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Xena...thx. When this level of contrition is being shown then changes are being taken seriously. Now, these EU entities and the FDA etal will all need to redefine their jobs. The they need to do the famous , "Parking lot exercise". The Parking lot exercise is by far the most painful/destructive process ever visited on any body. But, IMO it is definitely needed, particularly by the FDA.
2014..thx
In other words..."it's complicated".
The RETT trial start up will help when it happens. So, what's the hold up?
As Talon 38 has been trying to tell us this for a long time..BUT..It's complicated.
Read his linked short paper from NE Journal which outlines how life has changed in IND land and Trial land.
http://www.nejm.org/doi/full/10.1056/NEJMra1510062
After you have read this answer a few questions:
1. If you were Dr.M., which trial method/protocol would you select?
2. If you wanted to optimize A2-73 trial quality would you have a larger or smaller population of patients?
3. Considering new knowledge is being developed every day, when is the best time to start? Start now, or wait for more (now due) information which promises to improve likely best outcome?
4. If we can stop in midstream and redirect, should we? Why/why not?
5. Considering this Rett S. trial will likely lead to an entirely new field of CNS medicine WW. Why not start ASAP?
6. Is this the end of biotech boom-bust investing as we know it or is it just the start of an even bigger cycle?
fish56..[quote]Who knew that pioneering a promising new scientific approach to diseases that big pharma has failed and failed again[/quote]
This is the point of course. We all know that change is not fun and we see the consequences in the CNS market and perhaps other areas of medicine. Even positive changes present uncertainty. And we all know what accompanies uncertainty...the "R" word....RISK. RISK is of course simply lack of knowledge or understanding in some context. Example: What would happen if the FDA and their political structure took a position of..."OK...Listen UP...No One starts ANY NEW TRIAL unless they can satisfy the panel that you have done your homework and identified exactly what markers/condition (....)fill in the blank. The FDA has determined that far too many BP products are on the market with serious unintended side effects and they are (or should be) getting our asses kicked by lawyers. ...BUT< BUT< BUT
Yes, we know you all(BP) have large organizations built around our previous 40+ year practice of trial and error but there's a new sheriff in town and he wants REAL PRECISE MEDICINE or you are all going to be sued. (The we demonstrate a few management by EXAMPLE principal)s...which is what we are seeing now. We are seeing the new world of risk averse medicine development which many would say defies the laws of logic. It cannot be done. Maybe, but there it is. IMO, at least AVXL is on the right side of this argument b/c (like the man says) all he is trying to do is restore CNS cellular homeostasis. BUT.... What is going to happen to all the toxic fixes and radiation machines? Who is going to pay all the lawyers and the ad people who write the FDA disclaimers???Ohhhh the humanity. Change happens. AVXL will be on top of the pile shortly, but first the FDA has to figure out what it's REAL job is. BTW, there is NO GOING BACK....stay tuned
Bios, on this point.[quote Perhaps, the way BP has stuck to the Beta Amyloid theory and failed to get better strategic positioning at an earlier stage in this game ][/quote]
Academia points out and I have observed first hand many times that top heavy/engineering/technical organizations tend to be silos. Once the path is set and the structure is established the outside world influence is very heavily filtered by the structure. The people on the inside do not run off with new ideas on alternatives, if they want their jobs. This can be a brutal process for newbies, particularly true when auf Deutsch.
Can you imagine a scientist in and AVXL research meeting suggesting they give the plaque thing a try? The courage shown by M. when he declared Homeostasis to be their strategic choice kinda sealed the envelope on that one. Now, all we have to do is prove it. The other good news is, no one else has even brought it up. Yet.
see bear msg.
Pfizer won't have to pay Biogen royalties for a competing multiple sclerosis drug after a court invalidated a patent.
T...Yep,
I have also read these reports. I consider that these BP powerhouses have been doing hard work decades. Whole lab staffs have been built, huge investments. Suddenly, WW they all decide in a narrow window to drop it all and JUST WALK AWAY in a matter of weeks. No explanation. They should have each individually concluded the same thing over a period of time and I might agree. The plaque thing has been a farce for years, according to the data and they kept going. In fact BIIB still did not get the memo.
The only reason I even care is it raises the question on what else we do not know? Where the hell is this Motley fool dude who attacks at the drop of a hat? What about all the patients, who told them or their care givers? Do they stop giving meds? Why the silence? Surely this is a learning opportunity, AT LEAST.
Nothing personal here but my instincts are telling me there is a lot more to this, one way or another. These moves are even potentially good news to AVXL and yet we see no corresponding changes. These BP who just stopped are tough, smart people. They do not just quit anything. What was it that guy wrote about the trees moving and Ides of March?
NP...you're good.
NO, she didn't REALLY say that, did she?
Thanks...I selected the examples below as some I thought would qualify as RWE. Just a guess.
Fig.8 Is a chart of Anavex 2-73 improving components of cogstate tasks.
ANAVEX 2-73 treatment demonstrates reduction in overall Hamilton Depression Rating Scale (HAM-D) after 31 weeks. Over 31 weeks of treatment, ANAVEX 2-73 was associated with a sustained benefit in psychomotor function, attention and working memory. The specificity and consistency of these benefits establsh that ANAVEX 2-73 sustains activation of attentionaJ and working memory functions with repeated dosing in Alzheimer's disease.
Table 3 and Fig.9 presents EEG/ERP data that ANAVEX 2-73 Rescues
Cognitive Effects on a Cellular Level on the subjects of the Phase 2a study.
ANAVEX 2-73 effect on synaptic networks and effect on cognition and behavior at daJy doses of 10mg-50mg is shown. ERP peak measures (P300) are shown. The P300 (P3) wave IB an event related potential (ERP) component elicited in the process of decision making. It Is considered to be an endogenous potential, as its occurrence inks not to the physical attributes of a stimulus, but to a person's reaction to it More specifically, the P300 is thought to reflect processes Involved in stimulus evaluation or categorization. ERP target detection task is a direct measure of attention, speed of brain, processing, and simple behavioral performance. Psychometric measures (Cogstate) cognitive measures: Detection: processing speed (psychomotor function),
Identification: reaction time (attention), One Bade working memory (cognition), One Card Learning: visual learning (visual memory), ISLT: verbal learning, ISLT-delay:
verbal memory. Psychometric measures (MMSE): cognitive measures.
Behavioral measures (ADCS-ADL): behavioral measures. Notably, Rg.9 shows that all tested areas exhibited i improvement at 5 weeks as compared with the starling baseline (hence, absent expected decline).
Oral daily doses of ANAVEX 2-73 ranging from 10mg to 50mg exhibit a converging and consistent response for all measurements (MMSE, ADCS-ADL, CogstHto, EEG/ERP) throughout 31 weeks (7 months) of ANAVEX 2-73 treatment Patient retention rate at week 31 was 84%. Treatment of ANAVEX 2-73 and related drugs demonstrates reduction in overall HAM-D score after 31 weeks, notably through reductions in insomnia, anxiety and agitation. Seventeen week data as well as 31 week data of all available patients derranstrate that ANAVEX 2-73 preserves average MMSE and ADCS-ADL scores across the entire patient group. In a dsease state where progression is invariable over time, a stable MMSE and ADCS-ADL score is considered a positive outcome. When the group is tentatively stratified into mild to moderate and MCI (mfld cognitive impaired) AD patients, no significant difference was observed within the MMSE or the ADCS-ADL score, respectiveiy. Likewise, when tentatively stratified between ANAVEX 2-73 alone and ANAVEX 2-73 PLUS donepezfl administration, no significant difference was observed within the MMSE or the ADCS-ADL score, respectiveiy. For cognitive assessment using the Cogstate test batteries, ANAVEX 2-73 continues to show benefits over baseline at 17 weeks and 31 weeks. ANAVEX 2-73 related improvement in psychomotor function, attention and working memory are preserved through 17 weeks and 31 weeks of treatment Repeated-measures ANOVA reveals that Cogstate values maintained the baseline values through week 31.
An additional benefit of the therapeutic regimen disclosed herein is the beneficial control of systolic blood pressure in AD subjects taking daily oral dosages of A2-73 of from about 10mg to about 50mg. Systolic blood pressure was monitored over the first 25 days of dosing. A1-41 and A19-144 are similarly useful therapeutics.
Table 3 shows that A2-73 therapy significantly reduced systolic blood pressure in hypertensive subjects with greater reduction for increasingly hypertensive subjects.
And further surprisingly, systolic blood pressure rose is subjects that exhibited high- normal systolic blood pressure.
EXAMPLE 1
Maintenance Insomnia Therapy
A 48 year old female presents as suffering from maintenance insomnia for one year. She Is started on oral A2-73 at 10 mg/day. Follow up at 30 days of dairy dosing reveals she is sleeping well. She is currently maintained on 10 mg of A2-73 and is sleeping weil.
EXAMPLE 2
Anxiety Therapy
A 51 year old female presents with anxiety of three years' duration. She is administered A2-73 at 20 mg oral per day every other day. Resolution of the anxiety is noted after two days of dosing. She is maintained on this dosing schedule for 60 days.
EXAMPLE 3
Agitation Theraov
The patient is a 29-y8r-o(d male exhibiting agitation. He is treated with 30 mg A2-73 oral daily for 30 days. Clinical evaluation reveals normal affect without agitation, depression, anxiety, or substance use. He Is currently maintained at that dosage and is not anxious.
EXAMPLE 4
Maintenance Insomnia Therapy
A 68 year old female presents with MCI and reports maintenance insomnia for one year. She is started on oral A 1-41 at 10 mg/day. Follow up at 30 days of dafly dosing reveals she is sleeping well. She is currently maintained on 10 mg of A1-41 and is sleeping well.
EXAMPLE 5
Anxiety Therapy
The patient is a 52 year old female with diagnosed AD and reported anxiety of three years' duration. She is administered ?1T-144 at 20 mg oral per day every day for 90 day8. Resolution of the anxiety is noted after two days of dosing. She is chronicaly maintained on this dosing schedule.
EXAMPLE 6
Maintenance Insomnia Therapy In MIC
A 66 year old male diagnosed with mild cognitive impairment presents as suffering from maintenance insomnia for one year. He is started on oral A2-73 at 50 mg/day. FoBow up at 30 days of daily dosing reveals he is sleeping well. Ho is currently maintained on 50 mg of A2-73 daily and is sleeping well.
EXAMPLE 7
Maintenance Insomnia Therapy in Alzheimer's Disease Related Insomnia and
Agitation
A 72 year old male diagnosed with Alzheimer's disease presents with
insomnia/WASO and agitation and a systolic blood pressure of 145 mm Hg. He is started on oral A2-73 at 30 mg/day. Follow up at 30 days of daily dosing reveals he is sleeping well through the night and not waking up repeatedly and Ms systolic BP is 129. He is also less agitated. His results on afl cognitive tests and HAM-D improve. He is currently maintained on 30 mg of A2-73 daily.
EXAMPLE 8
Maintenance Insomnia Therapy in Alzheimer's Disease Insomnia and
Agitation
A 72 year oid male diagnosed with Alzheimer's disease presents with
insomnia/WASO and agitation. He is started on oral A2-73 at 100 mg/day. Follow up at 30 days of daily dosing reveals he is sleeping well through the night and not waking up repeatedly. He is also less agitated, His results on all cognittve tests and HAM-D improve. He is currently maintained on 100 mg of A2-73 every other day.
EXAMPLE S
Maintenance Insomnia Therapy in Aizhflimer's Disease Related Insomnia and
Agitation
A 77 year oid male diagnosed with Alzheimer's disease presents with
insomnia/WASO and agitation. He is started on oral A19-144 at 50 mg/day. Foflow up at 30 days of daily dosing reveals he is sleeping well through the night and not waking up repeatedy. He is also less agitated. His resulte on all cognitive tests and HAM-D improve. He is currently maintained on 50 mg of A19-144 daily.
EXAMPLE 10
Malntenanca Insomnia Therapy in Alzheimer's Disease Related Insomnia and
Agitation
A 77 year old male diagnosed with Alzheimer's disease presents with
insomnia/WASO and agitation. He is started on oral A1-41 at 30 rnp/day. Foflow up at 60 days of daily dosing reveals he is sleeping well through the night and not waking up repeatedy. He is also less agitated. Hie results on all cognitive tests and HAM-D improve. He is currently maintained on 30 mg of A1 -41 daily.
The pharmacologicaly active compositions of this invention can be processed in accordance with conventional methods of Gaenlic pharmacy to produce medicinal agents for administration to subjects, e.g., mammals including humans.
The compositions of this irivention individually or in combination are employed in admixture with conventional exdpients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral {e.g., oral or inhalation) or topical application which do not deleterfously react with the active compositions.
Suitable pharmaceutical ty acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arable vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, caibotiydrates such as lactose, amylase or starch, magnesium stearate, talc, titanium dioxide, sKdc add, viscous paraffin, perfume oil, fatty acid esters, hydroxy methytcellulose, polyvinyl pyrroiidone, etc. The pharmaceutical preparations can be sterlHzed and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the Ike which do not aeleteriously react with the active compositions. They can also be combined where desired with other active agents, e.g., vitamins.
In some embodiments of the present invention, dosage forms include instructions for the use of such compositions.
For parenteral application, particularly suitable are Injectable, sterile solutions, preferably oily or aqueous solutions, as wefl as suspensions, emulsions, or implants, including suppositories. Ampules, vials, and Injector cartridges are convenient unit
You missed this one...
[quoteChristopher Missling knows exactly how to dismantle them. ][/quote]
YUP, he has a good eye for the weaknesses in this system. There's an Grimm's tale about ,"Brother Rabbit", that comes to mind. If we are right, it's brilliant and it will not cost him a dime. In fact, if BP are VERY smart they are lining up to buy AVXL before the ambulance chasers show up.
If being toxic or not is an open question then it must be answered. A2-73 would seem to be better than the known brain swelling, etc of alternatives already in use. If my guess is right about why BP pulled out then BP has a lot of splainen to do...maybe in many other areas. When the FDA rewrote the process they effectively pulled the legs out from continuing trials, IMO. Not exactly a level playing field but it at least reshuffles the deck.
Greenspam..pls send link...is this a pub?
will it ASO be effective???Let's see. But, as far as we know it is at least not toxic. Lets ASO =ALSO
All..
Agreed, the BP AD trial shutdowns just strikes me as a very significant event from a research standpoint, which someone needs to explain. The point is that during the virtually simultaneous shut down by the biggest Pharma companies on the planet for a CNS disease that is devastating the country....no one has the stones to explain their actions. There is a message on competence there but I am not sure what it is yet. They have just said..."Never Mind"... HUH?.
We would probably agree that the AD learning process is continuing even as the A2-73 precision medicine trials are started for RS. I was surprised that BP seem to have cleared the field on AD, such things do not happen on a whim. We may never know why they all dropped respective trials at the same time. I d believe they had discussions w/FDA first. I have done work w/Pfizer in the way past and agree they are serious-smart people, clearly there is a sense of change about. We shall see.
Let's hope/pray for the RS patients. I have granddaughters in that age group and cannot imagine how these families must suffer daily.
Talon,
Thx. Very interesting. Data interpretation and controls are key.
Investor suggests a qood point on WW trial sites v belief.