution are imminent, hence the "at least" qualifier. In regard to the many other initial disclosure filings for combo etc. , they provide coverage in that the Anavex claims precede all other potential claims in the relevent areas. For example, although the long term usage of donepezil is dubious, it may still have some usefulness in combo at the onset of treatment, so if that can be patented, they need to try. Otherwise, if it turns out that combo can't, it also means that nobody else can either.
To deny the documented and observed evidence of patients getting better after taking Anavex 2-73 and to deny the implied value of that, is to deny reality. It appears that most of the standard short-thesis playbook items have been exhausted so falling back on espoused fantasies amounts to scraping the bottom of the negativity barrel at this point.
"Platonism" is a term coined by scholars to refer to the intellectual consequences of denying, as Plato's Socrates often does, the reality of the material world. In several dialogues, most notably the Republic, Socrates inverts the common man's intuition about what is knowable and what is real. While most people take the objects of their senses to be real if anything is, Socrates is contemptuous of people who think that something has to be graspable in the hands to be real. In the Theaetetus, he says such people are eu amousoi (e? ?µ??s??), an expression that means literally, "happily without the muses" (Theaetetus 156a). In other words, such people live without the divine inspiration that gives him, and people like him, access to higher insights about reality."
It is a failed philosophical assumption but people keep falling for it throughout the ages. Apparently there is some thin hope to get a few people to fall for it here. (Not likely)
re: "Is Donezepil affinity to s1R is stronger than other drugs which causes these drugs not able to attach to s1R leading to lower efficacy? "
That could be. Evidently, many different compounds can attach to it.
The lock and key receptor/ligand analogy might considered in the context of an experiance I had when a coworker and myself stepped outside one night for a smoke break. We noticed this guy going around to different cars tryng to unlock them. My friend decided to call plant security. I was about to kid him for being too paranoid, but then the fellow managed open one and I had a sudden realization. "Hey, wait a second. That's my car!" Perhaps it was due in part due to three cars being stolen out from under their noses a few nights before, but security was remarkably quick getting out there. Long story short, turns out he wasn't a car thief after all. A lot of cars do look alike. Sometimes the wrong key will still work in a lock it wasn't made for.
There are a lot of receptors dedicated to sensory input, notably, the sense of smell. The ability to sniff out food is an evolutionary advantage pretty much all creatures have adopted over the eons. In our modern age, *80,000 different chemicals have been added to the potential menu over the last 100 years. It turns out that cyanide, an extremely poisonous industrial chemical, smells just like almonds. It's the wrong molecular key, but due to pure chance, it still fits into the almond smell receptor, even though its chemical properties are radically different, to say the least.
( * "The Human Experiment" documentary video)
Donepizel was developed to inhibit the enzyme, acetylcholinerase, from performing its normal regulatory function of breaking down acetylcholine. Acetylcholine works as a neuromodulator in the brain and as a neurotransmitter elsewhere. It appears to be pure chance that donepizel also has a chemical affinity to several receptors. In the case of M2 amd M3, undesirable, but donepizel is applied as a therapy anyway.
S1 (Sigma-1) is beneficial but "An endogenous ligand for the s1 (S1) receptor has yet to be conclusively identified" . Which means that what activates it naturally "isn't completely understood" (another phrase one comes across frequently in CNS research literature).
https://en.wikipedia.org/wiki/Sigma-1_receptor
Another interesting thing about these receptors is that they are depicted as a circle of corkscrew molecules that serve as a kind of security system for a pore in the middle. When they encounter a molecule that they recognize, the pore will dialate open, which allows molecules to be sucked in to proceed along the labyrinth of passageways inside the cell to affect cell function e.g. protein dynamics.
Just like artficial sweeteners have no nutritional value, it's possible that donepizel, among the many different compounds of known affinity, may not exactly be what the S1 receptor needs, compared to 2-73, which was actually developed for receptor therapy.
"Maybe monotherapy is a better option in this case and dose optimization should be done with A2-73 only"
Agreed.
re: "And these are drugs that showed promising preclinical and Phase 2 results."
Not all that promising, really:
"Overview
Name: Idalopirdine
Synonyms: Lu AE58054, SGS 518
Chemical Name: 2-(6-fluoro-1H-indol-3-yl)-ethyl]-[3-(2,2,3,3-tetrafluoropropoxy)-benzyl]-amine
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia
U.S. FDA Status: Alzheimer's Disease (Phase 3), Schizophrenia (Inactive)
Company: Eli Lilly & Co., H. Lundbeck, Otsuka Pharmaceutical Co., Ltd.
Background
This orally available drug is an antagonist of the serotonin 6 (5-HT6) receptor. This receptor subtype is expressed primarily in the brain, particularly in the cerebral cortex and hippocampus, where it has been proposed to play a role in cognitive impairments associated with schizophrenia and Alzheimer's disease. The 5-HT6 receptor antagonists are thought to enhance cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission. Apart from some affinity for adrenergic receptors, Lu AE58054 has been reported to be highly selective over other G-protein coupled receptors. The compound enters the brain and was able to dose-dependently reverse deficits in a rat model of cognitive impairment (Upton et al., 2008; Arnt et al., 2010)."
Adrenergic receptors trigger the "fight or flight" response. More so than "10 cups of coffee", the wide spread effects of an adrenaline rush are going to perk the person up temporarily. But it takes its toll and cannot be maintained.
"Lu AE58054 is being developed as a symptomatic adjunct to cholinesterase inhibitor treatment in Alzheimer's disease. Lu AE58054 was originally discovered by Lilly, which licensed it to the biotechnology company Saegis for clinical development in cognitive impairment in thinking disorders such as schizophrenia. In 2006, Saegis was acquired by Lundbeck, which in October 2013 launched a global Phase 3 program in AD. This program consists of four trials planned to enroll a total of about 3,000 patients (see company press release).
Findings
No Phase 1 trials on this drug are listed in publicly available databases. In 2005, Saegis conducted a Phase 2a trial in 20 schizophrenia patients in the United States, evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of giving this drug as an add-on to Risperidone (see company press release). In 2009 and 2010, Lundbeck conducted a Phase 2 trial in Europe and Asia to evaluate the compound as an adjunct to Risperidone for its effect on cognitive deficits in 124 patients with schizophrenia. Results were not published in the peer-reviewed literature, but development of Lu AE58054 for cognitive deficits in schizophrenia appears to have ended."
And it did not end well, apparently.
"In 2010 and 2011, Lundbeck evaluated Lu AE58054 in a Phase 2 study in 278 patients with probable Alzheimer's disease. Conducted in Australia, Canada, and Europe, the trial compared the effects of a six-month course of 90 mg/day of Lu AE58054 with 10 mg/day of Donepezil to the same dose of placebo. In June 2012, the company announced that the trial had met its primary cognition endpoint as measured by the ADAS-cog. On secondary endpoints, such as measures of global status and activities of daily living, Lu AE58054 treatment showed trends for a benefit but fell short of achieving statistical significance. Elevated liver enzymes in the treatment group, and higher dropout than in the placebo group, were also noted in this trial (see Jun 2012 news).
ADAS-cog is heavy on immediate recall and spatial recognition of geometric shapes, important cognitive functions, for sure, but these things can vary depending on whether the person is paying attention, and how much natural sleep they get. Continuously stimulating a person to greater alertness may boost this kind of test scores for a while but it is not a good thing. There may be a tendency to dismiss 2-73's non-narcotic benefit to alleviate insomnia, however, the brain needs sleep to repair itself, lack of sleep even causes further damage.
What's bad about AD, is forgetting things already known, such as family recipes, or even how to cook most things, even though they had been proficient at it for years. 2-73 is shown to produce especially good results in this area. All indications are that it is a good drug, an excellent candidate for a new AD SOC.
AE58054 is just yet another crappy drug to which lipstick is being applied in the form of these large trials, staged to compensate for the high dropout rate due to it not working and making people sick(er).
re:"Biotech investing is risky and pumping does no one any favors"
Neither does equating apples to oranges. Yes, they are both fruits, but dismissing the relative potential of one investment over another in the same field affords a similar disservice.
http://www.alzforum.org/therapeutics/idalopirdine
re: ..."planning their trip to ring the nasdaq opening bell."
I kind of wish they wouldn't, or at least take a rain check. It's happened a couple times on other stocks where it seems like ringing the bell was a jinx or maybe it triggered a Pavlovian response in short sellers. :)
re: galantamine side effects
"Common (1% to 10%): Dizziness, headache, tremor, syncope, lethargy, somnolence"
I had to look up "syncope" :
"Temporary loss of consciousness caused by a fall in blood pressure."
Probably don't want to take it while driving.
Now is that % each ... Seems to be by the wording. So, cumulatively could be more like 50% gets at least one. And this is just one of the many categories of side effects.
re:"but at least Donepezil is known to remove plaque (regardless of the stance of it actually being helplful or not). "
Um. sorry to contradict, but donepezil does not actually remove plaque. It slowed down accumulation of certain plaque components in mice that were engineered to develop CNS disease. There was "signicantly less accumulation" at the end of the test period compared to no treatment, but it didn't actually remove any.
"...we sought to determine whether long-term administration of donepezil would slow amyloid plaque deposition ... Administration of the 4 mg/kg dose of donepezil, as compared to vehicle and lower doses of donepezil, significantly reduced brain tissue soluble Abeta(1-40) and Abeta(1-42), Abeta plaque number, and burden at the study end point in Tg2576 mice. "
http://www.ncbi.nlm.nih.gov/pubmed/19799879
These narrowly focused researchers end with the rather conventional wisdom conclusion that if some is good maybe more is better. But in human practice there are some problems that show up, besides, plaque removal probably not being the right answer anyway.
Firstoff, donepezil's intended function is for use as an acetylcholinesterase inhibitor. Acetylcholine is produced and serves as a neuromodulator in the brain. It's level is regulated, held to a limit by production of acetylcholinesterase which nuetralizes ( or we might say "-erases", excess acetylcholine to maintain a balance (homeostasis). Brain cells calling in sick with AD evidently slack off on acetylcholine production, so the idea was to keep the existing acetylcholine from getting nuetralized by removing the limiter.
Meanwhile it turns out donepezil also engages in some receptor binding, outside its original purpose. There are a lot of different kinds of receptors. It may well be it chanced to bind to something that unterferes with Abeta(1-40) and Abeta(1-42). But what is known is that it also inadverdantly activates M2 and M3 receptors. M3 triggers nausea and vomitting side effect (among other things) but what I find notable is that M2 shuts down acetylcholine production as part of the regulation mechanism. This would suggest a reason why donepezil stops working after a while. Maybe ok to provide a low dose initial boost but with new production shut down, existing acetylcholine gradually diffuses away and it becomes self-defeating at that point.
2-73 instead puts the cells in a kind of maintenance mode or enhanced survival state via the S1 receptor while avoiding the M2 and M3. It also doesn't screw around with the acetylcholine system which simply needs proper regulation restored, as well as maintained in other parts not sick with AD, whereas donepezil circulates everywhere with its effects.
Another thing to keep in mind:
"The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is by no means conclusively established. An alternative hypothesis is that amyloid oligomers rather than plaques are responsible for the disease.[26][46] Mice that are genetically engineered to express oligomers but not plaques (APPE693Q) develop the disease. Furthermore, mice that are in addition engineered to convert oligomers into plaques (APPE693Q X PS1?E9), are no more impaired than the oligomer only mice.[47]"
https://en.wikipedia.org/wiki/Amyloid_beta
In the context of biochemistry, an oligomer usually refers to a macromolecular complex formed by non-covalent bonding of a few macromolecules like proteins (or nucleic acids). Of relevance is that with AD, protein assembly is screwed up. Anavex's approach is to correct the process resulting in misfolded proteins.
One can spend hours reading (and writing) about it. Some further reading is below that I found interesting in regard to protein misfolding. Suffice to say that the extensive prior research done to develop 2-73 and its specific targets differs greatly from the current soc/plaque mania and will continue to succeed as others fail, (imo) :
https://en.wikipedia.org/wiki/Aggresome
re: "AD-4833"
Just some more info.
"Pioglitazone (AD-4833) ameliorates insulin resistance in patients with NIDDM. AD-4833 Glucose Clamp Study Group, Japan"
http://www.ncbi.nlm.nih.gov/pubmed/0009550126
Offhand, Pioglitazone doesn't seem too stellar.
"Pioglitazone (brand name Actos) is a prescription drug of the thiazolidinedione (TZD) class with hypoglycemic (antihyperglycemic, antidiabetic) action to treat diabetes. While pioglitazone does decrease blood sugar levels, studies on the main cardiovascular outcomes have not yielded statistically significant results.[1]
Its cardiovascular safety profile compares favorably with that of rosiglitazone, which was withdrawn from some markets after concerns about an increased risk of cardiac events. Pioglitazone has been found to be associated with bladder tumors and has been withdrawn in some countries."
Side effects don't seem to have hurt sales in the US.
"Actos was the tenth-best selling drug in the U.S. in 2008, with sales exceeding $2.4 billion.[2]"
More side effects:
Contraindications[edit]
Pioglitazone cannot be used in patients with a known hypersensitivity to pioglitazone, other thiazolidinediones or any of components of its pharmaceutical forms. It is ineffective and possibly harmful in diabetes mellitus type 1 and diabetic ketoacidosis.[5] Its safety in pregnancy, lactation (breastfeeding) and people under 18 is not established.
Given previous experiences with the related drug troglitazone, acute diseases of the liver are regarded as a contraindication for pioglitazone.
Pioglitazone and all other drugs of its class (thiazolidinediones) are absolutely contraindicated in patients with heart failure.[5]
Side effects[edit]
A press release by GlaxoSmithKline in February 2007 noted that there is a greater incidence of fractures of the upper arms, hands and feet in female diabetics given rosiglitazone compared with those given metformin or glyburide. The information was based on data from the ADOPT trial. Following release of this statement, Takeda Pharmaceutical Company, the developer of pioglitazone (sold as Actos in many markets) admitted that it has similar implications for female patients.[6]
The risk of hypoglycemia is low in the absence of other drugs that lower blood glucose.
Pioglitazone can cause fluid retention and peripheral edema. As a result, it may precipitate congestive heart failure (which worsens with fluid overload in those at risk). It may cause anemia. Mild weight gain is common due to increase in subcutaneous adipose tissue. In studies, patients on pioglitazone had an increased proportion of upper respiratory tract infection, sinusitis, headache, myalgia and tooth problems.
Chronic administration of the drug has led to occasional instances of cholestatic hepatitis, reversible upon drug discontinuation.[7]
On July 30, 2007 an Advisory Committee of the Food and Drug Administration concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of "myocardial ischemic events" when compared to placebo, but when compared to other diabetes drugs, there was no increased risk. Pioglitazone is currently being reviewed. A meta-analysis released subsequently showed that pioglitazone reduced the risk of ischemic cardiac events rather than increased the risk, but increased CHF.[8] The PERISCOPE study compared pioglitazone with glimepiride in diabetics; atherosclerotic plaque volume was measured and followed over time. Glimepiride therapy had highly significant progression of plaque volume over time of 0.73 percent. In comparison, pioglitazone had a -0.16 percent regression in plaque volume. This is the first study to show that diabetic therapy slowed progression of atherosclerosis. Therapy with pioglitazone raised HDL, and lowered triglyceride and hsCRP; these are all beneficial effects on risk factors for coronary artery disease; however, to date, no oral anti-diabetic drug has been shown to reduce the risk of cardiovascular complications.[9]
Bladder cancer[edit]
On June 9, 2011 the French Agency for the Safety of Health Products decided to withdraw pioglitazone in regards to high risk of bladder cancer.[10] This suspension was based on the results of an epidemiological study conducted by the French National Health Insurance. According to the results of the epidemiological study, the French agency found that patients, who were taking Actos for a long time to aid in type 2 diabetes mellitus, significantly increased risk of bladder cancer compared with patients who were taking other diabetes medications.[11] On June 10, 2011 Germany's Federal Institute for Drugs and Medical Devices also advised doctors not to prescribe the medication until further investigation of the cancer risk had been conducted.[12]
On June 15, 2011 the U.S. FDA announced that pioglitazone use for more than one year may be associated with an increased risk of bladder cancer, and two months later the label was updated with an additional warning about this risk.[13]" ...
"Brand names[edit]
Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe, Glizone and Pioz in India by Zydus Cadila and USV Limited, respectively and Zactos in Mexico by Takeda Pharmaceuticals. On August 17, 2012 the US FDA announced its approval of the first generic version of Actos.[18]"
https://en.wikipedia.org/wiki/Pioglitazone
Seems they might welcome the addition of a safe drug like 2-73. The connection to Anavex is interesting. Could be something has been in the works for a while.
Looks like it was worth the long wait. Starting to feel vindicated here. To say the least. :)
re: "...keep shorting all the way "
What US broker allows retail selling short below $5?
I never seem to get an answer to this question when I have asked it in the past on other stocks in a similar situation...
Suretrade (based in the Bahamas, I believe) offers it but it is not available to US investors. So maybe I should inquire, what country? Otherwise, not a retail investor posting such, so what hedge fund.
Just curious. :)
re: "...read Level 2"
That 105k block at 3.01 by EDGX has been there a while.
Past days when these big 100k+ blocks showed up on the bid slightly above 3.00, initially they got nibbled down pretty fast, then slower. Checked late in the day Fri and there was still 50k left. Today doesn't seem to be much interest by anyone to sell at 3.01...
per yhoo, open short int went from 4.6M to 3.92M last month. Going by that looks like quiet short covering being attempted. Except now, despite shaking, less fruit falling off the tree every day.
ok just checked down to 82k now. That is still slower than this time last fri.
Amyloid is your friend. Destroy it at your own peril.
Ok, maybe that's a bit over the top as a headline. :)
Well, perhaps a bit of sensationalism is warranted to compete with all the current media hooplah over Anavex's competitor Biogen. Biogen's amyloid shattering therapy is being hailed as some kind of amazing breakthrough. I seriously doubt that it's anything of the sort. In fact, the currently fashionable "war on amyloid", displacing cholinesterase inhibitors as the industry darling, is ill conceived. It's all based on early total acceptance of the "amyloid hypothesis" which is also looking ill advised. imo
After one of the previous bubbles burst, there were all these brand new office buildings, unoccupied. Nobody to rent office space. Yet construction continued on more. Why? Because contracts had been signed. They had to be finished. I think something like that sometimes happens in (big) bio-tech. Amyloid plaques are discovered. The conclusion is jumped to that it is the cause of the disease. Now a space race to the moon is launched. Billions are committed to get rid of the nasty amyloid, who will be first. They have to finish. Meanwhile guys like the research below indicating a contrary result apparently didn't get any more funding.
Found this research article from a few years that confirms my scepticism about getting rid of all the amyloid.
"Guardian Amyloid?
http://www.alzforum.org/news/research-news/guardian-amyloid-av-hexamers-help-multiple-sclerosis-mouse-model
Amyloid is an electrical insulator, just like the myelin sheath around axons. The sheath is composed of flat Schwann cells which wrap themselves around the axon like wrapping paper around a wire. They are mostly lipid (a kind of fat) which isn't known for being sturdy, but their main function is to insulate. This allows charge to build up underneath which speeds the action pulses on their way to the next neuron must faster than without. Damaged insulation is a characteristic of Multiple Sclerosis.
Although the new plaque therapy is better than reformulated painter remover as I initially feared, I'm not sure if it really is that much better. I also previously joked about yet another bizarre new therapy being announced that involved training brain-eating amoebae to eat amyloid. Seems I wasn't so far off. Microglial cells in the brain, which normally perform cleanup duty at a leasuirely pace, have different modes and can tranform themselves as required including an amoeboid form. Go figure. :)
The new therapy involves tagging amyloid which stimulates the microglia into becoming a hoard of amyloid devouring berserkers. OK, so we have some amyloid stuck on an axon. Is it possible that some of the flavor has imprinted on the myelin, what if our newly energetic little packmen start chomping on that? My other concern relates to the idea that AD may be caused by errant immune response. In which case we would want to calm things down, not add to the mayhem. (aka Anavex 2-73)
Oh well. Time will tell who is more right...
re: "I would politely disagree if only because with the current burn rate and lacking a catalyst BV computations will certainly decline daily and without further dilution eventually reach zero. The infusion of cash raised from the shelf authorization would appear a Ponzi scheme under that scenario. "
That's certainly the case with a lot of OTC scam companies. Pump up a story when they basically have nothing. Issue shares into oblivion, do a 1:100 or 1:1000 reverse split, rinse and repeat. Other clues are they don't pay their bills because virtually all the money is going into somebody's personal pocket. There are lot's of other clues to spot an actual scam. Either some of the accusers of Anavex can't really tell the difference or they are being disingenuous.
Sorry I wasn't really arguing a serious case for BV. Given what is known, it's hard to fathom the low share price. If someone was actually using that, it seemed a little fun to extrapolate it proportionally. Also, it's another way to view capital from dilution as not being a bad thing if it's used to advance the company's goals and not squandered or stolen.
It's also fun to work the math on lofty potential future profits but the reality is probably going to be somewhere in between and take a long time.
re: "I am more interested in corporate execution, transparency, and funding flexibility than BV in this type of security."
As well we should be. I happen to think that Anavex is a real company and has some valuable goods. There are competing theories about AD and right now but the established, or might we say, entrenched interests have the home court advantage. The big issue for a AD space investor now is how much weight to give to each differing approach to treatment.
There is an orthodoxy factor in medical science just like about everywhere else. It's true that 99% (or whatever high percentage) of AD drugs fail but most of the trials like all the mediocre prescription drugs already out there come from the same pharma behemoths. Many big breakthroughs have small beginnings like the guy that discovered penicillin. There is a traditional suppression of new ideas in human societies. The "germ theory" of disease was even hotly contested for a while even in the face of evidence, until the evidence became overwhelming.
There are clues, the challenge is how to interpret them.