Workin' on it
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Glad you made it in one piece.
Don't see the shorts backing down yet, could put some fizz in Mondays trading.
Leo, How was the trip? Old guys and motorcycles, from personal experience, can be problematic.
What do you think of Corvettes now boasting over 1,000 hp?
I think it's scary with the level of ability and judgement required to obtain and keep a drivers license.
Volumetric Reduction
Alzheimer Disease.—Alzheimer disease is a degenerative disorder and the most common cause of dementia with hallmark cognitive deficits. Imaging assessment of medial temporal atrophy (MTA) is an important diagnostic biomarker, and degeneration of the stratum radiatum, lacunosum, and moleculare (SRLM) is a potential one (5). The Scheltens scale is based on evaluation of the choroid fissure, the temporal horn of the lateral ventricle, and the hippocampus, on a scale of 0–4. Cutoff points are still controversial, but the original proposal suggested an age-adjusted cutoff point: an MTA score of 2 or greater in either of the hemispheres is abnormal under 75 years of age, while an MTA score of 3 or greater is abnormal over 75 years of age (Fig E1). Other scores have emerged, such as the entorhinal cortex atrophy (ERICA) score, used for assessing the entorhinal cortex (Fig E2) (16).
The classic earliest imaging pattern involves atrophy of the entorhinal cortex and eventually the hippocampus, followed by predictable involvement of the precuneus, with sparing of the sensorimotor strip. Although the pattern is bilateral, it is not always symmetric: along with disease severity, the atrophy seems to progress faster in the left hemisphere than in the right (Fig 5). In cases of the posterior variant of Alzheimer disease, posterior parieto-occipital cortical atrophy may occur with relative sparing of the medial temporal lobes, in which atrophy may become more prominent with disease progression (17). Therefore, it is important to note that hippocampal atrophy is nonspecific to Alzheimer disease and can be implicated in non–Alzheimer disease neuropathologic conditions.
https://pubs.rsna.org/doi/10.1148/rg.210153
I can paste it, doesn't mean I understand it..
I do think Anvex' chances for success increase with its ability to sustain brain volume.
Thanks Christmas everyday, I'm late to Lecanumab's funeral procession and cheering for sanity in Europe.
EMA denies Biogen Eisai drug. Just saw the flash on Bloomberg.
We'll be lucky if the EMA sees the opportunity here to help its health care system. And so will they.
pete [quote: These unsolicited studies crediting Anavex with advances in Science are very positive signs of good things to come.]
we are involved in an evolutionary learning process, like it or not. My advice is to roll w/it, the learning process is building on itself, not a trial and error roll out at this point, we should know better.
I think most of us agree that we have now looked- recognize a glimpse of what is next. Clearly the CNS (makeup and functional works) is little more than a blank piece of paper to us as wee sit here. At least we are recognizing a little more of , "what we know, we do not know", and that is a good start.
We would all like to see-recognize some giant leap from here but that may take a long time or AVXL might present a brilliant flash of new insight. We must keep walking the perimeter else what we think we know gets lost . Being human comes w/responsibilities and obligations....I guess.
Trading seems to be counter intuitive, when it's at a high PPS you admire it and just want to see it appreciate, then...
Well, you know what happens then.
It doesn't matter how many times you get fooled the feeling stays the same.
That's the day you become an investor, if you have any money left.
I’m sure Missling and the team have weighed the “what if” outcome and felt that it was better to give it a shot even though it could waste years.
My questions run to next phase progress..
Everything so far has been very good to great but with our friendly bashers regurgitating it in an awful light. There have been so many presentations, with little feedback. Then there's been numerous publications crediting remarkable advances in medicine to ANAVEX LIFE SCIENCES.
These unsolicited studies crediting Anavex with advances in Science are very positive signs of good things to come. Do I need to list them, it would just be from memory, Autophagy, Remylenation, Calcium Balancing, Gaba, Homeostasis, these just a few.
Soon a submission to a regulatory agency, the EMA! Since this is new science, Anavex can't really screw it up, can they? Anavex is writing the book here, the EMA will be moving Science forward in a partnership with Anavex is how I perceive it. There will be learning during this process, it will evolve, this is a departure from the incremental affectations of specific maladies.
This is exciting and I doubt I'm as excited as Anavex is but I'm excited for this.
The data is broad, covering the requirements to proceed to Commercialization for Alzheimer's disease and that is enough but how much more will be learned?
S1-r, M-1,4, epigenetics, then FragileX, Schizophrenia. This a lot to digest for any Agency in the business of processing medicines to help people.
Just rambling.
Tracking XBI.
How’s one to know what’s going to happen next?
I think the avxl on the pill looks cool.
For now it refers to something people could relate to as much as Anavex, both pretty much made up names. For investors it's a natural, for others, I don't think it will turn anyone off and if when searching for info, if they like what they see, the price for avxl will be attractive.
No harm, no foul and it looks cool, plus I also liked george's explanation on dosing.
It's a nice presentation which is coherent and readable, remember they are also in the midst of a NDA which I hope is also coherent.
How about those options?
Are you betting on the 3 legged mabs or Secretanavex?
Good question.
I don't know specifically for each country what their requirements are, if they have a regionalized cooperation agreement or what have you?
I would guess after an EMA approval each country might be open to considering an approval. At that point Anavex or some agency would prolly approach them to go over the introduction of Blarcamesine and begin organizing prescribing, distribution, labeling, pricing, etc...?
Then perhaps some feedback procedures to cover any issues arising out of the uniqueness of the population?
I think it would require some considerable effort on the part of Anavex, unless the country did their own trials and testing. Licensing with a company who had existing products in the area might make sense.
If Europe approves Blarcamesine, Australia will do the same. They are single payer and will not balk at the price.
With the U.S. pushing mabs, people will clamor for a safe affordable drug that works. This nonsense about big pharma being able to push the black box drugs because of their position won't persuade doctors to prescribe.
Remember the medical groups that black balled Biogen when Aduhelm got approved?
I got a kick out of that. No family member will be able to perceive the slower rate of cognitive decline with a mab but they'll quite aware of the costs, side effects and nuisance of taking them.
Maybe we could start with a modification on the drug approval process?
Norman Vincent Peale wrote The Power of Positive thinking which describes the placebo effect but I don't know if studies have been done to determine for exactly how long?
Maybe if you stay positive the effect can continue indefinitely?
Now, you could write a book entitled, The Power of Negative Thinking. The subtitle could be, Misery Loves Company.
Dr. Walter Kauffman from Emory University summarized recently published work from his team investigating the ameliorative (positive) effects of ANAVEX2-73 (blarcamesine) in FXS8. Blarcamesine is a Sigma-1 receptor (S1-R) agonist. Activation of S1-R leads to release of calcium, which in turn influences multiple signaling pathways and regulates key synaptic processes such as firing rate set point (e.g., hippocampus) and homeostatic synaptic plasticity. Multiple pathways downstream of calcium influx are impacted by FMRP deficiency and many of these pathways result in the production of brain derived neurotrophic factor (BDNF). BDNF plays an important role in several cognitive and sensorimotor deficits and S1-R induced changes in BDNF have been observed in many different neurological disorders. Therefore, Dr. Kauffman’s rationale is that drugs maybe be more effective if they target a common ligand that influences multiple downstream pathways. With this justification they used the Fmr1 KO mouse model to test the efficacy of Blarcamesine and found that 1) S1-R occupancy by Blarcamesine is similar in both WT and Fmr1 KO mice making it an effective drug, 2) rescued hyperactivity and associative learning, 3) improved behaviors that resonate with anxiety and perseveration observed in humans, and 4) restored levels of BDNF. Importantly, BDNF could be measured in blood samples from mice, making it a feasible biomarker of drug efficacy.
https://fragilex.org/get-involved/international-fragile-x-conference/
The next FragileX conference is July 25–28, 2024, in Orlando
Thanks Powerwalker,
The long anticipated basket approach. I don't know anything about it except it was proffered several years ago as a possibility. Maybe?
I just look at biomarker data as ammunition in a skirmish to cross a line. Anavex just needs the football to touch inside the goal line by a millimeter, not 15 yards. I'd say we're first and goal to go. They've got Alzheimer's, Rett, Schizophrenia, FragileX, PDD, Parkinson's and an undisclosed rare disease for starters. So, maybe 6 downs?
With BDNF as a biomarker, as George showed us, reduction in brain shrinkage, improved cognition, Autophagy, Cellular homeostasis, Gaba/Glutamate, calcium balancing, improved sleep, mood, seizures, all with little or no adverse events..
I like the odds.
We're going to win.
Thanks george, BDNF looks like a strong possibility to me. Very good.
Anavex learning..
https://fragilex.org/get-involved/international-fragile-x-conference/
Join Us July 25–28, 2024, in Orlando!
Appropriately, where Mickey hangs out.
Nidan,
I'm looking forward to learning what the FragileX data point biomarker they've found is.
FragileX is turning into the precursor for many CNS diseases. I believe Dr. Hagerman pointed out it is the culprit in Autism Spectrum disorders, among other things.
https://www.cdc.gov/autism/data-research/index.html
One in 36 children is a scary number for any parent to live with.
This data point might/must be pretty far upstream and could be the crux to support all Anavex indications. Also, one which they may have been seeking for a long time to tie things together.
Lessons learned..
At least?
Where does that leave the AD application to the EMA?
Considering how much hinges on the successful result of the AD NDA, I wouldn't diminish the resources and time needed to insure it is airtight.
All of us drooling over the likely profits of our investment have to understand the stress and workload Anavex is working under now.
Once that application is submitted, other things can happen but they are knee deep in data and who knows what, at the moment. I don't believe Anavex is rushing but the pressure is on.
You're right, with no real alternatives, there should be a rush to fill the next Rett Syndrome trial.
It wouldn't hurt to have the Rare Disease Advocacy Movement, RAM, and the Rett Foundation help in promoting Anavex and encouraging patients to sign up. And it's not too late to have them write letters and emails to the FDA demanding access to Blarcamesine, given the poor safety record of Trofinetide.
It's disgraceful, the poor choices these patients are given, to be offered a second rate drug due to a data point on an irrelevant endpoint. SMH.
Here's why... A transcript done of Dr. Hagerman's presentation at the Thalman presentation Dec. 2020:
Hi I’m Dr. Randi Hagerman,
I’m a Clinician, I’m a developmental and behavioral Pediatrician and I have a great interest in the use of targeted treatments for a variety of neuro-developmental disorders. And again by targeted treatments, I mean medications that can modify the neurobiological changes that are made in the brain and individuals with neuro-developmental disorders. I participated in the Adult Rett Syndrome Study using Anavex2-73.
The results are being released now and these are very exciting results.
I was blinded during the control trial where individuals were randomized either to active drug, about 5mg a day vs. placebos so I didn’t know who was on what.
I saw a number of individuals who did very well on this medication and others who didn’t but also I have been involved now in the follow up where they go on the active medication so I can see actually the results now in individuals that I know are on medication.
I saw a variety of improvements and again as you heard in the last talk from Jeff, these individuals are very severely impaired.
They can’t talk or talk very little, often they’re in wheel chairs. They can’t use their hands well . They often times can have agitation, other types of problems like constipation and what we saw is that individuals were calmer, less agitated, they seemed to be happier. They were able to concentrate better. They made better eye contact and they seemed to understand questions or directions given to them and were able to follow through in many cases on some of the commands that their parents made.
There was less anxiety, better understanding and in general the parents felt they were calmer and less agitated and often we saw improvements in the gastrointestinal problems.
One patient that stands out that I just recently saw, was able to swallow her food better. She didn’t have any problems choking now that she’s on the active medication.
She was able then to eat better, happier. She had less bloating, less constipation and having better function GI wise I think can lead to less agitation.
The families were able to mark on the main outcome measures that were improved. The Rett Syndrome Behavior Questionnaire that the parents answered and also the Clinical Global Improvements Scale. The CGII that the Clinicians do. There were significant improvements with the Anavex2-73.
So this is very exciting.. So far the patients want to continue on the Open Label Extension on this medication.
This is a relatively unique medication that can actually improve the calcium dis-regulation, the mitochondrial function, the oxidative stress and the neural connections. These problems can be seen in variety of other neural developmental disorders and also neurodegenerative disorders.
They’ve carried out studies in Alzheimer’s and in Parkinson’s Disease looking at cognition in Parkinson’s disease. It improved cognition in both Alzheimer’s and Parkinson’s disease.
I do a lot of research also in Fragile X syndrome and this medication can improve the Fragile X symptoms in the mouse model of Fragile X so I’m very excited about this medication causing improvements not just in Rett Syndrome but in other neuro-developmental disorders and neurodegenerative disorders.
This medication can be a boon. I think in general for aging and certainly for aging syndromes like Parkinson’s Disease and Alzheimer’s and I can’t wait to start it on other neuro-developmental disorders like Fragile X Syndrome.
I am very excited about this medication and also as I age I would definitely like to take Anavex myself.
I’m excited that this is a break through medication and for not just Rett Syndrome but other disorders of aging and also neuro-degeneration.
We are open to answer questions that you may have.
This is an exciting new treatment.
The new biomarker data for FragileX, to be released next month, will fit seamlessly into the next Rett trail.
I almost guarantee it!
I heard biomarker data for FragileX will be presented next month, in July. Also Rett will be a 12 week study.
Whereas, I believe the biomarker data for the Mabs is over 100 years old and getting weaker by the day.
No, I haven't seen the breakdown. That data would be welcome to see for those of us who haven't given up.
I don't think Dr. Missling has given up either.
Thanks for your input, Powerwalker.
Filed under outside chance;
Dr. Missling said he would file for NDA after adult Rett trail met endpoints. Then it seemed he was waiting for Excellence which made sense.
Excellence had an issue with 1 or 2 in the placebo group showing improvement, throwing off the Stats, so step back and regroup. However there was a large effect and it was a very positive result despite the lack of statistical significance.
Now the focus is all on AD and that is looking very good. Yes, another Rett trial is being planned but the most important aspect of Excellence was confirmed with the safety of Blarcamesine in children and stat sig was missed by a hair.
I believe there is a case for approval for Rett, with the next trial moving into a P-4 as confirmatory.
That would qualify as a surprise, which has been promised.
It would at least open the door for off label but not sure how the money metrics would make that attractive.
That would seem to me to be the most prudent path. Also one that might not give the maximum return on the price point where that takes place.
I don't think anyone here would begrudge Anavex for playing it safe in the garden of good and evil.
Anavex will not proceed toward NDA without the production/marketing/distribution infrastructure beinging in-place before drug approval and they are too small to do it all themselves!
By Ern's account, family and caregivers he recovered from Alzheimer's. This was from a 32 person trial where 5 others had similar results. 6 out of 32?
Any of the mabs got vids showing ANY of their many thousands of Alzheimer's sufferers getting better? No?
Maybe you and the Bigs Pharmas might be a touch jealous?
Thanks george,
Thanks, georgejjl,
Until Valitramiprosate becomes a household word, what is your opinion or guess as to how efficacious or dangerous valiltramiprosate will be?
Thanks to georgejjl, for the link, A quick summary of the Anavex portion of the conversation:
Sharon Cohen, MD, and Marwan Sabbagh, MD, share their thoughts on the pipeline of Alzeheimer's drugs.
Marwan:
A couple of drugs I'm very excited about... Valeltiriprersate? an oral drug, an aggregation inhibitor, going to report out their P-3 data in the next 6 months.
There's now a Sigmar 1 receptor agonist called Blarcamesine, which is showing they met their pre specified endpoints in their Phase 2b/3 in CDR Sum of the Boxes and in the Adas Cog and people are looking for alternatives to monoclonal antibodies and that's also an oral medication.
People are kind of saying, we didn't know about this so..., there are a few sleeper surprises coming up the ranks that could really change the World and not just make it a monopoly on the monoclonals.
I'm glad to give these learned folks credit for their dedication, education, etc., They are smarter than me, not saying much.
But I also feel like Charlton Heston in the Planet of the Apes, when he's talking to one of the Ape Scientists.
Or,
as John McEnroe used to so eloquently put it; You've got to be kidding me! Or, another of his well worn retorts; You can't be serious!
I miss him.
Yes, they aren't kidding and they are seriously still talking about amyloid as the culprit in Alzheimer's disease.
This is the level of comprehension Science has after 100 years of Alzheimer's Disease.
https://www.neurologylive.com/view/alzheimer-s-disease-pipeline
Episode 9, Blarcamesine, mentioned at 6 minute mark.
There are two posters that like to estimate event times.
Their initials are I and G.
Of the two, which has the better track record?
The CEO has been optimistic in his estimates of catalysts timelines.
I've adopted listening to the skeptical side lately since, overall, they have been the most accurate. At this point, as Crescent Motor points out, it doesn't matter anyway.
The Market and Shorts are far more skilled in what they do than any retailers here.
While it's been chugga, chugga for many years now, It could be closer to a bullet train soon. Imagine Anavex creating the Doppler effect? That's funny.
The worst investment strategy is what I'm left with, hope.
Would like to add a few thousand more in the next week or so.
P.S., OT. Watch for a slew of advertisers using the train analogy to represent acceleration in product advertising. If I had a nickel for every time I've made them millions...
I think she left out the safety factor which is a multiplier for every other aspect, especially the increased efficacy. Increased efficacy with SAFETY.
She lists out the other indications and diminishes their value while making no mention of possible off label uses for other multiple indications once the MOA is revealed fully, possibly in the peer reviewed article.
And as already pointed out, brain volume, pill format.
It must have taken a lot of effort to omit the best features while droning on about the modest increased efficacy compared to what's out there.
C minus
Drugs Advisory Committee (PCNS) on Monday, June 10, 2024, to discuss donanemab, which Eli Lilly and Company (NYSE: LLY) has submitted for the treatment of early symptomatic Alzheimer’s disease. The open public hearing portion of the meeting will be conducted virtually.
The Phase 3 study submitted as part of this application, TRAILBLAZER-ALZ 2, is a double-blind, placebo-controlled study to evaluate the safety and efficacy of donanemab in participants ages 60-85 years with early symptomatic Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with the presence of confirmed Alzheimer's disease neuropathology. Alzheimer's disease is a progressive and fatal disease that in its early symptomatic stages affects 6-7.5 million Americans. The trial enrolled 1,736 participants, across eight countries, selected based on cognitive assessments in conjunction with amyloid plaque imaging and tau staging by positron emission tomography (PET) imaging.
The TRAILBLAZER-ALZ 2 study results were published in the Journal of the American Medical Association (JAMA). Lilly continues to study donanemab in multiple clinical trials, including TRAILBLAZER-ALZ-3, studying donanemab for the prevention of Alzheimer’s disease.
https://investor.lilly.com/news-releases/news-release-details/lilly-statement-fda-advisory-committee-meeting-donanemab-early
And on that day your name will become extremelycreamyzig.
I would cream in my pants for a $6 SP right now..
Let's not forget there is no brain swelling, bleeding or dying from taking Blarcamesine.
That has to be worth something, right?
"What Dr. would have a problem prescribing a safe drug to a CNS patient that will slow their brain shrinkage?"
Yes. Fully agree. I tagged a $15 billion MC price because it's obvious what kind of break through therapy this is. Your right. You can't really put a price on this when everyone after 49 years old needs to preserve their brain from shrinking.
How many drugs are out there that reduce brain atrophy? - ihidfromthex
That right there is worth a $15 billion Market Cap. - bb8675309
What Dr. would have a problem prescribing a safe drug to a CNS patient that will slow their brain shrinkage?
I think more than 15b. It's foolish at this point to try and predict how much but yes, more.
Here are Rett Clinicians and Doctors talking about improving Rett trials.
I believe Dr. Hagerman helped run P2 Rett Trial for Anavex.
Jeffery Nuel, Thalberg Conf. December 2020, paraphrased;
…There are certain challenges in clinical trials in Rett Syn. …It’s trying to have things that could be good biomarkers that might track with disease severity especially things that might identify who would respond or not respond and things that could be used during a trial that would show an early response, even before a clinical response. The other is having outcome measures because that’s really what we want to see is clinical improvement. They need to be reliable and valid and have been shown to be useful.
Aspartate and Glutamate were increased in the blood of people who had Rett Syn. Whereas as the other ones were not changed.
He talks about the CGI scale, rating and reliability, disease specific anchors and guidelines..
Rate or rating training, trying for uniformity in ratings.
RSBQ, etc.
Question to Dr. Hagerman;
It seems a lot of the testing is based on subjective measurements.. In other words, what’s your subjective opinion on the statistical significance?
Answer;
My objective opinion is that there was significant benefits seen by the clinician but also the Families. Anavex looked at Biomarkers too. Particularly the Glutamate biomarker that’s elevated that you heard Dr. Nuel talk about. They correlated the improvements or the lowering of glutamate with what was seen clinically, so this is something that is not subjective but an objective measure of improvement in the neurobiological abnormalities and how it relates to what we see clinically.
Question;
Based on your understanding of disease and what you’ve seen in other Rett trials; Do Pediatric patients generally respond better than adult patients to therapeutic treatments?
Answer;
Dr. Hagerman;
In general I think that is true. There will be studies in the future looking at younger children with Rett Syndrome who received this medication and this study was at a relatively low dose but in general, if you can start this medication early on, you’re much more likely to build a better brain. The problem is, with the FDA, they like to show safety and efficacy in adults first but for neurodevelopmental disorders that is somewhat counterproductive in the sense that it probably will have it’s biggest effect in younger individuals…. The general rule is; The sooner you can start it, the better to build a better brain and not just counteract the lifelong effects of an abnormal gene impacting brain development.
I'm looking forward to hearing the next Anavex update, hoping it will include;
FDA guidance on Rett.
When Anavex plans to submit a new drug application.
Progress on other indications;
Parkinson's, schizophrenia, Fragile X.
How long it will take to prepare the Alzheimer's OLE for top line data?
I'm glad to see the FDA guidance on Early Alzheimer's align with Anavex priorities, that is encouraging.