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Again, Rett Results Will Be Hard To Confine
Interesting the note in a posting below that girls being selected for the Rett trial have to display sufficient numbers of daily seizures to be enrolled.
That clearly reveals that seizure control or suppression is the target outcome of Anavex 2-73 in the upcoming 3-month trial.
Now, just how difficult will it be to quantify a reduction in seizure events in the girls in the study? Will blood have to be drawn and analyzed? Will electrodes have to be stuck on the girls and electromagnetic activity of the brain digitally charted and analyzed? Perhaps.
But, in fact, the mothers of every one of those little ladies will know in a day or two when, simply, their little girls lived a day or two without seizures. Useful assessment of Anavex 2-73 efficacy in seizure reduction in girls with Rett syndrome genomes will be rendered by motherly perceptions of the well-being status of their girls. Mothers know.
I'm not aware of the typical frequencies of seizures in Rett syndrome girls. But let's say it's once a day. How, then, will mothers react when they notice, say, in the fourth week of the trial, their girls went 7 days without a seizure? Will they think (as some here would), "Well, that's interesting. But who knows? Can't be that drug Little Susie is taking. Must be just chance. I'll keep quiet about this and won't say a thing until the trial is over. What could I know? I'm not a doctor."
No, Susie's mother will be telling all her friends that the drug is actually starting to work, that her girl now has the chance to live a normal life.
At that point, will anyone knowing of this post a message here, telling the whole world?
Let's see.
Market Populations Not Clinical Trials People
Picking, Using Only Favorable Clinical Participants
Do not presume the variable results of the Phase 1 / 2 Australian trial will be those of the big Phase 3 clinical study.
The two studies are not parallel, by any means. Offhand, it could be presumed (as many here do) that the new Alzheimer’s trial will be simply a bigger one, with a much larger n=, number of participants. With that (were it the only thing to consider), statistical significance of any of the measured outcomes will not be in question — as they are with the Australian study.
That study yielded a variety of results; most of which trended very favorably. Cognition was either maintained, or, for some, actually enhanced, improved.
So, were those data merely a result of happenstance, where by chance a good number of people were favorable responders to the drug; or were there just by chance people who would keep or improve their cognition regardless? Chance, or direct cause?
Did Anavex 2-73 cause any or all of the favorable outcomes; or, was it only by chance, with no real cause/effect connections? Since the number of participants was small (32?), many (here) will argue the by-chance causation, not an authentic, unique efficacy of Anavex 2-73 against mid- to mild-stage Alzheimer’s disease.
Now here’s the big thing; where the upcoming big n= Phase 3 will be utterly different. The difference will not be merely size, number of participants (200?). Rather, it’s not how many in the trail, but who.
Anavex Life Sciences Corp has engaged firms who have precisely and minutely detected any number of personal variables that affected favorability to positive Anavex 2-73 outcomes. This time, before any trial participant is administered her first Anavex 2-73 tablet, Anavex has a high-probability understanding how each individual will respond.
As per the new FDA drug testing protocols, (precision medicine), Anavex is going to be highly discriminatory. To participate, one must have more than diagnosed Alzheimer’s disease. The person must also have genetic, metabolic, or other detected traits that assure the highest, best response to Anavex 2-73.
In fact, it may be only 25% of the general Alzheimer’s population with high levels of Anavex 2-73 response. Those will be the people allowed to participate. People with traits negating or suppressing a strong response to our drug will not be allowed to participate. Again, profound discrimination; stacking the deck in Anavex’s favor.
And, creating the best chances for eventual FDA approval. Remember, again, to gain approval Anavex merely needs to show equivalent safety and better efficacy of any of the existing four Alzheimer’s drugs. The safety profile, from the Australian study, is exceptionally strong. It should be replicated in the new study. All four of the existing drugs merely slow symptomatic progression, and only for short to moderate periods. If only the best responders in the Australian study are the types allowed in the Phase 3 study, Anavex 2-73 approval is unquestioned. Poor responders won’t be in this trial. Strong responder data sets will greatly exceed those of the existing drugs.
Because of precise analysis of the Australian data, and because of new FDA drug testing rules allowing or encouraging precision medicine (matching specific drugs with particularly favorable populations) Anavex will have just the best patients to prove both the safety and profound efficacies of Anavex 2-73 against mid- to mild-level Alzheimer’s patients.
More Than Gut pH
It's the Thalidomide Regs, Not Thalidomide Itself
Of course, few women who might take Anavex 2-73 to treat Alzheimer's will be carrying a child. But some Alzheimer's patients exhibit early, prodromal indications in the forties --- when women do carry babies.
But that's not my contention. It's that the restrictive regulations that prevent some FDA official to simply call up Anavex and tell them to start selling the drug came about because of thalidomide.
Sorry, like it or not (in this case, because of all of what is positively known about our drug, I don't like it), NO WAY AROUND IT.
All the posts (including mine) telling how good and appropriate it would be for prompt FDA approval of Anavex 2-73 are folly. We are screaming into the distant wind. No one will hear us, or if they would (happen to see our postings), they'd just chuckle and click off.
Preliminary approval without trials comporting to new regs is ILLEGAL.
End of story. Laws still control the matter.
It Was Thalidomide; No Apples Nor Oranges
You apparently did not read my earlier post on this matter. Here, I’ll summarize it.
In 1957 a German drug company began selling a new drug whose active ingredient was thalidomide. It was sold as a new, putatively effective sedative. European physicians began prescribing it, and it was soon found to have an additional application. It very nicely stopped the morning sickness of pregnant women.
The company wanted then to sell the drug in the US, so they had to submit to the FDA safety and efficacy data. At the time, both in Europe and the US safety and efficacy testing was solely the duty and purview of the drug manufacturer, not the government.
But an FDA official examined the safety data provided by the drug company, and she determined that it was inadequate. She personally prohibited the sale of the drug here. Soon after, the deformed babies the drug caused in Europe became known, and it was prohibited globally. (Yes, it is now used, carefully, in non-pregnant women, as a cancer treatment — after proper clinical studies.)
The woman who prohibited thalidomide in the US, Frances Oldham Kelsey, received a number of national awards for her diligence. As a consequence of the thalidomide affair, the Kefauver Harris Amendment or "Drug Efficacy Amendment" was passed by Congress in 1962, establishing the FDA’s requirements and monitoring of pre-clinical drug safety and efficacy tests.
Those rules are under revision and will soon be announced by the FDA, allowing Anavex Life Sciences Corp to proceed with new, detailed 21st-century drug testing rules.
Those rules, in fact, the entire drug testing requirements of the FDA, derived directly from the thalidomide incident. It is a thalidomide thing. No FDA official ever wants to be responsible for an untested drug to come to the market, as did thalidomide so tragically.
The use of the drug in only 31 Australians is statistically insignificant to ascertain complete safety. Hence, the up-coming Phase 3 clinical trials of Anavex 2-73, with safety and efficacy testing in much larger cohorts, using the most sophisticated assessment methods.
https://en.wikipedia.org/wiki/Kefauver_Harris_Amendment
https://en.wikipedia.org/wiki/Thalidomide
https://en.wikipedia.org/wiki/Frances_Oldham_Kelsey
Simple Answer
May Be Related To Rapid, Complete Cellular Absorption
Not So, But Very Good Thinking
Well Said. I Forgot To Mention Optimized Dosings
Human Biology Not For Those Easily Offended
BIG Topic — Gut Microbes, Health, And Drugs
Previous, Other Work By Firms Not Applicable
Phase 3 Cohort — Not Like Phase 1/2, Better
Consider this.
Here’s what we know about those Australians selected to participate in the Anavex 2-73 Phase 1/ 2 safety and tolerability study. They were all typical Alzheimer’s patients, in the mid to mild stages of the disease. I know of no other selection criterial. As such they represented to some degree (if small in this case) a reasonable, typical example of people with Alzheimer’s at those disease stages.
In that early study, there was no selection of people more likely to respond favorably to the drug. Selection was apparently entirely random.
Importantly, that will NOT be the case in the upcoming Phase 3 Alzheimer’s study. Anavex has a computer disk full of participant traits and trial data points. Front-line, high-grade statistical analyses, by retained firms with proprietary statistical expertise and algorithms are now parsing out all of those data for several purposes — the most significant would be to favorably select new trial participants with the highest probabilities of favorable responses, yielding high-score endpoints that will best result in FDA approval.
Anavex critics here have pointed out that only a portion of the Australian trial participants were “strong responders,” that only a few really got better from the drug. The rest (conveniently disregarded, as though insignificant --- ha) merely stayed near initial cognition levels. It is claimed that all of that was only chance, facilitated by the small number of participants.
In truth, if the Phase 3 trial has similar ratios of stay-the-same to get-better responders (along with similar adverse events occurrences) Anavex 2-73 is a lock-in for approval. Beats anything on the market, both as to safety and efficacy.
But, with the intense, deep, and precise analysis of the Aussies in the earlier trial, and how each responded, Anavex now knows, at least to some degree (probably very deeply) just what kind of Alzheimer’s patient will best respond to Anavex 2-73. Only those sorts of people will be let in to participate. Anavex has the ability and opportunity now to stack the deck in its favor. There will be an over abundance of aces in the new trial. Anavex has to start with a shuffled deck of typical Alzheimer’s patients to consider for their trial. But with all of the selection criteria derived from the Australian trial, Anavex will be lifting each card in the deck first, so it can pull off for the hand being played in the trial only the aces, the Alzheimer’s patients most likely to respond well.
This time, the game will be played with a loaded deck, ideal trial participants only. Anavex takes the pot, early.
Same thing, too, perhaps, in the Rett trial. Anavex may already have biomarkers, genetic or others, that signal responsiveness to Anavex 2-73. Those would be the only little girls to get enrolled in that trial. Parkinson’s? Perhaps something selective there, too.
It IS The Lawyers
It’s Still Simple. It’s Only: Is It Safe, Does It Work?
Eager To See Our Statisticians Critique FDA
I marvel at the dissections of the Australian trial data by the resident biostatisticians who post so frequently and precisely, telling why the Anavex contentions are simply wrong, unsupported by real numbers.
Of course, we don’t see any of this from external professional biostatisticians. Not a single posting has appeared from any professional research biologist claiming that Anavex Life Sciences Corp misrepresents the trial data. Our guys, of course, know more.
So, won’t it be fun to see their statistical critiques when FDA, using published data from any of the three up-coming Phase 3 clinical trials actually approves Anavex 2-73 for retail clinical use?
The Anavex people are on the same level of competence as the professionals at the FDA. In fact, one Anavex principal was a big-time, top line FDA trials guy himself. But he left FDA to work at Anavex. Unlike our statistical experts, he simply was unable to recognize the numerous flaws in the Anavex 2-73 trial data from the Aussies.
Perhaps that will explain how Anavex 2-73 gets approved; inadequate consideration of statistical data by the FDA. When that happens, we can sleep well knowing that our resident experts will detail in precise focus how the Rett, Alzheimer’s, or Parkinson’s trials data were inadequate to justify approval. Good to know, our guys know all of this better than Anavex, FDA, and all of us amateurs here.
The real experts are here, aren’t we?
Simple Answer
[Don’t Read This, Too Speculative] Anavex In Animals
Those familiar with, and objectionable to my sometimes over the hill speculations, stop reading, now. Don't even bother to respond. This is all too weird, without out any reasonable evidence. Stop! Click to the next post. Thank you.
******
Now, for the rest, ponder (but don’t act on yet, in any way) this potential set of future events.
What is the largest market for the miraculous antibiotic drugs discovered in the last 7 or 8 decades? Nope. Not hospitals. Nothing “medical” at all. It’s big-time commercial animal agriculture; pigs, cattle, and fowl. Thousands of times more drugs, in this case, antibiotics, are fed to animals than are prescribed to humans, by orders of magnitude.
So, what might be the results for Anavex Life Sciences Corp if it’s discovered that any of their molecules provide useful and profitable benefits to agricultural animals? What if an Anavex drug facilitates optimal systemic homeostasis, thereby increasing milk production in dairy cattle, or muscular growth and quality in beef cattle, or increased natural immunological control of disease microbes in all animals?
The Anavex 3-71 Factor
Read Anavex Announcement — More Journal-published Confirmations
Controls Seizures in Animals (Humans Are Animals)
Should We Take A Short Position Then?
The Thalidomide Factor
Anavex Needs To Get Into The Public Mind
Should Bill Gates happen to mention “Anavex” somewhere, well and good. Hope that it might cause writers and news people to do their own scrutiny on this tiny, new company.
As I’ve previously suggested, we need to start seeing headline titles, to the effect, “New Drug Fixing Rett Syndrome.” “Short Parkinson’s Drug Trial Showing Promise.” “In Drug Trial, Family Members of Alzheimer’s Patients Happy.”
Gates Emails Must Be <500 Keystrokes
I tried to paste in my Anavex Traits posting to Gates.
Just the first paragraph got in. My text way too big.
So, I took a few moments and worked out a short, data-intense note on my word processor (to monitor keystrokes). Got up a pretty good statement, was sent.
Of course, some functionary at a back desk reads all of those "Bill, my Aunt is dying of cancer. She needs $$s. Help us, please"-type emails.
Tried to word my note so the low-paid girl back in that cubicle wouldn't reflexively hit the Delete key. (Perhaps she's got an aunt with Alzheimer's.)
I did get a pro forma, boilerplate response, saying they got my email; but it will take some time to consider, and that few actually get acted upon.
Not holding my breath.
No, Best Question Is: "Which Pays Best?"
Is it better to have an early "announcement" of any sort, thereby scratching the itches of day traders wanting small, quick, gains, or; better to let the insiders work out all of the undisclosed trial design machinations required to comport with the yet undisclosed and perhaps incomplete new FDA drug trial rules, which in time (several more months or longer) may cause AVXL share prices to rise into low double digits?
Pondering the odds on either outcome, most of us are patient; will grin handsomely even if "announcements" are delayed. We will grin when the share price consequently begins its eventual ascent. The wait will have been worth it.
Haste is probably waste.
A "Vengeance" Sale?
"I'll get 'em! I'll SELL my big AVXL position. That'll show 'em! They don't know anything about how to run a pharmaceutical."
Will Stay with Digital Slide, PDF Oral Presentations
As it happens, I have many thousands of digital slides on natural history topics related to my biology teaching and other professional biology duties (for which it would be inappropriate to divulge here --- my employer would not be pleased).
I am an accomplished nature photographer. I have several digital presentations on natural history topics I present: interesting slides, with topical, offhand narration. These programs are universally well-received. Enjoy giving them.
But I've never migrated my interest or graphic activities to the video realm. Have ample digital cameras, equipment, etc. But all for stills. Video format is another animal; like all, if not done well, crude and amateurish. Don't have access to either a required studio or equipment to even consider putting up any sort of video, on Anavex science or any other topic. (And, with Anavex, there would be questionable copyright and other legal issues I'd prefer to stay away from.)
I can put up a pretty professional website (in fact, have one, featuring one of my natural history competencies; rather highly regarded, dare I say). I can construct rather professional PDFs, too.
But Anavex will have their own in-house and contract professionals do all of that. I might be competent, but certainly not qualified with any commercial experience. I'm mostly an educator, not a salesman.
Soon enough, let's hope to see amateur videos, to the effect, "Hey, this lady here is Aunt Millie. She's 75. But, today, she's got the mind of a 50 yr-old. Let me tell you just how that happened!"
Thanks, I'm Staying Here, No Matter
Well, Anavex Life Science Corp really wouldn't want me listed in their panoply of consultants or spokespersons. No curriculum vitae of any qualifying significance. Merely a retired biology teacher (with other scientific qualifications, too) out here in fly-over land.
Yes, I write with facility, able to bring complex subjects into focus for interested readers. (I do pretty engaging verbal presentations, too --- another matter).
Actually, I'd love to review and edit corporate announcements, PR text, etc. From my long science teaching career, I pretty much know how lay people wrestle with difficult or confusing science topics. In most cases, I can carefully lay out the subjects in ways best understood by the uninformed.
For example (and this is NOT intended as a negative for any other IHub posters here), I take (and have) the time to edit my postings, making them readable and interesting (for the most part, anyway). I cringe when I have the urge to so easily use any of the standard acronyms. New readers have no idea what an "AD SOC" is. I spell 'em out: Alzheimer's disease Standard of Care.
Enough. I'm working on a retrospective telling many chapters of interesting events in my career. Haven't yet started the Anavex chapter; too early. But soon as possible (With Phase 3 results?) I'll get on it. It will be connected to two other medical research and treatment protocols I've been intimately, successfully involved with developing.
All in the book. Gotta get it done.
Thanks.
Sorry, Don't Gamble (Even with AVXL)
Actually, I don't play cards, play the lottery, or anything of the kind.
There are those who do, who know and play the odds (favorably it is hoped). Just not my kind of fun thing. I'm pretty dull when family and friends open the card table and sit down. They don't even ask me to come over. They know....
What is Keno? (No, I don't know --- but no need to go off topic.)
(Well, in retrospect, I have placed a bet with my small AVXL holding. I've scrutinized the data, and weighed the odds. I think I'll win, probably a few years from now, when I can start spending Anavex dividends.)
Intracellular, Cytosolic Concentration Versus Serum Concentration
Here’s a matter that needs consideration.
The question of serum (blood liquid) concentrations of Anavex 2-73 during various points and durations of the Australian clinical trial is important. Doubtless, concentration of the molecule will effect efficacy outcomes. At the lowest, non-detectable concentrations, parts per trillion, likely no detectable therapeutic effects. Conversely, at extreme, high concentrations, induction of adverse events (side effects) would be complicating, even therapeutically negating. The search is for optimized doses to determine the most effective therapeutic concentrations.
But, might the following be a matter complicating the assessment and determination of “concentrations.”
To whit, are intracellular (in the cell), cytosolic concentrations of Anavex 2-73 or its metabolite accurately measured by assessing serum concentrations? Do serum and intracellular concentrations vary independently? Does an assessment of serum Anavex 2-73 always reveal the actual, active concentration in the cell itself, or, perhaps, further in, in and on the target organelles, endoplasmic reticula and mitochondria themselves?
It is very reasonable to consider the possibility that extracellular, serum concentrations of Anavex 2-73 do not relate linearly or directly to their abilities to re-connect dissembled endoplasmic reticula and adjacent mitochondria. Once the sigma-1 receptors “recept” (receive) Anavex 2-73 molecules, once those molecules bind to the receptor binding sites, they may possibly saturate all available receptors, thereby making the concentration of un-bound Anavex 2-73 irrelevant, outside or inside the neuron.
All of the desired activity happens in the cytosol, the internal aqueous solution outside of the nucleus and within the plasma membrane. Very difficult, perhaps impossible to measure Anavex 2-73 concentrations there in living clinical trial participants. Blood can be drawn and serum concentrations can be accurately determined, but the actual concentrations of the drug actually bound to the sigma-1 receptors and performing their organelle connection functions may be impossible to directly determine. How does one pull out nerves, extract their cytosol and organelles, and accurately determining functional drug concentrations? Too complicated, too lengthy, too chemically disruptive for practical accuracy.
In fact, it’s probably not important. The only important matter is clinical outcomes, as they will be revealed and determined by varying dosing regimes. Those, of course, will be the sorts of data the Phase 3 trial will sufficiently lay out.
Additionally, what is the therapeutic contribution of the metabolite. It has a much longer serum half-life; it may saturate and maintain organelle restoration activity at length, irrespective of initial Anavex 2-73 dose concentrations.
Are we debating concentration matters external to the organelles where the drug and its metabolite actually function? If the sigma-1 receptors are easily bound to and saturated by even low cytosolic concentrations, we are arguing over an irrelevant matter. Serum concentrations of Anavex 2- 73 may not be narrowly operant within the neuron. Other factors, such as genetics, may be at greater play. Genomic assessments will be revealing.
"Conclusion: the world is waiting for ANAVEX!!! "
Well, no it isn't, sadly. Anavex is one of the greater secrets of the medical and investment worlds. Mainline media, nor the public, know nothing (yet) of it.
Just how the word gets out to the world remains to be determined.
The time isn't right just yet. No believable story can yet be told to writers, journalists, or broadcasters. We read the typical naysay postings here. Those who can't understand Anavex science, or don't believe it, can't possibly write up anything editors or the public would believe just now. Fake news, as it were. Too good to possibly be true.
Nothing big until new, real numbers or external professional comments appear from any of the three upcoming Anavex clinical trials. 'Til then, we are talking (joyfully but fruitlessly) amongst ourselves.
Yes, I Emailed Gates People
Report Tells of US Alzheimer’s Diagnosis, Treatment Inadequacies
Well Said, I Concur
Yes, you are correct. The real story is in the real humans who have taken and benefitted from Anavex 2-73, while they had mid- to mild-level Alzheimer's.
Anavex is no longer just a lab concept. In humans, with Alzheimer's, it has safely rendered favorable outcomes---beyond any yet demonstrated by previous Alzheimer's drugs.
Yes, it was only a bit over two dozen people. But the absence of negating failures among them is definitive. Readers should calculate for themselves the probabilities of arbitrarily and by chance pulling out for a clinical trial two dozen Alzheimer's patients all of whom would respond so favorably.
Mere chance, or real cause, real efficacy?
But Where’s the Anavex Wreckage?
I Learn From Them, Not Them From Me
If anyone at Anavex deigns to read my Ihub postings about their company and technologies, I'd be honored.
But, should it happen, it's of little consequence. Would be merely a surmising of what one particular AVXL share holder publicly relates about his particular understandings of Anavex technologies and where he, from time to time, thinks they might lead.
Because I'm a biology professional, having written and presented technical papers (none related to neuroscience in any way), and an accomplished biology teacher (retired), I have both the training and desire to make my presentations clear and informative. I attend to good grammar, punctuation, spelling, terminology, and all of the other science writing factors that can keep a presentation of topical text from being regarded as amateurish or inaccurate. As I taught my students, "If you can't say or write it well, accuracy and perception are, at the start, very compromised."
The delight here is the we have a broad and large body of inquisitive, scrutinizing readers who take the time to learn and consider that appears here. Had we not such a fine readership, all of this would be for naught.
And I do so much appreciate the correcting posts from others. How many times have readers discovered inaccuracies or insufficient presentations of mine? I gratefully invite skeptical questions or evidence-based corrections. We are in this together, perceiving and presenting a truly significant change in 21st-century medicine. It is an honor and delight to play a small part in advancing the Anavex revolution.
Sent Gates Foundation Our CTAD PDF
For what it's worth, I just sent a short note (<500 characters) to the Gates Foundation, asking that Bill Gates' people scrutinize the Anavex CTAD presentation.
Anavex 2-73 is exactly the drug Mr. Gates is searching for, matches all of his search and selection criteria.
Don't hold your breath, but let's see if anything comes of this.
I left my real name, address, and contact info. For good Bill (with no bill), I'm not anonymous (nor just a falconer).