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re: "Book value is not a very relevant valuation method for young biotechs. BV is really for companies with a lot of physical capital (companies with heavy inventories (eg Best Buy), real estate (mall owners), financial assets (banks) or little goodwill or other balance sheet intangibles). "
Actually I agree. I would also add it as being somewhat useful in evaluating certain mining companies.
I suppose I was being a little tongue-in-cheek in response to a remembered criticism that appeared in a past negative article. i.e. Niether is it relevant to beat up on Anavex because it has a low BV.
The question is I guess is what sort of criteria is being applied? There haven't been any radical changes in fundamentals compared to the extent of some of the price action.
I don't believe I've used the word here but I also don't subscribe to the new definition of "conspiracy" as "something that doesn't exist". :)
re: "If that was the case, we would be a lot higher right now, without the extra shares. The market is funny."
I did say I was having a bit of fun. :)
The problem as always, is perceived value. It's highly variable and mallable.
There's intrinsic value, like with gold or oil. Put a few dollars worth of gas in a farm machine and do in a day the work of 10 horses or 100 people, well, whatever, a lot of valuable work. Seems like that would be a constant, but even items of intrinsic value are subject to supply and demand and, of course, price manipulation. Right now the Saudi's have pretty much total manipulative over control the price of oil. Currently they choose to dump as much as necessary to keep the world price low. They are evidently willing to forego some per barrel profit if it means hurting their geo-political rivals such as Iran, or drive competing producers out of business and into bankruptsy, such as is happening in North Dakota.
Then there is the "Efficient-Market Hypothesis"
"In financial economics, the efficient-market hypothesis (EMH) states that asset prices fully reflect all available information. A direct implication is that it is impossible to "beat the market" consistently on a risk-adjusted basis since market prices should only react to new information or changes in discount rates (the latter may be predictable or unpredictable)." (en.wikipedia.org · Text under CC-BY-SA license)
Obviously that's on shakey ground from the get-go. Is "the market" all available investors acting on all available information? Kind-of true for most large caps. But what about a relatively low float developmental stage company like Anavex?
Is the stock exchange the "market"? Actually, it's what the MM makes of it, "MM" being "Market Makers", or as some mighy say "Market Manipulators" :) The stock price is an artifact or artist's conception of what they think the price should be at any given moment. That's their job. A MM is given special trading priviledges to dampen sudden price spikes either way by providing liquidity. They can "temporarily" create shares out of thin air if necessary. Theoretically, they are governed by how far they are willing to go in the hole. If a big order comes in, they can get overwhelmed after which the prudent thing to do is try to cover, or stop buying, sit back and let nature take its course. You can have a high roller (who also could be a MM) by or sell the whole float. Basically, he becomes "the market". Only he knows what he is going to do next with the stock price. So much for the investment community at large having "all available information". Kind of makes a mockery of all the rules for delaying and reporting insider trading. If they're not an insider, they can pretty much do what they want at any time.
So, in our case, the stock price, present, is pretty much completely disconnected from the true value of the company. It's up to the individual investor to figure out what he (or she) thinks the company is really worth, which, of course, has resulted in some keen message board discussion...
Here's another article on same.
http://www.fiercebiotech.com/biotech/biogen-s-aducanumab-data-impresses-media-but-not-market
Oops, just noticed I goofed a little. Forgot to add new shares into os count.
Book value per share is now $28,763,827 / 35,000,000 +6,754,609 os = $0.67 (per share)
Using the exact same price to book ratio = 12.5 :
12.5 X $.67 = $8.35 (Anavex share price)
Been thinking about just how is it that amyloid tangles and plaque are supposedly interfering with cognative function (according to the "amyloid hypothesis").
So, can amyloid "short out" neurons? It would need to be conductive for starters.
Not real easy to find research on electrical properties of amyloid. Here's one:
"These experiments complemented work carried out on the conductivity of amyloid fibril networks, using fabricated interdigitated electrodes. In the unmodified state, amyloid fibrils formed from bovine insulin, fungal hydrophobins, and crude crystallins were all shown to have low conductivity, with current values in the range of 10?8–10?¹° A recorded at bias voltages of 0–2 V"
http://ir.canterbury.ac.nz/handle/10092/6718
It would have been nice if the researchers had displayed a little more electrical knowledge and included a volumetric quantity. But this is good enough ball-park to establish naturally formed amyloid plaques as insulators. Average 2000 megohms, about the same as paper, (although if amyloid fibrils were (probably) smaller than the thickness of paper, it would mean even higher resistance). Anyway, paper is a good electrical insulator, used for years to insulate capacitor plates. 450 volts, no problem.
Furthermore, the neural equivalent of output signal wires, axons, have myelin insulating sheaths in similar manner to regular electrical wires in house wiring. So. You wrap some paper around an electrical appliance cord in your house. What's that going to do? Basically nothing, except that it's a little more insulated now...
re: "They just registered those shares last week! LP could not by more then 50 k shares a day, at the discretion of AVXL. Even if they buy every day it would take 135 days to purchase 6.7 million shares..."
In spite of that we've seen some dire predictions about dilution (as well as disparaging remarks about book value.)
Regarding an equity raise and "dilution"
Well, if a company has profits, and if one assumes that the price is based on earnings per share, a price to earnings ratio and that that is the sole criteria, then earnings per share would be reduced proportionately and the share price would be expected to follow.
You can't really use PE (price to earnings ratio) ratio on a developmental company because they have no earnings yet. It's a different ball game. To get a positive number, it must be that book value is figuring into "the market's" calculated share price.
Assuming no goodwill or intellectual property value, we don't have any debt, so don't have to subtract that, just using free and clear cash on hand, using book value:
say, we still have $8.5 million cash
divide by 35,000,000 outstanding shares = about $0.24 book value (per share)
current share price of $3.00 / 0.24 = 12.5 price to book (ratio)
BTW, lots of companies have higher price/book than 12.5, like Rite-Aid(13.39) and Netflix(17.28).
Now we add LPC's 6,754,609 shares bought @ $3.00
Cash on hand is now: ($3.00 X 6,754,609) + $8,500,000 = $28,763,827
Book value per share is now $28,763,827 / 35,000,000 os = $0.82 (per share)
Using the exact same price to book ratio = 12.5 :
12.5 X $.82 = $10.25 (New Anavex share price)
Isn't math fun? :)
Unlike all the other current approaches to treating Alzheimers, Anavex 2-73 targets the sigma1 receptor (Sig1R)
Read about the sigma 1 receptor (it's an odd little cancer research article but within it they do provide an interesting description of S1 (slightly editted for readability):
"... Sig1Rs have been associated with many diseases including stroke, cocaine addiction, Alzheimer's disease, amnesia, amyotrophic lateral sclerosis, retinal degeneration, and cancer. Nonetheless, the way Sig1R operates in such diseases is still poorly understood. Su and colleagues'work on neurons and CHO cells have shed light on the molecular mechanisms underlying Sig1R functions. Sig1R is mainly located at the E[ndoplasmic] R[eticulum], in close contact with the mitochondria, in the so-called mitochondria-associated-ER membrane domains (MAM). In resting condition, Sig1R resides in ceramide- and cholesterol-rich lipid microdomains associated with the ER-resident chaperone GRP78 (BiP) Under cellular stress leading to ER injury, Sig1R dissociates from BiP and binds IP3 receptors, enhancing in turn cell survival through the control of calcium signaling between the ER and mitochondria. In addition, Sig1R translocates to other cell compartments and binds to different membrane proteins. The stimulation with sigma “agonists” mimicks stress-induced Sig1R dissociation from BiP and Sig1R delocalization, while sigma ligands classified as “antagonists” impede this process. Altogether, these results have led to a model in which Sig1R is [(relatively?)] “silent” in normal physiological conditions, whereas in case of a disease, Sig1R behaves as a chaperone that binds client protein to the benefit of cell survival . This exciting hypothesis has been validated by recent studies demonstrating that Sig1R molecular silencing reduces brain recovery after experimental stroke and promotes retina degeneration after acute damage to the optic nerve. ..."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712323/
The researchers in the article think it's "exciting" because they seem to assume that it only mainly benefits cancer cells. They seem focused on blocking S1 to fight cancer cells so they may be a little off assuming it is "silent" in normal cells. I don't know, smart as they are, researchers sometimes seem prone to tunnel vision. It may not be as silent as they thought. It seems more like a "dead man's switch". Take your foot all the way off the pedal and it becomes literal. Is that it. They do say "poorly understood", so I guess shouldn't be too critical. No question though that it is a very important receptor.
The reason I suggested "relatively silent" is that totally silencing the S1R results in programmed cell death. This has been proven experimentally.
"Silencing of sigma-1 receptor induces cell death in human lens cells"
http://www.ncbi.nlm.nih.gov/pubmed/16472803
Programmed cell death of certain cells is also a natural process of growth during reproduction. For example, when the fingers form, they are initially joined and pcd allows them to seperate. So, it looks like if S1 shuts down, the cell sickens and dies. Conversely, if it is switched on, it helps the cell make the right proteins. Switching on strongly yields a kind of enhanced survival mode which seems to relate to a kind of downstream repair that I was envisioning in a previous post.
Somehow I can't envision blocking s1 becoming much of a viable cancer therapy. They would have the same problem as with poisons causing collateral damage to surrounding tissues.
OTOH Anavex 2-73 promoting sustained S1 activation, would seem to be just the right thing to do to help stressed-out brain cells suffering from injury to their ER .
May we also recall that 2-73 binds (agonist) to muscarinic receptors M1 and M4 while avoiding M2 amd M3 activation. Current SOC side-effects suggest errant activation of M2/M3 by Aricept.
M1 - The M1 muscarinic acetylcholine receptors facilitate cue detection behaviors and are necessary and for most direct effects of ACh on pyramidal neuron excitability. Pyramidal cells are principal cells, as opposed to interneurons, that are connecting one brain region or subregion to another. - ok, good to keep that working
M2 - M2 muscarinic receptors are located in the heart, where they act to slow the heart rate down to normal sinus rhythm after positive stimulatory actions of the sympathetic nervous system, by slowing the speed of depolarization - good thing to avoid (too slow of a heart rate) as a side effect. [Also (see below) if Aricept/donepezil (as it appears to do) errantly binds to M2 in the brain, this throttles down new acetylcholine release, which is self-defeating to its purpose of increasing acetylcholine by slowing down the breakdown of existing acetylcholine. Eventually the existing acetylcholine is going to dissipate anyway, but now we are left with even less acetylcholine than before. Probably why it stops working/becomes counter-productive after a while. ]
M3 -smooth muscle contraction, bronchoconstriction, Increase intracellular calcium in vascular endothelium, increased endocrine and exocrine gland secretions, e.g. salivary glands and stomach, In CNS Eye accommodation, vasodilation, induce emesis (vomitting) - good thing to avoid as a side effect
M4 - M4 muscarinic receptors are coupled to Gi/o heterotrimeric proteins.[5]
It function as inhibitory autoreceptors for acetylcholine. Activation of M4 receptors inhibits acetylcholine release in the striatum. The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus and cerebral cortex.
Muscarinic acetylcholine receptors possess a regulatory effect on dopaminergic neurotransmission. Activation of M4 receptors in the striatum inhibit D1-induced locomotor stimulation in mice. M4 receptor-deficient mice exhibit increased locomotor simulation in response to D1 agonists, amphetamine and cocaine.[6][7][8] Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M4 activity may contribute to conditions such as Parkinson's Disease.[9][10][11]
[I.e.. Probably why Anavex 2-73 is helpful in inhibiting seizures, spasms and inflammation.
With M2, we don't want to inhibit the hippocampus and cerebral cortex. but with M4 in the in the striatum (a different part of the brain that Parkinson's afflicts), we do because it regulates/inhibits uncontrolled movement e.g.Parkinson's Disease. I recall reading about another experimental drug that is intended to help with Parkinson's but it screws up M4 and they were looking for something to ameliorate this. Could be that 2-73 fits the bill right now... ]
"A balanced interaction between dopaminergic and cholinergic signaling in the striatum is critical to goal-directed behavior. But how this interaction modulates corticostriatal synaptic plasticity underlying learned actions remains unclear—particularly in direct-pathway spiny projection neurons (dSPNs). Our studies show that in dSPNs, endogenous cholinergic signaling through M4 muscarinic receptors (M4Rs) promoted long-term depression of corticostriatal glutamatergic synapses, by suppressing regulator of G protein signaling type 4 (RGS4) activity, and blocked D1 dopamine receptor dependent long-term potentiation (LTP). Furthermore, in a mouse model of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson’s disease (PD), boosting M4R signaling with positive allosteric modulator (PAM) blocked aberrant LTP in dSPNs, enabled LTP reversal, and attenuated dyskinetic behaviors. An M4R PAM also was effective in a primate LID model. Taken together, these studies identify an important signaling pathway controlling striatal synaptic plasticity and point to a novel pharmacological strategy for alleviating LID in PD patients.
"
http://www.cell.com/neuron/fulltext/S0896-6273(15)00933-2
re: "can you please translate? "
*Pourrait ont juré que je tapais en anglais. :)
What , the remark about warrants? You buy the right to buy a stock at a certain price after a certain date. Often it's offered as a "sweetener deal. Say a stock is at $0.25, buy the stock and get a $0.50 warrant, but you pay less than that. The stock goes to .75 , the date rolls around. A million new shares, whatever, get bought @0.50, many or most, depending, are expected to be turned around and resold right away. Firstoff a bunch of sales are going to start going through the bid, using up existing buy offer blocks, so MM is going to keep notching down the bid price, but selling will tend to cease at or just above 0.50 because nobody wants to sell at a loss.
"Somebody is holding the share price down"
I was agreeing with the idea that the current stock price is too low but some big block buyer(s) appear to be getting shares from somewhere at $3.00 or a few pennies above. This suggests the seller(s) would lose money below $3.00 so selling is curtailed there. When the trickle of new buyers start sending the price up a bit, selling resumes, holding the share price back down again.
It's not warrants but the price action is similarly artficial, strictly monetary/trading based, appears governed by some pre-arranged ball-park, round-number price and not fundamental stock metrics. Of course, a developmental stage company's perceived valuation is mostly dependant on speculative sentiment and intangibles, so any money in excess of the low volume on any given day will set the price. This is the opposite of a large cap where metrics such as the price of oil, same store sales, i.e. tangible fundaments, all get tallied up by analysts and result in a calculated valuation based stock price. Also large caps trading in the billion dollar volume range are beyond the clout of a typical hedge fund or high-roller's $10 to $100 million, to move the stock price in any significant way.
re:" Not sure (if true hypothetically) what this means going forward."
It probably means that some pre-positioning is going on at somewhat arbitrary cheap-as-possible prices. In spite of various hooplahs, some of us, some people, have their own theories about AD, and who's right, and are making investment decisions accordingly.
Maybe it's short covering. Maybe, as somebody else voiced a concern recently, a takeover attempt could be made. Come to think of it, registering a bunch of shares to hold in reserve would make a leveraged takeover less attractive.
It means that not everyone is dropping everything to go off and buy Biogen. It means Anavex is going to go back up at some point in the future. imo
*Could have sworn I was typing in English. :)
re: "Sombody trying to hold it down"
Wasn't there some kind of $3.00 threshold in the LP contract? This sort of tight range being held is pretty common with stocks when there is anticipation of warrants being exercisable at a certain price. We haven't had those, have we, but the action seems similar.
This morning may have been some kind of test to gauge the trickle of new buyers and how much selling is needed to contain it.
Seems to have been some new developments but haven't really looked at the latest s3. Containment of the share price likely has something to do with terra forming the trading environment to take advantage of an anticipated equity raise. imo
After a year of treatment with aducanumab
"Brain scans of those given the highest dose shown virtually no amyloid left at all."
If amyloid was the main cause suppressing cognitive function, then removal of the amyloid should have restored at least some cognitive function. It didn't. All exhibited continued cognitive decline.
The side effects, fluid build-up and brain bleeding are dangerous and life threatening.
The degree of spin and hype currently promoting this abject failure as some kind of great success in the media is offensive.
Meanwhile, Anavex, which has an extremely promising drug 2-73, that has demonstrated unprecedented actual reversal of decline, has proven tolerability, and an excellent safety profile, gets pointedly ignored, when it is not being actively smeared.
AD sufferers and investors are being misinformed. It's not fair to either.
This is an outrage!
Whew. Ok, I think I need to go lay down for a while now :)
Just in case someone still thinks Stem Cell of America is competition for Anavex:
Or curious about what a real AD etc. scam looks like.
http://www.skepdic.com/rader.html
re: "Remarks were not "similar".
Agreed. In fact, the ostensible giddy Macfarlane/Prana/Lawler report seems to be completely bogus.
A lot of investigation into this has already been done on this by one of our esteemed colleagues.
DD regarding allegations questioning the credibility of Steve Macfarlane, Anavex media coverage, and P300 trends:
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=116069551
re: "DND* is a perfect example BA at the end they had 100mm os and 300 million short,yes for real..."
I think I remember that one.
http://seekingalpha.com/article/34988-dendreon-the-short-story
I can't find the article right now but there was another one where there was a guy that bought up all outstanding shares of a small company. He checked with the transfer agent. Yup, he now owned 100%. The next day the stock continued trading back and forth with the volume in millions and millions of shares as if nothing had happened. Apparently most of the traders didn't know that they were all phantom shares.
It's also pretty likely that the nice little periodically updated "official" tally showing shares short in no way indicated the true state of affairs. Which could be cause for a bit of scepticism regarding the current "aggregate" low number for AVXL
There was this little company (who shall remain nameless) that kept most of their stock in trailers parked in the back lot. One day I came in and noticed that they had all disappeared. Oh, the audit's tomorrow. There is this little thing called inventory tax. They were back a few days later. I imagine something analgeous can be done with shares to temporarily reset the aggregate count when you know the date that the report comes out.
This is from a 2008 article but it seems unlikely things have changed too radically:
"The [SEC] inspector general's report said the SEC received some 5,000 complaints alleging possible market manipulation using short sales between Jan. 1, 2007 and June 30, 2008. Of those, 123 or 2.5% were forwarded for investigation and no cases were brought, the report said. By comparison, about 12.5% of emails alleging insider trading prompted an investigation.
The report, by SEC Inspector General H. David Kotz, said the agency lacks uniform procedures for handling tips. He also noted understaffing, saying four people were charged with reviewing the 1.38 million emails that came in during the year-and-a-half period.
In a written response, the SEC's enforcement staff played down the likelihood of naked short-selling abuses. ..."
http://www.wsj.com/articles/SB123742141942278703
We can rest easy knowing that if another Martha Steward pops up acting on an indirect $48k tip from their broker, they'll be on the case, handcuffs and jail at the ready.
If one looks at the history of naked shorting (eg wikiped), people have been grappling with it for literally, centuries. It's one of those market mechanisms that are helpful if not abused but the problem is that it's hard to pin down when it is being abused.
This is kind of interesting.
Does this actually work? If a company declares a dividend, all the shares have to be tallied up and identified. Obviously, this might put a bit of a squeeze on somebody who has synthesized a major boatload of phantom shares. I wonder if Anavex could declare a token dividend (say, $0.01) to see how many of the shares that got dumped out there are actually real. Or would the dividend need to be more substantial? Come to think of it, I can't think of any dividend stocks offhand that have experienced trading activity resembling a short attack...
http://seekingalpha.com/article/1645772-biolase-ceo-takes-dead-aim-at-naked-short-sellers-main-street-cheers
re: "So going from p1 to p2 is not a big deal - if it reaches P3 - it will be good news. "
It's in the bag.
Prof. MacFarlane, who ran the trials, indicated in his remarks about phase 2 that results were so good he could scarcely believe they were real, and has given the go-ahead for phase 3.
Preparations for additional recruitment under an FDA approved adaptive trial model are underway.
re:"Why hasn't fda given accelerated approval or breakthrough designation if the there is proof from clinical studies that 2-73 works better than the soc? "
Looked at pr's for 2016 and 2015 I notice that they didn't pr applying for each Orphan Drug Designation. They did PR when they got it. Looks like for 3 different indications. Ne'er do well OTC's will pump their stock by announcing the application but then that's as far as it gets. Here, by granting the designations the FDA acknowledges the work done proving efficacy so far and OK for further human trial. Also, the FDA can withdraw the designation at any time. They haven't done so.
Orphan drug status has some real benefits. Besides years of exclusivity they also get to deduct 50% of their R&D expense from their future tax bill.
Accelerated approval, breakthrough, and fast track are all pretty similar. I was looking at "fast track". It's not very fast, the FDA will get back with you in 60 days after you apply. Then you still have to go through the required trials but get to submit partial paperwork instead of all at once at the end. It may reduce approval time from 10 months to as little as 6 months. Apart from some bragging rights, not that great.
So far as I can tell, Anavex meets the criteria. Since they didn't make a big deal about applying for Orphan, we don't know that they didn't apply for one of these.
Or they may have taken a pass. The adaptive trial design they worked out with the FDA seems to offer the same benefits, may actually be better.
re: "Perhaps 2-73 prevents the gene mutation, which in turn prevents protein degradation (that leads to misfolding causing beta-amyloid plaque and tau tangles?). Just maybe... "
It would be nice if that was true but I don't think that's possible. Firstly, it seems more likely that a bad gene would be inherited, not spontaneously mutate in the same way in every affected cell. Editting or repairing a gene requires some pretty heavy molecular machinery beyond what a small molecule would be capable of. Remember that it has to be small enough to squeeze through the closely spaced glial cells that protect the brain's neurons like a sort of living *HEPA filter (i.e. the brain-blood barrior).
Since I may be at hereditary risk, obviously a bit of concern here. Well, we know it helps the transgenic mice who obviously get it from heredity so hopefully one is not totally doomed by a wonky gene if that's the case.
The more I try to learn about what goes on inside the cell the more I am in awe. The complexity is beyond that of a modern automated vehicle assembly plant. But one could still make an analogy. Nowadays there are many manufacturing methodologies but in the old traditional assembly line, what would happen is this. Let's say they run out of rear view mirrors. The line keeps going but the vehicles are now defective at that point because they are missing mirrors. All is not lost, further down the line, mirrors are brought in and installed so the defect is repaired before it leaves the final line.
Been meaning to try to learn more about ionic transport but one thing I gather from reading about the current theory of operation, salient here, would be that 2-73 serves to correct problems with the molecular machinery inside the endoplasmic reticulum which is a kind of assembly line conducting transcription of genetic information into proteins. Whether the defect is from genetic or possibly environmental cause it looks like it is still possible to repair the process or ultimately the product before it leaves the assembly line.
If there is a human "AD" gene the best pkace to try to fix it would seem to be in the DNA somewhere around the time of egg cell fertilization, before cell differentiation into brain cells occurs. But I believe tinkering with human DNA even for benign purposes remains highly controversal. Anyone who watches sci-fi can be aware of the dangers if it isn't done with adequate knowledge, wisely, and responsibly. e.g. I'm not sure how I'd feel about glow-in-the-dark humans. :)
It looks like there are several interesting articles accessable from that page.
*High-efficiency particulate arrestance (HEPA)
Who would have thought "arrestance" was a word? :)
Thank you for the link.
From the text:
“They seem to be significantly improved in terms of what they can do. It is function that has improved and in many cases mood as well,” Prof Macfarlane said.
“To me, seeing real improvements to patients is much more important than seeing a statistically significant improvement on a rating scale."
“Seeing people regaining abilities is far more powerful and important than that.”
Transcribing directly from the audio:
"What's important in the trials is not so much how well people do on some memory scale, what's important is the outcome for the patients themselves and to see changes in people's lives is the most important thing."
"The information we've heard from our patients today is that it's people outside the family who notice these changes as well, people who haven't seen the patients for several months commenting on how remarkably well they've done."
Interviwer: "Obviously there's a long way to go, but the promise of this, it's looking good."
Prof. Macfarlane: "It's looking good at this stage, what's required is a much larger trial with a placebo control group to see if the changes we've observed in this early study are actually real and pan out in a properly well conducted study."
OK so he makes a caveat at the end. He's not being dismissive. It's same thing astronomers say when they find a new planet. Findings that don't pass the first hurdle get discarded right away. But when the data looks promising for a candidate, it gets reported because it "probably" is a planet, but of course they will stipulate that more data is needed to confirm it. Exo-Planet detection is still relatively new but the longer they stay at it the better they get at screening out false positives. There are now thousands of confirmed exo-planets in our steller neighbrthood. Similarly, Macfarlane has been at this for a long time now, has witnessed a lot of failures and if he really thought it was a dud, I think he would have actually said something like your statement below.
"McFarland agrees that the accounts of the drug improving a few patients symptoms are not proof of anything. ..."
Also, (see above transcript) what Macfarlane agrees with is that "It's looking good."
This is a little like analyzing Janet Yellon's remarks. :)
Now, one could jump all over "...pan out in a properly well conducted study." and put a negative spin on that. Is he implying that the current study is no good, not properly well conducted? No. Consider the context. The study in question was primarily designed for dosage determination, extended safety and secondarily, statistical memory tests to put on charts. It was properly well conducted for that. What it wasn't looking for was remakable real life functional improvents. That's why they are described as "unexpected", but nevertheless duly recorded, as on the recent conferance poster presentation.
Getting back to the planet analogy, at first they didn't really expect to find any around red dwarf stars, so they didn't look for them there. When one was found, it was unexpected. Now that they know to look are not only finding lots of them in orbit but even in the habitable zone.
Previous AD drugs were so poor they didn't structure trials to look for such functional improvements.
re: "There are no provisions in our articles of incorporation or our bylaws that would delay, defer or prevent a change in control of our Company"
Do you think some one, or, dare I say, some thing, might try a (hostile) takeover of the company?
(Maybe I should apologize for a bit of attempted humor in the phrasing. It's a familar expression of conjecture in sci-fi (of which I am a bit of a fan) when investigating heroes uncover evidence of an unknown enemy.)
:)
re:"...holding some fair cards at a decent price imo
... pair with a straight flush draw,
worth a little gamble "
After high-rollers with enough clout to buy or short the entire float muscle their way in, it's hard to guess what they are going to do next.
At least with regular gambling you get free drinks. :)
re: "... bloodbath in the biotechnology sector yesterday... Now I don't what to think! Is it Greed or Marketing or Cost? "
Health care cost keeps going up. It is now about 19% of the US economy. Too bad it's mostly fluff.
http://www.bloomberg.com/news/articles/2012-06-13/health-care-spending-to-reach-20-of-u-s-economy-by-2021
I think the sector can thank price-gouging poster-boy Martin Shrkreli, not for jacking up the price, but bragging about it. Now people are starting to realize it's a widespread practice. People are outraged. Makes for great politics. Direct some wrath at obvious offenders, win a lot of votes while directing attention away from your biggest benefactors. Great stuff.
from the article:
"The problem is that Mylan has been jacking up the price of the EpiPen. A two-pack of the injectors now lists for more than $600... "
The thing is, the active ingrediant is Epinephrine, the actual product delivered to the bloodstream is a hormone and not patentable. The actual retail cost of a dose is probably a dollar or two since there is presumable enough in one bottle for many doses.
from another article:
"I paid $5.89, cash price for this (bottle of epinephrine), no insurance required," said Dr. Romanello. Less than $6 for the life-saving medicine. Add an Altoid tin and syringe and you've got an epinephrine injector kit for under $10."
http://www.americanthinker.com/blog/2016/08/epipen_too_expensive_you_can_get_the_same_dose_for_ten_bucks.html
One would think that if medicines were getting better, people would be getting less sick and health care costs would be going down. Instead we have the opposite. Investing in a bubble while it is inflating can pay off, but likely some investors (and fund managers) are starting to be concerned about hints that the bubble might burst, so are cutting back in case the sector turns really sour.
I suspect that there is still currently a sizable short position in AVXL and that the covering process so far, with the necessity of doing a little minor shorting to hold the price down, hasn't yielded a lot of net shares being shaken loose from retail. They need a new infusion of fresh shares which is why I get the impression of waiting with bated breath for Anavex to be compelled to do an equity raise. It must be frustrating to watch Anavex taking their time about it. Meanwhile, after observing the big (200k) absorption block on the bid Friday, it looks like certain funds may be helping their cause by pulling out of the sector a bit.
As much as some if us may be irked by getting slammed by short sellers, the sooner thay are able to finish covering the sooner they will the let price start wandering back up.
Also from the comment section of the article you submitted, another reason we have a sector bubble:
" ...For every $100 Dollars of Corporate debt, Corporations now only have $15.00 Dollars in cash to service that debt! Corporate America is drowning in debt, unlike the Government, this debt must be paid back!! With an economy not growing fast enough, (or not even at all in real terms) where will the money to pay back the debt come from?? This is true for 90% listed Corporations!!
http://www.bloomberg.com/news/articles/2012-06-13/health-care-spending-to-reach-20-of-u-s-economy-by-2021
By comparison, Anavex has no debt overhang. Which is remarkably good for an early stage company. At least we are not contributing to the bubble. Also, I think that Anavex will not be tempted to resort to price gouging, they will be able to do quite well charging a fair price. I don't know how much 2-73 costs to produce, but the thing about small molecules is that they are, well, small, and relatively simple compared to many other bio-chemical compounds that are highly complex. I therefore expect that 2-73 is not all that expensive to make. It will be affordable for a huge market.
re: "Trade MS for improved Alzheimer's symptoms anyone? "
MS symptoms include pain, vision problems, bowel and bladder, loss of walking/balance, weakness, depression, fatigue, and...
Cognitive issues
These issues include difficulty with memory, concentration, and problem solving, which many people refer to as “cog fog.” Memory loss is the most common mental change in people with multiple sclerosis (MS). It can occur at any time in the course of your MS. Even if you do not have physical signs of the disease, you may experience memory loss.
Examples of memory loss include:
1. Forgetting names, telephone numbers, and recent conversations
2. Difficulty remembering what you just learned
3. Not knowing why you entered a room
4. Losing or misplacing things
http://www.mslifelines.com/common-ms-symptoms
What improvement?
re: "McFarland agrees that the accounts of the drug improving a few patients symptoms are not proof of anything. ..."
Just as some seem to have mischaracterized his factual reporting as giddy, you seem to be putting words in his mouth the other way as pessimistic. I don't recall him ever saying that.
Are you paraphrasing? What did he say exactly? Can you provide a link? Probably not, right?
re: "We do know it's very safe. But not if it 'works.'"
Of course it works. We have proof from clinical trials that it works better than anything else out there. We just don't know how much better. It's a viable replacement for donepezil right now. The FDA requires p3 trials. I expect that the less sick the person is to begin with, the better it works. I also expect improvement to level off at some point. We are seeing a much better response well beyond donepezil, how long that can be sustained will be in future data.
Success is relative to the current standard of care drug which, as I may have mentioned, is crap.
re:"A2-73 seems to cross blood-brain barrier and is non-toxic so is very good candidate for development but does AVXL has any capacity to develop it further?"
Years of laboratory research have already gone into it. 2-73 is a finished product, already developed. Similarly, 3-71 is the improved version, just not as far along in testing. The pipeline if full enough. In a sense, they have infinite capacity. If they decide they need more lab work, they can contract it out or work with university labs. They have the expertise to decide what kind of work and who would be the best to do it. Do you think they made their own pills for the trials? No, they provided the specs and chose a pill manufacturer.
Anavex and the Competition
Anavex 2-73 works by repairing internal damage that has occured in the cell due to stress and also strengthens the cell's internal processes to resist damage. Since it's mode of operation is to get cells functioning again, it doesn't affect cells that are still functioning normally. Clinical trials to date have proven that people have gotten better taking 2-73, improvents over and above and longer than the current standard of care Aricept (donepezil). Donepezil is among a class of drugs that promote accumulation of acetylcholine. This will stimulate a brief increase in neural activity but subsequently has no effect on continued progression of the disease. Unlike 2-73 which is quite safe, boosting acetylcholine can produce undesired side effects. Heart failure is one such listed. Nevertheless, acetylcholine boosters continue to be administered as treatment for Alzheimer's even after they have become completely ineffective.
*AD is currently treated by increasing acetylcholine concentration by using acetylcholinesterase inhibitors to inhibit acetylcholinesterase from breaking down acetylcholine. Current acetylcholinesterase inhibitors approved in the United States by the FDA to treat Alzheimer’s include donepezil, rivastigmine, and galantamine. These drugs work to increase the levels of acetylcholine and subsequently increase the function of neural cells. However, not all treatments based upon the cholinergic hypothesis have been successful in treating the symptoms or slowing the progression of AD. Therefore, a disruption to the cholinergic system has been proposed as a consequence of AD rather than a direct cause.
*Martorana, A; Esposito, Z; Koch, G (August 2010). "Beyond the Cholinergic Hypothesis: Do Current Drugs Work in Alzheimer's Disease?". CNS Neuroscience & Therapeutics. 16 (4): 235–245. doi:10.1111/j.1755-5949.2010.00175.
Now there is a lot of hype and pumping about amyloids and tau "breakthroughs" in the biotech media arena while Anavex continues to be ignored or derided. Even though, like acetylcholine, amyloids and tau have also been a dead end for a long time.
*The expanding interest in dementia has nurtured a worldwide initiative exploring a wide array of disease mechanisms and approaches to treatment. The divergent perspective on the exact cause of this destruction have fostered different theories about what initiates the process and how best to intervene. The theory with the largest following remains the "amyloid hypothesis," which assigns a central role to abnormal pro-cessing of amyloid precursor protein (APP), a protein found widely throughout the body. This abnormal processing yields a fragment called beta-amyloid (Aß), which aggregates by stages into the amyloid plaques that is a hallmark of Alzheimer pathology. Proponents of the amyloid hypothesis see production and aggregation of Aß as the key event in nerve cell disruption and destruction. Neuropathology studies are inconclusive as to the pathogenic role of amyloid in Alzheimer's disease. Quantitative radio immunoassays show that equal amounts of soluble APP are found in the brains of people with Alzheimer's disease and age-matched individuals without Alzheimer's disease, casting doubt on the role of APP. This makes determining the relationship of amyloid to Alzheimer's disease more difficult: dense plaques accumulate with age even in individuals who have no cognitive impairment.
The second most prominent Alzheimer theory assigns a causative role to tau aggregating into neurofibrillary tangles. Many experts remain convinced that understanding tau will reveal crucial clues about Alzheimer’s devastating effects on nerve cells as well as chemical steps vulnerable to intervention. However, there is no conclusive evidence indicating that amyloid plaques and neuro-fibrillary tangles are the cause and not a product of Alzheimer's disease. Plaques and tangles can be observed in the brains of individuals without any detectable form of dementia.
*Snowdon DA., “Aging and Alzheimer's disease: lessons from the Nun study.” Gerontologist 1997; 37(2): 150-156
re: "AXON over $17 today - sickening!!!! Anavex better than any compound Axon has, IMO!!!!!!!!!!!!!"
Ignorance is bliss. The biotech community's cultivated ignorance is Axon's bliss.
For now... :)
re:"mouse models are a double-edged sword. "
An argument could be made. How much more can be learned from mice than in-vitro testing on actual human cells.
Then there's all the things being done to the mice. There is concern over GMO grains, now we have all these animals being genetically modified.
This used to be the stuff of science-fiction. I have mixed feelings about ad software monitoring my browser history. Maybe it thought I was some kind of researcher but I started seeing offers for gene-splicing kits you could buy on-line. One was a do-it-yourself for plants that glow in the dark. Or you could just buy already grown glowing plants. Evidently someone figured out how to combine fire-fly and plant DNA. Maybe it isn't all that hard once the sequences have been identified. Now I notice the same thing has been done to create glow-in-the-dark mice.
Your neighbor's pet giving your pet trouble? With the Acme gene-splicing kit you can grow your pet to enormous size. But will people consider the consequences of their actions? Will they even pause to consider the huge increase in pet-food costs. People can be so irresponsible. :)
Of course there's the old sci-fi cliche' where mistakes get loose in the world and start multiplying out of control.
Looks like a whole lot of gene-splicing is going to be going on. What will the future hold?
How much mouse testing is really necessary? Maybe just test on some regular mice. If it's safe for the mice, I'd be inclined to try it at that point. A lot of people would like to try Anavex 2-73, it even tested safe on humans now, but they are still prevented.
I recently saw something about a "Right-To-Try" movement of sorts. I think there is proposed legislation in some states but my impression is that it has been rather bogged down for some reason. I don't know too much about it, but it seems like that could be a good idea.
re: "What do you think is it applicable?"
Interesting.
Say we go back to the idea of misfolded proteins. Is the plaque from human AD a less soluble positional isomer of the mouse plaque, in other words abnormal? The mice are overproducing amyloid but could it be considered a "normal" amyloid.
Obviously the solvents and chemicals cited would be poisonous to living tissue but maybe there is something in the plasma that will slowly dissolve amyloid, depending?
We can also deduce that all transgenic AD mice are not alike. Because we are progressing from the standpoint that plaque is not the root cause, per se, it appears that Anavex picked the best type of mouse for what they were testing for.
"The 3xTg-AD mice show cognitive deficits in the Morris water maze at 6 months of age and present visible Aß plaque deposition in the brain at 6 months of age17,18,19,20,21. They are also known to develop Aß plaques more slowly compared with other transgenic mice, making the 3xTg-AD model fit for studying the relationship between AD and the plasma and CSF Aß level alterations before the plaque formation."
http://www.nature.com/articles/srep20185
"Endogenous murine Aß increases amyloid deposition in APP23 but not in APPPS1 transgenic mice.
Endogenous murine amyloid-ß peptide (Aß) is expressed in most Aß precursor protein (APP) transgenic mouse models of Alzheimer's disease but its contribution to ß-amyloidosis remains unclear. We demonstrate ~ 35% increased cerebral Aß load in APP23 transgenic mice compared with age-matched APP23 mice on an App-null background. No such difference was found for the much faster Aß-depositing APPPS1 transgenic mouse model between animals with or without the murine App gene. Nevertheless, both APP23 and APPPS1 mice codeposited murine Aß, and immunoelectron microscopy revealed a tight association of murine Aß with human Aß fibrils. Deposition of murine Aß was considerably less efficient compared with the deposition of human Aß indicating a lower amyloidogenic potential of murine Aß in vivo. The amyloid dyes Pittsburgh Compound-B and pentamer formyl thiophene acetic acid did not differentiate between amyloid deposits consisting of human Aß and deposits of mixed human-murine Aß. Our data demonstrate a differential effect of murine Aß on human Aß deposition in different APP transgenic mice. The mechanistically complex interaction of human and mouse Aß may affect pathogenesis of the models and should be considered when models are used for translational preclinical studies."
http://www.medscape.com/medline/abstract/25911278
re:"It looks like they have had the same issues with share price...4.xx to 12.xx back to the 6's."
Well, not lately anyway. I just have it. Did a lot of DD initially, made an investment decision. Now just glance at it once in a while.
You know, one would think that it would be enough, to do a whole lot of work to find a nice little company with good prospects. Then only to have a bunch of weirdness come out of left field trying to screw everything up as with AVXL. It's rather irksome
"Orveko also said this: "There is a patent application that would protect A2-73 as a monotherapy for the treatment of Alzheimer's, but it has been dormant for years. Maybe there is life in it yet - who knows? "
The application was granted "allowance" which means the PO thinks it should be approved.
In general, by applying, you file a disclosure which means no one else can patent it (well, without challenge) but you don't want the actual patent until you are ready for it (bringing the product to market) since that would cut into the years of protection granted.
On top of that, after FDA approval, you qualify for extension equal to whatever time was lost bringing product to market due to FDA testing requirements.
re:"A lot of parents of children demanded for DMD medicine from SRPT in FDA meeting as there is no alternative medicine."
re: " Well FDA did not listen - they demanded more evidence."
I don't believe that's accurate. So it isn't really a good comparison with AVXL in regard to future FDA approval.
As I recall, the FDA's main objection was that SRPT's approach was to alter the patient's DNA, an irreversible process. Hacking a person's DNA is tricky and not exactly safe. Moreover, they do not repair the code, just in effect, delete the bad part resulting in a truncated protein that is kind-of like the one the cell was supposed to produce, and hope that it is better than nothing. Moreover, the the targetted exon, which might be likened to subroutine data they are skipping over, is only relevent in 13% of the patient population. Also, results so far indicate that the cells seem to be reluctant to produce enough of the new protein, not as much as expected. They may be missing something there. So, the evidence is that it's not a very good solution for DMD and the best that could be said is that it needs more work. Considering the evidence, one would tend to side with the FDA in this instance.
Just to clarify what we are talking about:
"Duchenne Muscular Dystrophy is an X-linked recessive form of muscular dystrophy, affecting around 1 in 3,600 boys, which results in muscle degeneration and premature death. The disorder is caused by a mutation in the gene dystrophin, located on the human X chromosome, which codes for the protein dystrophin"
re:"A lot of parents of children demanded for DMD medicine from SRPT in FDA meeting as there is no alternative medicine. "
fwiw, Actually, there is an apparently largely unknown underdog in p3 trials that imo has a much more promising solution. But it's a long slog, because, after the initial diagnosis, it takes several years for the dibilitating and ultimately fatal symptoms to manifest. It has occupied a small place in my portfolio next to AVXL for some time. I'm not going to mention it by name but if someone does some DD they can find it.
Muscle fibers need to be able to slide over each other when the muscle moves otherwise the stick and can basically tear themselves apart. The kids are initially ok because the cells produce utrophin, a soft more grease-like lubricating substance. After muscle growth is complete, the cells are supposed to switch over to dystrophin, which is a more hard and permanent coating, which could be likened to teflon. With DMD, the dystrophin doesn't happen and because utrophin production has ceased, the existing utrophin wears away, gradually disappears. Then the patient is in trouble.
From the competitor's website:
"Our utrophin modulation approach aims to use small molecule drugs to maintain the production of utrophin to compensate for the absence of dystrophin in DMD patients and so protect healthy muscle function. A significant advantage of utrophin modulation is that it is independent of the underlying genetic fault and therefore has the potential to treat 100% of DMD patients."
Gee, AVXL uses small molecule drugs don't they? Also they don't harm or otherwise irreversably alter the cells DNA or anything like that. Obviously differences, different diseases, but a much better overall approach with much better prospects for success. So thay have that in common.
So far, the company hasn't come under media attack. Maybe the daily volume has been too low with its wide spreads are unattractive for shorting . I don't know, I was a little reluctant to even mention it here. I hope it stays under the radar of being a target for "unusual trading activity" like has occurred with AVXL.
re:"therapy manufactured by Longeveron LLC using stem cells derived from healthy adult donors and
that are delivered into the bloodstream of people with mild Alzheimer’s disease.
At least they're not injecting them into the brain. Still pretty weird though.
re: "Human trial showed that 2-73 and Donepzil give no benefit whilst the mice data said the reverse. "
Current evolutionary science has both humans and mice descending from the same shrew-like creature. In fact, all mammals. How the platypus figures into that I don't recall, further down the evolutionary tree maybe a duck fell in love with a mongoose. Maybe it proves that love conquers all, even interspecies reproductive incompatibilty. Could make for a cute Disney movie. :)
A shrew looks a lot like a mouse to me. There is the classic battle cry: "Are you mice or men?" Well, both, if you go far enough back in ancestry. Mice are popular for research because at a very basic "no frills" biological level, they are very similar to humans. Mainly they're used to establish initial safety. If the mice all die suddenly, that would be unfortuneate, but, well, better them than us, right?
Anyway, weren't the mice specially bred to develop AD? So, what the mouse results prove is that the Aricept (donepezil) component exhibitted synergy with 2-73 against AD that is strictly hereditary in origin. Considering that AD could be triggered by other factors such as infection, the aftermath of infection such as exosomes, or prolonged exposure to currently "acceptable" levels of heavy metals, Aricept's removal of the limiting factor on acetycholine level evidently becomes counter-productive at some point. The mice were in a sterile laboratory environment. That could account for a difference. 2-73 counteracts the effect of some kind of contamination. After 2-73 restores normal cell function, resumption of normal production would likely mean too much acetycholine due to the Aricept. I think I read that Aricept also binds to some receptors along the way. Maybe not the ones we want long term.
A quick 2-73 Plus patent would have been nice but I think they still have a shot at it due to Aricept having some utility at the start of treatment and 2-73 acting synergisically to counter Aricept's side-effects. This would defuse the patent examiner's complaint that they were simply additive. Otherwise, Anavex will qualify for a patent extension for however many years they were delayed in bringing their product to market due to FDA testing requirements.
I'd call that "cutting edge".
re:"...Longeveron stem cells"
Offhand, that's just plain creepy. The only successes I've seen with stem cells has been with pancreas, simple secretion. The results of injecting neural stem cells for spinal injury have been abysmal. The trial results I saw had them keep upping the dose when it didn't work. Finally at 10,000,000 they got a change. Now instead of simple paralysis, the patients were still paralyzed but now also in pain.
It seems obvious that the cells that finally managed to connect, connected to the wrong places. How can they not expect it to be even worse, injecting stem cells into the brain?
I was just kidding before about Frankensteinian injection of hypothetical amyloid eating amoebae, this seems almost as bad, if not equally absurd. brrr.
re: "Four cutting-edge studies will receive $1 million each over 2 years, but the remainder will go to the clinical trial that demonstrates the most promise for treating Alzheimer’s disease."
That should include us (Anavex), but...
Do they even know we exist or, worse, only read AF articles.
The trouble with AD is that it progresses slowly over many years and although biological in origin, incremental changes need to be detected by tedious psychological evaluations. Trials for AD are necessarily going to take a long time. Which is why the other indications shouldn't be ignored since they would have a much shorter predictable path to approval (and market). Epilepsy, for example.
The nice thing about epilepsy... well, there's nothing nice about epilepsy, but the nice thing about epilepsy trials would be that the results would be known quickly. Observing that seizures are gone is pretty straight forward.
It seems pretty clear we have something (good) here with this drug.
In the review, there is also a prior paragraph noting the model is highly predictive.
"Results:
ANAVEX 2-73 exhibited dose-dependent significant anti-convulsive action by providing almost complete to complete protection from tonic seizures in three established seizure models. 30 mg/kg AV2-73 provided between 85% and 90% seizure protection in MES and PTZ models, while 60 mg/kg AV2-73 had also a long-lasting effect with 100 % seizure protection after both 4 and 6 hours in the PTZ model, respectively. AV2-73 and its metabolite demonstrated robust synergistic effect in combination with three drugs currently on the market, Ethosuximide (ETS) (Zarontin®), Valproic acid (VPA) (Depakene®), and Gabapentin (Neurontin®). The combination of 10 mg/kg AV2-73 and 200 mg/kg ETS provided 80% protection in MES-induced convulsions, while no protection at all was observed at the same dose of ETS alone. In the (PTZ)-induced convulsion model, the combination of 10 mg/kg AV2-73 metabolite and 200 mg/kg VPA showed 92% protection from tonic seizures, compared with 12.5% protection when 200 mg/kg VPA was administered on its own. In the MES test, the combination of 5 mg/kg AV2-73 metabolite with 100 mg/kg gabapentin resulted in 90% protection from tonic seizures as compared to 40% protection with 100 mg/kg gabapentin alone.
Conclusions:
AV2-73 demonstrated convincing data in three well-established and predictive preclinical anti-seizure models with potentially more favorable side effect profile than currently marketed epilepsy drugs. The cognitive-enhancing features of AV2-73 might be a differentiating factor since seizures cause neuro-cognitive impairments, which can be worsened by current epilepsy medications.
https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/2321147
Let's not forget a lot of preclinical drug work, milestones met, if you will, on other indications like Rett and Epilepsy which I believe are FDA requirement before allowed in human trials.
re: "Say, Thanks for Understanding :)
And isn't it nice to know both definitions.
Yes I agree some news and communication from the company would be welcome / needed.
It would be nice if they provided some expanded commentary on the poster. For example, the wording of the statement about with/without Aricept is overly brief. Ambiguous. Probably is being misunderstood by many as a negative when it was supposed to be a positive. Data needs context.