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Parkinsons: any combo drugs possibilities?
Anyone familiar enough with Parkinsons to know what the drug landscape is in Parkinsons, and will they be testing 274 in combination, for synergy, with SOC Parkinsons drugs, in the just started MJFF preclinical trials for Parkinsons?
LPC is plan B, Plan A is partnership deal with a very nice upfront payment making Plan B unnecessary.
Missling has an MBA and is also a finance brain ... do not be tricked into worry about dilution IMO..
maybe you can see now why there adaptive trial is very smart....and gathering information quickly is also smart..
"BTW; since Phase 2A Part A had such excellent results in non steady state AND non-optimized dosage, it makes sense that part of what they are testing for in the remaining Phase 2/3 is Population Pharmacokinetics/Pharmacodynamics so that they can in fact determine ideal dosage. This could very well increase the efficacy we have seen. As they state in their PR, one of the reasons to do so is to enter Phase 3 with optimal dosing to reduce/eliminate dosing as a cause of Phase 3 failure. Clearly the FDA is guiding them in how best to do so."
Marky YMB
DATA ACDS-ADL data -- not understood by market yet IMO .. to the extent of
how important and "meaningful" this data is ....
"As noted in umpteen posts I've made, donepezil has proven both that placebo AND donepezil have shown statistical significance (proven in clinical treatment/disease parlance) to result in DECLINE from baseline in patient ACDS-ADL scores. So in fact has RVT-101, and the FDA has determined themselves that a) whatever minor lessening of the decline DZP provides it is insignificant to patients actual Activities of Daily Living (walking, feeding, continence, dressing, etc) over time AND that regardless it only results in decline, not improvement from baseline.
Much was made of the fact that Avanex's (IMHO groundbreaking) results in IMPROVING 11 of 14 patients was not *statistically significant* since it was not observed vs placebo groups. Clearly the next step is more patients over more time vs controls including dpz and control BUT the odds of this occuring as I've pointed out are TRILLIONS to one.
I've pointed out that both DPZ and RVT have done large-scale and long-term studies vs placebo (and one another) giving us a great data set of placebo i.e. untreated patients who believe they may be being treated as a comparative data-set.
Other HUGE datasets have proven that ADL scores decline over time for dementia patients. Feel free to review ncbiDOTnlmDOTnihDOTgov/pmc/articles/PMC1522014/ which was done on a cross-section of 66,742 patients across the US. (n ~ 6,000).
"a mean decline in ADL off 1.78 and 1.70"
"change of 1 point in denotes a clinically meaningful change..defined.. as a change in the abilities of an individual, but also a change in the cost of their care"
Despite the mean decline, 10% of patients showed some improvement. Avanex showed mean INCREASE o over THREE points and *80% * improvement.
FDA study for 'Memantine', 252 vs 84 placebo MINUS 4 vs MINUS 9 placebo
The placebo ACDS-ADL regression results are HUGELY stat sig, every drug tested ditto. 12 weeks might not be enough to "prove" but 3 point mean and 80% patients is HUGE Less
and to clarify:
"change of 1 point in denotes a clinically meaningful change..defined.. as a change in the abilities of an individual, but also a change in the cost of their care"
Avanex showed increase in over THREE points. And again this is an increase from BASELINE i.e. from when the drug was administered to the patient. In twelve weeks. When ONE point is defined as meaningful and a change in abilities and cost of their care. If this highly unlikely results on 14 patients carries through to 26 weeks and on more patients, this will be life changing hope for Alzheimers patients that doesn't exist. Think this scares some people? I do."
they have to make it look like they are trying to help the retail shorts they suckered into this..
"There may be multiple binding sites because donepezil displacing all the 2-73 at S1R and effectively inactive M1 would not explain preclinical data suggesting synergy between DZP and 2-73 http://goo.gl/lBZGvZ
There is more to the story here. I do not claim to know the full story yet, just that there is more."
OFP on SA questioning Kline's post today... BTW if you did not notice he is the same poster who questioned Whiskeysausage on his SA blog and asked about p300 latency...he is credible imo and does not take sides (he says what he thinks period)....furthermore, he is very knowledgable on all sigma 1r drugs and companies in space..IMO he is up there with MEH76 on science, but does not show his cards, so is less obviouus....and way less patient..
One last comment on Dr. Kline, and this is more of a question, but do you think he is the one that writes any of his comments? or does he just ok the externally prepared messages, , to go out on his name? ...It almosts seems like he was picked for his unique characteristics, someone who does not need to worry about his medical reputation (since left the practise), lives far away out of the country and so can not be contacted easily...I am not sure the answers here, but sometimes when things look too convenient and the pattern is there, it raises questions...
Dr.(10 years ago, IT now) Kline's molecular bio logic flawed:
On SA a counter to Dr. (10 years ago, IT now) Kline logic is as follows:
"The binding affinity of Anavex 2-73 was performed against "human" s1 receptor, which as conducted by CEREP (Paris,France).
Whereas the high binding affinity of donepezil to sigma-1 receptors ((IC50= 29.1 ± 0.2 nM) was performed on "mouse" brain membranes.
I do not think they can be compared."
An additional thought is it defies logic, why top practising scientists (who are specialists in AD now not juniors 10 years ago) would suggest to use DPZ, as a control Placebo arm, as they have suggested for next P2/3 trials, if DPZ crowds out 273 effects, as his innuendo filled post today said.... this is more of the uncle JC teachings, to his minions, of creating a "new truth" here ... they are very predictable..
Dr. (10 years ago, IT now) Kline's proven suspicious history supporting the cartel in social media, is a further red flag on anything he says....
They realized they failed in creating a "new truth" around AVXL (as the science is too strong) ....so to flush retail the only tool they have is market price manipulation: namely sell into good sentiment, set up short and longer FADES all backed with naked shorting from offshore, ...in an attempt to crack the positive sentiment around AVXL and flush retail out.....
anonymous offshore accounts naked shorting for cartel:
Underlying value is not in question...
If AVXL is not already close to having a partner in the bag, I would be thinking outside of the box right now, if I were them (some possibilities):
-take the company off the NASDAQ (back to OTC or even Toronto);
-take the company private themselves (before a hostile attempt) ;
-look for foreign partners (if no local BP has come forward as it may indicate that the cartel is interfering with their NA partnering);
Personally I would rather be a part of AVXL as a private company or on a different exchange at minimum...
yes and they also trick some sucker retail shorts (that like to follow them) to jump in also to add to selling, and then add to that if AXON want to do a hostile take over they likely have money in off shore bank accounts to support naked shorting, from anonymous accounts, when needed (like when they are loosing sentiment to their side)...
you forgot how complex AD is and how complex the interrelation of the different receptor actions is with a new drug like 273, thats why information gathering quickly (i.e. an open adaptive trial) was used .... nice try though..
by manipulating price fades, they try to frustrate investors (distract from the good news of science) and cause investors to sell, ...fades are created by cartel by using naked shorting...its all an illusion of what true value is , and well practised by them to steal shares from retail...
Cartel simple sell into time of positive sentiment...
just like the did with the great news pr after nov 7
Dr Maurice , world expert on sigma one, positively mentions AVXL pipeline drugs 141 and 371...This coming from a man who is very cautious with words and involved in preclinical work, is very promising. I am familiar with 371 but have the is the first time I have heard 141 mentioned up front with the other lead drugs..
wildcard on YMB said Parkinson preclinical trials have started....
The risk with this manipulation down,as far as BP, is the same as the Avanir story, 6 months ago....the cartel will put a very promising bio company in foreign hands... Why did Avanir go foreign? I believe because the cartel muddied the waters with local BP...Unless a local BP is smart and does not follow the manipulation trail....The manipulation down may be a gamble that no BP steps up, and Axon can buy on the cheap...its a very risky gamble since many other suitors interested in AD, white knights, can come forward both foreign and domestic, and scoop it up from them...our SAB are all international scientists, so they have the connections... Besides AXON , Teva is another pharma name I think could be involved...
The data results IMO are much better than the doctors at AVXL and bullish writers are revealing, partly because they have been subject to massive pavlovian conditioning buy the negative side..and in the doctors side just possibly being cautious and under promising on purpose..... A poster who has been very busy on YMB today discussing the data goes by markyhwh , and he although not a scientist, shows a remarkable understanding of the data presented recently and its significance...I would suggest anyone who want to look deeper into the importance of the recent data go to YMB, and click on his name to read all his recent posts on AVXL....
cartel trying to take positive sentiment away from longs .......this is why they are selling at end of day. It shows desperation and that they know they are loosing in the battle for sentiment...and further that they are very weak in the media now (usually their strong point) , having had all of their arguments proven as baseless and highly misleading...leaving them only to price manipulation tactics to try to counter back...do not let your positive sentiment be weakened by slime ball tactics..remember price means nothing in relation to value when a cartel sells the market down in this way....its a trick...
when you have lost the battle of facts, to critisize a company ...price manipulation is all thats left in your tool box, to manipulate price....
Dumb money selling ....naked shorts..they lost control of the media (and sentiment) and so had to resort to selling into the market to try to get back in control... This is not smart money selling here .... Think of it like a smaller version of the manipulation after the pr on nov 7th, to counter that good news(which was also powered by naked shorting) , well today is the same thing where they sell into the good news (or sentiment) to try to reverse sentiment.....its all manipulation and they are so easy to read...this is not smart money selling...
Thats what you do when there is too much irrefutable good news coming out ....just sell it down ...even a dummy can do it as its is brain simple...sell it down and try to make the positive news flow go quiet...not likely..
"More on just how "meaningless' Avanex ACDS-ADL scores were:
As noted in umpteen posts I've made, donepezil has proven both that placebo AND donepezil have shown statistical significance (proven in clinical treatment/disease parlance) to result in DECLINE from baseline in patient ACDS-ADL scores. So in fact has RVT-101, and the FDA has determined themselves that a) whatever minor lessening of the decline DZP provides it is insignificant to patients actual Activities of Daily Living (walking, feeding, continence, dressing, etc) over time AND that regardless it only results in decline, not improvement from baseline.
Much was made of the fact that Avanex's (IMHO groundbreaking) results in IMPROVING 11 of 14 patients was not *statistically significant* since it was not observed vs placebo groups. Clearly the next step is more patients over more time vs controls including dpz and control BUT the odds of this occuring as I've pointed out are TRILLIONS to one.
I've pointed out that both DPZ and RVT have done large-scale and long-term studies vs placebo (and one another) giving us a great data set of placebo i.e. untreated patients who believe they may be being treated as a comparative data-set.
Other HUGE datasets have proven that ADL scores decline over time for dementia patients. Feel free to review ncbiDOTnlmDOTnihDOTgov/pmc/articles/PMC1522014/ which was done on a cross-section of 66,742 patients across the US. (n ~ 6,000).
"a mean decline in ADL off 1.78 and 1.70"
"change of 1 point in denotes a clinically meaningful change..defined.. as a change in the abilities of an individual, but also a change in the cost of their care"
Despite the mean decline, 10% of patients showed some improvement. Avanex showed mean INCREASE o over THREE points and *80% * improvement.
FDA study for 'Memantine', 252 vs 84 placebo MINUS 4 vs MINUS 9 placebo
The placebo ACDS-ADL regression results are HUGELY stat sig, every drug tested ditto. 12 weeks might not be enough to "prove" but 3 point mean and 80% patients is HUGE Less
and to clarify:
"change of 1 point in denotes a clinically meaningful change..defined.. as a change in the abilities of an individual, but also a change in the cost of their care"
Avanex showed increase in over THREE points. And again this is an increase from BASELINE i.e. from when the drug was administered to the patient. In twelve weeks. When ONE point is defined as meaningful and a change in abilities and cost of their care. If this highly unlikely results on 14 patients carries through to 26 weeks and on more patients, this will be life changing hope for Alzheimers patients that doesn't exist. Think this scares some people? I do."
great DD and analysis from YMB today..
so easy to see price is being manipulated...let it pop a bit to reflect sentiment and then slow day fade it back to a close in the red, to join up with the longer term manipulated fade (9 days) ....however after pointing this out they may do something different but the point is they are so easy to read in the SP manipulation... naked shorts, fades, cartel reputations and bash pieces (and in that order) are the bread and butter of the manipulators...
Dr. Maurice adds weight to preclinical rodent studies:
I liked how Dr. Maurice was so very cautious with his words...adds a lot of credibility to him....Having been given this impression , from his interview, now I have more confidence in AVXL preclinical work....as he was responsible for most of those studies... and he just talked about how positive they were in the interview....
Basically, A2-73's agonism of sigma-1 and M1 receptors may work to alter the progression of AD, while its antagonism of the M2 and M3 receptors may work to improve the affects of donepezil on the symptoms of the disease.
Tauhydrae talking on a non-avxl board a few days ago:
"The FDA has been recommending adaptive trial designs as a way to cut cost and speed up new drug development. Safety and a tolerability were primary endpoints, and maybe bio-availability. Efficacy was a secondary endpoint as proof-of-concept. Powering a trial with hundreds or thousands of patients would be time-consuming to recruit patients and be very expensive, especially if no efficacy was found. So it's a small Phase 2a trial to quickly determine how many patients would be needed for a Phase 2b or Phase 3 trial to prove statistical significance. Perhaps also the data would be examined by the FDA to determine whether some form of accelerated approval is warranted or what would be needed next to get that.
What's interested me about the trial is they did the Mini Mental State Examination (MMSE), event-related potentials (ERP) and P300 tests, and Cogstate battery and found improvements on all tests and for every dosage of A2-73. I find that remarkable.
Professor Paul Maruff (CSO of Cogstate) said “The Cogstate tests measure people's ability to store and use information. The results of the Phase 2a study demonstrate that ANAVEX 2-73 improves psychomotor function, attention and working memory. For attention and working memory these improvements were statistically significant with a p-value of p."
I was thinking of something similar:
--a campain to raise funding to sue AF , JDallas etc, from shareholders, and
--another campaign for trials but funded by AD patients and families where they would receive medicine as dividends....
I think possibly several million at least could be raised but more importantly it would get huge publicity ---- and this is punch back for the cartel which uses strong media abilities in its attaches which hurt patients....and make it a public battle pf patients against the lifeless ones attaching...
maybe dr. V will invite long term shareholders that have held, on a holiday to Greece all expenses paid...
Yes correct....
1-the deal with Dr. V was done at a time before the knowledge and interest in Sigma 1 receptor agonist recearch was any where near what it is today...and;
2- Dr. V gets a 6% royalty from profits.
Now do not think this is insignificant, if you are a doctor that believes in the science and is mainly interested in seeing your molecule advanced through trials, a royalty is better than up front cash... First of all, the margins for this drug will be huge... maybe 90% ish...and so even though the royalty is on profits it will still be a huge royalty....maybe equal to 4% of revenue!!!!!
Second, with the size of the AD, and dementia markets, what could this work out to for Dr. V. In my best case estimation, if it is SOC and 4X better than the current SOC, do the numbers..whats 4% of 20 Billion rev worth?...
AF crew taught by Crammer -> make "new truth"
So is the AF crew using this foundation taught by Crammer? and What is the "New Truth" as they have used it in this attach against a treatment for millions of sick with AVXL? Well New Truth is just a way of saying fabrication, deception and lies,....but the principle is stick to your story (the "new truth")... That is why they do not talk the science..it is not part of their very simple story, the "real truth", just like uncle JC taught them, instead they keep on and on about their "new truth" and coming from many different angles.... AF says meaningless data...JDallas says scam ...but both target their new fabricated story...just like uncle JC taught them, and told them to never talk about the truth, that they will use their massive media power to blitz the investor community with ...over and over again..and drive this "new truth" into them.....
my thoughts also....some are more inclined than others to NSS to get good prices ..... Teva scares me the most...they make the generic....
Besides Europe (the biggest sales in-licence opportunity) the following marketing in-licence deals are also available to fund operations and P3 trials , without dilution, Japan might be interesting because of its aging population and huge healthcare costs caring for elderly) and Otsuka might be interested in a simple home country marketing deal:
-Japan
-Asia (non-japan)
-other common wealth countries (UK,Aus,CAD)
-Latin America
Note with in-licencing deals AVXL is still the operator of world wide manufacturing and controls all rights, all that is sold is distributor rights for specific areas, which are need anyways.
European marketing rights alone -> fund P3:
I would not be the least bit surprised if a foreign financier (Financial or BP) steps forward and funds P3 with a in-licencing deal for Europe...easily worth 40 million... and this would mean zero dilution and said company gets European rights only... European rights may be of similar value to USA rights, in market size.... and likely less risk...Missling knows what the company is worth, and shady cartel manipulation of share price will not forse him into a substandard partnership deal ...not with the front runner drug for the biggest open market in the world.... USA based BP better be smart and know this is not the typical cartel scam bash and see the underlying fundamentals or risk being left standing still like they were in HEP C, or even in the Avanir case this year.... European marketing rights alone should easily fund phase 3 ...so wake up BP... and do not let the cartel working lead you to poor decisions...
Wall Street manipulators may end up eating crow:
This might even include BP, if BP does not wise up to the ramifications of them being in bed with the same folks... Firstly, I would not be the least bit surprised if a foreign financier (Financial or BP) steps forward and funds P3 with a in-licencing deal for Europe...easily worth 40 million... and this would mean zero dilution and said company gets European rights only... Missling knows what the company is worth, and shady cartel manipulation of share price will not gorse him into a substandard deal ...not with the front runner drug for the biggest open market in the world.... BP better be smart and know this is not the typical cartel scam bash and see the underlying fundamentals or risk being left standing still like they were in HEP C, or even in the Avanir case this year.... European marketing rights alone should easily fund phase 3 ...so wake up BP...
Comments on social media aspects:
Social media was a big part of the price take down as we have generally discussed but if you look at it closer i think there is a bit more strategy involved... The usage of twitter, Facebook, and stock twits MB, and other SM are used by a much younger demographic... Stock market psychology is not rocket science , but wisdom and experience (not to be confused with intelligence) , is an absolute necessity in the foundation of a psychological defense against many of the typical bashing and fear mongering attempts at creating panic selling.. Unfortunately the younger will be intelligent but not wise and experienced... It is shameful of the cartel to prey on this weakness of the young... This is why when they did the big price take down they did the social media blitz first since youth would be easier to target with the many straw man , red herring, guilt by association false arguments and get the selling starlings....Then the older wiser investors would react to the quickly dropping stock price, started initially with the social media blitz... It is kinda of ironic that stock twits got up and running for the cartel just in time to help in this process as it is also the younger set and connected to the social media blitz....Also troublesome is that the youth will be more inclined to now believe in the likes of JF , AF, DW, AXON CEO etc... and now respect them even more as excellent forecasters of stock prices so as it becomes a powerful self fulfilling prophesy for the next attach... So is summary they manipulate youth through social media with ease and indirectly other segments of the market, as follow on, through momentum in market actions....a very dangerous tool that they have at their disposal IMO...
Negotiations with Partner like this now maybe:
AVXL: we ask for $250 mill upfront and fully paid P2B/3 for 75us/25u split
BP: wait a minute we have to call out Bank (but instead then they call the cartel and say: ok short their stock down 10% more).
BP: we'll give you 200 M up front, pay next trial but want 50% ..... and BTW did u notice how weak your stock price is now, in fact it just dropped 10%?
AVXL: we are firm on the 75/25 but can move on the upfront if u pay trials,and yes that is odd that our stock price has been dropping just now...
When a partnership is announced soon (IMO) we will know also who is partly to blame for this short attach... IMO the attach is not only an attempt at short term gain by WS crooks, but also coordinated with an attempt to get more favourable partnership terms by certain BP... ...All my opinion, and we should see soon...