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Sorry about that. Try this:
https://www.anavex.com/anavex-2-73-could-prevent-alzheimers-disease-in-addition-to-modifying-and-treating-symptoms/
”Mitochondrial dysfunction and resulting oxidative stress are critical hallmarks of Alzheimer’s disease pathology and believed responsible for increased amyloid-beta production and Tau hyperphosphorylation.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007397/
Alzheimer’s disease (AD) exhibits extensive oxidative stress throughout the body, being detected peripherally as well as associated with the vulnerable regions of the brain affected in disease. Abundant evidence not only demonstrates the full spectrum of oxidative damage to neuronal macromolecules, but also reveals the occurrence of oxidative events early in the course of the disease and prior to the formation of the pathology, which support an important role of oxidative stress in AD. As a disease of abnormal aging, AD demonstrats oxidative damage at levels that significantly surpass that of elderly controls, which suggests the involvement of additional factor(s). Structurally and functionally damaged mitochondria, which are more proficient at producing reactive oxygen species but less so in ATP, are also an early and prominent feature of the disease. Since mitochondria are also vulnerable to oxidative stress, it is likely that a vicious downward spiral involving the interactions between mitochondrial dysfunction and oxidative stress contributes to the initiation and/or amplification of reactive oxygen species that is critical to the pathogenesis of AD.
Bio:
Thank you. As you say, the merit of our science needs to be acknowledged. It should be acknowledged by anyone interested in a treatment for Alzheimer’s and other CNS diseases where no effective treatment exists -- especially a treatment or drug that has established the requisite degree of safety and is aimed at enabling the body to restore and heal itself. And yes, you would expect some reaction by the media to address such a drug. If we persist in trying, I think we will get there. We have many excellent posters on this board capable of getting the message across, the message about Anavex and another approach to treat CNS diseases.
Tred: Great! Send it around. Hope it helps.
A very good question. I should have considered and included these other forms of trauma that you point out.
The evolution of Anavex’s theory for treating Alzheimer’s and other CNS diseases.
I could be wrong about some of what I say below and still be correct in my overall belief that Anavex is on the correct path toward a treatment of CNS diseases.
AVXL 2-73 is a radical departure from mainstream science that believes that if we simply remove amyloid plaque all will be well with Alzheimer patients, except nothing is well as we all know. The Anavex approach is to correct the dysfunction within the body that causes the body to malfunction and prevents the body from clearing itself of waste, including amyloid plaque, and other offending matter resulting from a disconnect within the body’s central nervous system.
AVXL 2-73, a CNS drug, has evolved as something comparable to an immunotherapy drug in treating cancer. I think it is now postulated to be a small molecule drug that influences the central nervous system to heal itself.
Generally, over time (aging) the central nervous system, or parts thereof, become dysfunctional. Of course, some rare diseases involve genetic mutations that occur early in life as opposed to Alzheimer’s, Parkinson's and other CNS diseases that are prevalent or associated with aging.
Anavex is one of the first, if not the first, to adopt the ”immunotherapy” approach in the CNS area akin to that in the cancer area. Thus, the CNN article: Borrowing from the cancer playbook to find treatment for Alzheimer's disease.
Therefore, I suppose our Anavex drug does not directly treat CNS diseases, but it assists in restoring the central nervous system that becomes dysfunctional due to aging in the usual sense or because of a rare gene that causes a CNS disease early in life. In restoration of the central nervous system at an early stage, the body may in a natural way heal itself.
I have listed below some research references numbered 1-10 that I think support my thoughts. Therefore, please read my references, which are better than my thoughts.
CNS diseases may share the same genetic traits. See my number 1 below.
Anavex has identified gene variants and it seems the same the same variants will be used in all three upcoming trials. We may expect to receive some feed back for AVXL 2-73 trials near the end of this year or the first of 2019. Early reports from either the Parkinson’s trial or the Alzheimer’s trial may be applicable to any ANXL 2-73 trial as you may see, assuming you read everything below. Number 2 and more below.
Anavex has indeed borrowed from the cancer playbook and believes the drug "activates the body's own defense mechanism to restore cellular balance," Hampel said.” Number 3 below.
Lundbeck seems to confirm our approach as per 3 below.
Significantly, note this from 3 below: The good news is that once a link has been established between changes in biomarkers and a beneficial change in a patient's cognitive abilities, the FDA has indicated it will no longer require drug developers to prove that each potential new drug can modify Alzheimer's disease, Williamson said.
Once a firm connection is established, drug developers will need only to show their candidate drugs affect the biomarkers.
I have added 4-8 below in support what from the beginning about AVXl 2-73 influencing the body to heal itself.
See number 9 below. There is a definite connection between the central nervous system and the immune system.
Lastly see # 10. Restoration of that connection between the CNS and the immunne system seems to be relevant extending from the numerous mitochondria throughout the body to the brain.
The human body is incredibly complex, but I believe it was designed (or evolved) to work together in a way that we continuously struggle to understand. If we can nudge the body to regain and maintain homeostasis, it may be able to heal itself.
In any event, I believe that the recent genetic analysis announced at AAIC 2018 should give us some degree of confidence in the future of our clinical trials. Missling knows much more than we do, and he demonstrates confidence in where Anavex is headed. Perhaps his confidence is another reason why we too may be hopeful.
In the meantime, here is a partial list of research and references that provide support for my belief the Anavex approach to treating CNS diseases.
1. Many neurological diseases share some genetic architecture
https://www.illumina.com/science/customer-stories/icommunity-customer-interviews-case-studies/gleaning-genetic-insight-about-neurodegenerative-disorders.html
”It has been known for some time that neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS, better known as Lou Gehrig’s Disease) have strong genetic components.
The above Illuminia site mentions Alan Pittman, PhD, a Senior Research Associate in Molecular Neuroscience at the UCL Institute of Neurology. His research group is interested in finding the causes of neurodegenerative diseases. He says "If we can identify the genetics and how it influences the biology, we can begin unraveling the biological basis of these diseases.
”.... (Pittman) I believe that many neurological diseases share some genetic architecture. It may not always seem like certain diseases belong together. However, they do from a genetic standpoint. So, being able to look at individual diseases and groups of diseases at the same time will be very useful.”
2. Anavex has identified the gene variants, the same gene variants will apparently be used in the three upcoming trials, and we should hear something by the end of 2018 - first of 2019.
https://seekingalpha.com/article/4197432-anavex-life-sciences-avxl-ceo-christopher-missling-q3-2018-results-earnings-call-transcript?page=2
Missing:
”Out of the initial set of more than 33,000 genes KEM identified a gene panel of 102 genes linked to CNS, central nervous system. This is the magic, unbiased analysis of our data, identify genetic variance within the sigma-1 receptor and COMT genes as top ranking genes with a significant impact on response of patients exposed to Anavex2-73.
....all forth coming out of X2-73 clinical study designs, will incorporate the inclusion of genomic precision medicine biomarker identified in the Anavex2-73 Phase 2a study. We are very excited as we embark on this next phase clinical trials as this could be a unique differentiating factor for Anavex.”
”...The use of the biomarker which we identified will be done in the following way.
So we can stratify the patients which are coming into the study into those who have the gene variant. And those who have the wild-type variant and the wild-type variant is on average in a genetic biobank provided in the overall population to be in the range of 80%. And that population seems to indicate a response better to ANAVEX2-73, then the remaining 20% with a sigma-1 variant.
...it's important to appreciate that this approach is not limited to the Alzheimer’s study. This exact approach will be also incorporated in the Parkinson's dementia study as well as in the Rett syndrome study. So you have the ability basically to have two shots on goal if you say. So you will once find an outcome of all patients against the placebo arm in the study in all these three studies as well as then a pre-specified analysis of the outcome calculation of patients which are supposed to be more benefiting the drug without that gene variant against the control without the gene variant.
To compare apples with apples and oranges with our oranges, regarding the timing we said we would start the trial in the next couple of months. And we will update everybody at the same time with an announcement.
Jason Kolbert:
Thank you, Christopher. It sounds like we could see the Parkinson's dementia trial, the Rett syndrome trial and the Alzheimer’s disease trial, its possible we could see them all start by the end of this year, yes?
Christopher Missling:
We have announced prior that it will be within 2018 and we still stand by this.”
3. Borrowing from the cancer playbook to find treatment for Alzheimer's disease
https://www.cnn.com/2018/07/30/health/alzheimers-treatment-precision-medicine-immunotherapy/index.html?no-st=1535202492
”Restoring 'cellular balance'
Dr. Harald Hampel, a professor at Sorbonne University in Paris, explained that the experimental drug, Anavex 2-73, a precision medicine candidate from specialty pharmaceutical company Anavex Life Sciences Corp., activates the Sigma-1 receptor.
A worthy target for precision medicine, the Sigma-1 receptor "is involved in several important pathways related to Alzheimer's disease," Hampel said. It reduces beta amyloid (the signature plaque deposits seen in the brains of deceased Alzheimer's patients) and hyperphosphorylated tau (the signature protein tangles also seen in patients' brains), he said. It also lessens oxidative stress and inflammation in the brain, both of which have been linked to aging and age-related diseases.
The advantage of targeting the Sigma-1 receptor is that it "activates the body's own defense mechanism to restore cellular balance," Hampel said.”
Alzheimer's disease is a complex disease," he said. "The newest weapon in the fight against Alzheimer's disease might be your own body."
Lundbeck, a global pharmaceutical company focused on psychiatric and neurological disorders, also subscribes to this philosophy as it works to develop an immunotherapy for Alzheimer's patients.”
’...The good news is that once a link has been established between changes in biomarkers and a beneficial change in a patient's cognitive abilities, the FDA has indicated it will no longer require drug developers to prove that each potential new drug can modify Alzheimer's disease, Williamson said.
Once a firm connection is established, drug developers will need only to show their candidate drugs affect the biomarkers.
"An analogy to this would be cholesterol-lowering drugs and heart disease," Williamson said. Once the link between lowering cholesterol and heart disease was established, scientists no longer needed to conduct thousands of patient studies to show that a drug reduced heart disease. "You just needed to show you could reduce cholesterol.’
4. Anavex Mechanism of action.
https://www.anavex.com/anavex-life-sciences-reports-new-mechanism-action-data-related-anavex-compounds-targeting-sigma-1-receptor/
"Goguadze N et al presented preclinical data indicating that in addition to reducing oxidative stress, ANAVEX 2-73, ANAVEX 3-71 and ANAVEX 1-41 also demonstrated protective effects of the mitochondrial enzyme complexes I and IV during pathological conditions. The mitochondrial enzyme complex IV is directly involved in the synthesis of ATP, which provides energy within cells for metabolism. It is believed that energy production impairment and mitochondrial dysfunction play a role in the pathogenesis of neurodegenerative disorders and neurodevelopmental diseases."
5. Connection between mitochondria and endoplasmic reticulum
https://www.ncbi.nlm.nih.gov/pubmed/29309902
"The endoplasmic reticulum (ER) and the mitochondrial network are two highly interconnected cellular structures. By proteinaceous tethers, specialized membrane domains of the ER are tightly associated with the outer membrane of mitochondria, allowing the assembly of signaling platforms where different cell functions take place or are modulated, such as lipid biosynthesis, Ca2+ homeostasis, inflammation, autophagy and apoptosis. The ER-mitochondria coupling is highly dynamic and contacts between the two organelles can be modified in their number, extension and thickness by different stimuli. Importantly, several pathological conditions, such as cancer, neurodegenerative diseases and metabolic syndromes show alterations in this feature, underlining the key role of ER-mitochondria crosstalk in cell physiology. "
6. Endoplasmic function
Endoplasmic reticulum - Wikipedia
The endoplasmic reticulum serves many general functions, including the folding of protein molecules in sacs called cisternae and the transport of synthesized proteins in vesicles to the Golgi apparatus.
Endoplasmic reticulum - Wikipedia
7. Falconer's explanation of how AVXL 2-73 may work.
Falconer66a posted this on IHub.
"Unique, Effective Mechanism of Action. Anavex 2-73 addresses central nervous system diseases differently from any other drug currently or prospectively in use. It is a sigma-1 receptor agonist. There are a number of these, but none that work as effectively and safely as Anavex 2-73. The molecule causes dissembled rough endoplasmic reticula and mitochondria to re-connect and function collaboratively. It is well recognized that most CNS diseases involve mitochondrial dysfunction. Anavex 2-73 is able to re-establish the proper, healthful endoplasmic reticular/mitochondrial connection. With this, calcium ion exchange and adenosine triphosphate interchange (mitochondrion to the ER) can occur, restoring full, natural cellular functions, which result in clearance of the waste proteins (beta-amyloids, tau tangles) that cause Alzheimer's disease symptoms. "
8. http://nobleresearch.com/reports/AVXL_20170206_9669.pdf
”Anavex focuses on restoring cellular homeostasis: Alzheimer's is a complex disease potentially driven by amyloid beta, tau hyperphosphorylation, calcium ion imbalance, inflammation and mitochondrial dysfunction. Anavex is targeting treatment of Alzheimer's disease using a mixed muscarinic receptor and the sigma-1 agonist to restore cellular homeostasis by reducing chronic stress and protein misfolding. The sigma-1 receptor agonist activity is seen only under pathological condition and does not impact normal physiological activity reducing the potential for adverse effects.”
9. The immune system and the CNS system connection.
The immune system and the nervous system maintain extensive communication, including 'hardwiring' of sympathetic and parasympathetic nerves to lymphoid organs. Neurotransmitters such as acetylcholine, norepinephrine, vasoactive intestinal peptide, substance P and histamine modulate immune activity. Neuroendocrine hormones such as corticotropin-releasing factor, leptin and a-melanocyte stimulating hormone regulate cytokine balance. The immune system modulates brain activity, including body temperature, sleep and feeding behavior. Molecules such as the major histocompatibility complex not only direct T cells to immunogenic molecules held in its cleft but also modulate development of neuronal connections. Neurobiologists and immunologists are exploring common ideas like the synapse to understand properties such as memory that are shared in these two systems.
https://www.nature.com/articles/ni1078#abstract
Several mechanisms by which the nervous and immune systems might interact have now been recognized. The nervous system may affect immune function via direct innervation of immune organs and by secretion of hormones from the pituitary and other endocrine organs. Conversely, cells of the immune system may influence nervous system function by secretion of a variety of chemical messengers, among which cytokines are the best recognized. Also, although classically the brain was considered ‘immunologically privileged’, it is now recognized that cells of the immune system may be active in the brain, and that this may be an important factor in many central nervous system (CNS) diseases.
http://www.els.net/WileyCDA/ElsArticle/refId-a0000195.html
Working primarily with mice, lead author and University of Virginia neuroscience professor Dr. Jonathan Kipnis and his group identified a previously undetected network of lymphatic vessels in the meninges — the membranes that surround the brain and spinal cord — that shuttle fluid and immune cells from the cerebrospinal fluid to a group of lymph nodes in the neck, the deep cervical lymph nodes.
The newly discovered vessels — which were also identified in human samples — could explain a variety of pathophysiological conundrums, namely how the immune system contributes to neurological and psychiatric disease. “It’s early to speculate,” says Kipnis, “but I think that alteration in these vessels may affect disease progression in those neurological disorders with a prominent immune component, such as multiple sclerosis, autism and Alzheimer’s disease."
Alzheimer’s is thought to be caused by the build up and transmission of a protein called amyloid in the brain. It could be that the amyloid isn't being cleared properly via these lymphatic vessels, and that somehow improving their patency might help rid the brain of the pathologic protein.
It’s been clear for decades that there is some kind of relationship between the brain and the immune system. Abnormal immune activity was reported in schizophrenia in the 1930s, and numerous mental and neurologic illnesses are known or thought to have an immune component. However that Kipnis’ group identified a tangible, anatomical structure facilitating this relationship suggests that the brain and body are intimately intertwined, and that the brain is not the citadel it was once thought to be.
https://www.scientificamerican.com/article/important-link-between-the-brain-and-immune-system-found/
The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca2+ signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca2+ transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603014/pdf/12929_2017_Article_380.pdf
Chaperones are proteins that assist the correct folding of other protein clients either when the clients are being synthesized or at their functional localities. Chaperones are responsible for certain diseases. The sigma-1 receptor is recently identified as a receptor chaperone whose activity can be activated/deactivated by specific ligands. Under physiological conditions, the sigma-1 receptor chaperones the functional IP3 receptor at the endoplasmic reticulum and mitochondrion interface to ensure proper Ca2+ signaling from endoplasmic reticulum into mitochondrion. However, under pathological conditions whereby cells encounter enormous stress that results in the endoplasmic reticulum losing its global Ca2+ homeostasis, the sigma-1 receptor translocates and counteracts the arising apoptosis. Thus, the sigma-1 receptor is a receptor chaperone essential for the metabotropic receptor signaling and for the survival against cellular stress. The sigma-1 receptor has been implicated in many diseases including addiction, pain, depression, stroke, and cancer. Whether the chaperone activity of the sigma-1 receptor attributes to those diseases awaits further investigation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150837/
Mitochondrial dysfunction has been consistently reported as an early cause of Alzheimer’s disease and the treatment and cure for Alzheimer’s disease may be very connected to the cure for mitochondrial disease.
In a scientific study conducted in France at the University of Montpellier and INSERM, ANAVEX 2-73 demonstrated disease-modifying effects, including the ability to repair normal mitochondrial functionality in the hippocampus, the part of the brain involved with learning, memory and emotions.
http://mitochondrialdiseases.org/anavex-2-73-linking-mitochondrial-functionality-to-alzheimers/
http://www.anavex.com/files/1303_ADPD_Valentine.pdf
10. Mitochondrial dysfunction.
Mitochondrial dysfunction has been consistently reported as an early cause of Alzheimer’s disease and the treatment and cure for Alzheimer’s disease may be very connected to the cure for mitochondrial disease.
In a scientific study conducted in France at the University of Montpellier and INSERM, ANAVEX 2-73 demonstrated disease-modifying effects, including the ability to repair normal mitochondrial functionality in the hippocampus, the part of the brain involved with learning, memory and emotions.
http://mitochondrialdiseases.org/anavex-2-73-linking-mitochondrial-functionality-to-alzheimers/
http://www.anavex.com/files/1303_ADPD_Valentine.pdfeenous Neuroprotection in Neurodegenerative Diseases', at the University of Montpellier and INSERM. "Mitochondrial dysfunction and resulting oxidative stress are critical hallmarks of Alzheimer's disease pathology and believed responsible for increased amyloid-beta production and Tau hyperphosphorylation."
Australia and Spain - Excellent Choices for Anavex Trials.
Spain encourages clinical trials to be conducted in country, and Spain passed new regulations on clinical trials to increase transparency and simplify procedures. See: http://www.barcelonaclinicaltrials.org/en/spain-passes-new-regulations-clinical-trials-increase-transparency-and-simplify-procedures.
It seems that recruitment of patients for clinical trials in Spain with its National Healthcare system is likely to move along more quickly than in many other countries. http://www.farmaindustria.es/web_en/documents/press-releases/2017/03/09/clinical-trials-early-stages-growing-steadily-spain-already-make-51-total/
We do know that recruitment for the PDD trial in Spain commenced. http://pddtrial.com
The Spanish healthcare system is one of the best in the world.
https://www.expatica.com/new/es/healthcare/general-healthcare/healthcare-system-101467/
Life expectancy in Spain ranks number 3 in the world
http://www.worldlifeexpectancy.com/spain-life-expectancy
Spanish have highest healthy life expectancy in Europe
https://www.theguardian.com/world/2013/mar/05/spanish-highest-life-expectancy-europe
Australia is an ideal country for Alzheimer’s clinical trials because it offers more support for the trials, including funds for our trials.
It has also launched the world-first dementia network to fast-track treatment and research.
https://www.9news.com.au/national/2018/07/02/20/06/australian-dementia-network-launched-to-track-diagnosis-and-care-of-patients
As far as locations for Anavex trials are concerned we are good to go. I am thankful Anavex chose to conduct two of its clinical trials in Australia and Spain, and I say this after much research and thought.
There’s various rankings for the United States healthcare system. Unfortunately, it does not rank as high as Spain and many other nations. Google it and see.
Yes, Australia’s new initiative shortens recruitment. It fast tracks research to find a treatment for AD.
World-first dementia network to fast-track treatment and research
https://www.9news.com.au/national/2018/07/02/20/06/australian-dementia-network-launched-to-track-diagnosis-and-care-of-patients
This is probably another of several reasons why our AD trial is in Australia. We have the support of the Australian government and its people. Citing the length of clinical trial recruitment in other countries is meaningless.
The current Alzheimer’s trial is criticality important. Functional efficacy may be evident early on in this trial. That is the first thing I will be looking for as this trial progresses.
Anavex comments on FDA plan to expedite approval of new Alzheimer's drugs
”As reported by the New York Times, drugs in clinical trials would qualify for approval if people with very early-stage Alzheimer’s showed even subtle improvement in memory or reasoning tests. ANAVEX 2-73, the company’s lead compound for Alzheimer’s disease, has successfully completed a Phase 1 clinical trial in humans.”
https://www.anavex.com/anavex-comments-on-fda-plan-to-expedite-approval-of-new-alzheimers-drugs/
Current trial end points: ”Primary and secondary endpoints will assess safety and both cognitive and functional efficacy, measured through ADAS-Cog, ADCS-ADL and CDR-SB. ANAVEX®2-73 Phase 2a Alzheimer’s disease study previously demonstrated dose dependent improvement in exploratory endpoints of cognition (MMSE) and function (ADCS-ADL).”
Last and not least: ”Incorporating genomic precision medicine biomarkers identified in the ANAVEX®2-73 Phase 2a study is an incredibly important aspect of this study and we look forward to the insights gained through this data.”
I have done that and more. I try to think about and pursue all avenues when I have significant and worthwhile interests. I take proactive and positive steps in connection with what I believe is beneficial to me and to others, and I never consider any effort I make in that regard to be wasted.
Send this WSJ article to the World-first dementia net work to fast-track treatment and research, which is a new initiative in Australia. Ask them to fast track AVXL 2-73. Here is the WSJ article:
The Terminally Ill Need More Than the ‘Right to Try’
https://www.wsj.com/articles/the-terminally-ill-need-more-than-the-right-to-try-1534200199
Here is where you will find out more about the world-first dementia network to fast-track treatment and research
https://www.9news.com.au/national/2018/07/02/20/06/australian-dementia-network-launched-to-track-diagnosis-and-care-of-patients
Prevention, targeting disease earlier 'key' to tackling dementia
https://www.9news.com.au/national/2018/06/08/11/34/demnita-prevention-the-key-to-tackling-disease
The WSJ article mentioned above calls for immediate approval of an Alzheimer’s drug that has made it to Phase 3.
Treden:
Thank you for the excellent and valid points. I have been in this stock for years now, and we have made progress despite all of the criticism and ”flax.” I am pleased with Anavex, its financial condition, management and where we are today with the clinical trials. Tiny Anavex keeps chugging along slowly, but it is moving forward. It has come a long way for a small biotech upstart with limited resources. I realize this is not enough for some people on this board, but it is enough for me.
Great, thank you.
Kentucky, thank you for that interesting and informative analysis.
Tom:
What about the wedge like shape on the AVXL daily chart from early July, say July 3rd, to the present date? I am not skilled in technical analysis. However, looking at the daily chart, the prominent wedge structure formed over approximately 49 days from July 3 through today caught my eye. That to me is an unusual structure on the daily chart. What do you think about that?
Exceeding important find indeed as TTT’s reply points out. The correct title is CMC not CMS, which stands for chemistry, manufacturing and controls.
The chemistry, manufacturing and controls (CMC) section is a very important part of any clinical trial or marketing application. Drugs can be denied marketing approval if the quality of the product and the manufacturing process cannot be shown to be of a sufficiently high standard to satisfy regulators.
If you plan to MARKET a drug subsequent to APPROVAL you must meet regulatory requirements to demonstrate that you can safely and adequately produce the drug in commercial quantities.
Drugs can be denied marketing approval if the quality of the product and the manufacturing process cannot be shown to be of a sufficiently high standard to satisfy regulators. A simple way to state this is that regulators must constantly assure that the pill or capsule contains what it is supposed to contain. Good manufacturing practices must be established to ensure the pill contains the proper strength, that the pills or capsules are not tainted, etc. You must realize that to produce a drug in commercial quantities AS APPROVED is a big deal because it must be ensured that patients are getting the real thing.
I was just about to go to sleep, and this really woke me up. This is significant for me to know as an Anavex shareholder. It tells me something of extreme importance, but I do not give investment advice to anyone. So, go figure it out yourself.
As to proof, I agree. Personally, I have never thought of it as proof. However, now that you mention it, I have given some thought to what little Anavex has accomplished. All of the AVXL work done so far, which is extensive for this small company, falls in the category of circumstantial evidence. Still, it is not proof, but step by step it may get there. And, if it does, the world will be a better place for me, for you, but we must just wait and see.
"Think of your fellow man, lend him a helping hand
Put a little love in your heart
You see, it's getting late, oh, please don't hesitate
Put a little love in your heart
And the world will be a better place"
"Good luck, and goodnight" - as Edward R. Murrow ended his broadcasts.
I am an old man, and I go to bed early.
Good luck, my friend, in what ever you believe or do.
Responder groups may not be unusual, but I do not understand why that is a negative for Anavex stock investors, for what Anavex has done in studying responders in connection with its clinical trials, or for any drug company conducting a clinical trial.
I think the concept of precision medicine is based on determining what a patient may respond to for treatment and proceeding from there as opposed to simply applying the traditional ”cookie-cutter” medicine approach.
Here, Ariana has attempted to apply the cancer playbook to AD.
http://www.arianapharma.com/2017/12/arianas-kem-data-analysis-shows-positive-results-for-valiseek-val401-in-phase-ii-trial-for-non-small-cell-lung-cancer-nsclc-patients/
”Understanding “Super Responders” May Drive Personalized Treatment”. This his article begins by saying:
”Recent studies report that the future in health care lies in personalized medicine. Personalized medicine is a developing field of health care that takes into account individual clinical, genetic, environmental, behavioral and other factors in treating disease. This approach has been used successfully in some medical fields already, including oncology and pulmonology, specifically for cystic fibrosis. In late August 2017, personalized medicine took another step forward with the U.S. Food & Drug Administration approval of tisagenlecleucel (Kymriah®) for certain pediatric and young adult patients with acute lymphoblastic leukemia. Tisagenlecleucel is the first gene therapy approved in the U.S. that uses genetically modified cells from the patient’s own immune system, and “teaches” them to recognize, target, and kill cancerous cells.”
The latter article then goes on to state: ”To dive deeper, two researchers conducted a review and looked at what is already known about response to PAH-related medication, how clinicians identify “super responders” to these therapies and what the future might hold for personalized medicine in PAH patients. (https://www.ncbi.nlm.nih.gov/pubmed/28597766)
”Understanding “Super Responders” May Drive Personalized Treatment”’
https://phassociation.org/understanding-super-responders-may-drive-personalized-treatment/
See also: https://www.cancer.gov/about-cancer/treatment/research/exceptional-responders-initiative-qa
Yes,
“What is KEM®?
KEM® (Knowledge Extraction and Management) is a proprietary data mining tool based on Galois Lattices (also known as Formal Concept Analysis or FCA). KEM® uses association rules to fully explore complex datasets in order to reveal hidden relationships and to derive new hypotheses[1]. The technology originated from the laboratory of Professor Jean Sallantin, of the Artificial Intelligence Group at the CNRS (Centre National de Recherche Scientifique) in Montpellier, France. KEM® is the result of 10 years of further development for the life sciences at Ariana by experts in logic, drug development, biomarker research and development, statistics, chemistry, and biology [2,3,4].”
I believe it is a form of unsupervised learning. I think that is the problem with older standard analysis. I believe we recently saw an example of “supervised learning” when Biogen and Eisai, obtained a different outcome with a new measure of efficacy in the BAN240 trial. Biogen’s partner Eisai, a Japanese pharmaceutical company, came up with a new standard to measure ”success”. They, Biogen and Eisai, obtained a different outcome with a new measure of efficacy. Biogen’s partner Eisai, a Japanese pharmaceutical company, came up with a new standard to measure ”success” after failing with a previous measure. This ”success” measured by a new internally conflicted standard raised a red flag, and the scientific community called them out as we all know. Their strategy flopped.
What our trials show will be unbiased and should not subject to the criticism received by Biogen and Eisai. ”The machine learning methods are objective and purely data." (quote from the Anavex conference call). The data will speak for itself in each instance — each of the three Anavex trials.
“KEM® delivers unsupervised, unbiased, total data exploration”
http://www.arianapharma.com/technology/why-kem/
Doc’s earlier post gets it, and that is why I am not responding directly to his post and because what I am about to say is too basic for Doc. This only applies to posters that don't get it.
Let’s review what was said on the Anavex conference call the other day.
"The machine learning methods are objective and purely data driven...."
”...we have taken a completely unbiased data driven hypothesis free approach to the systematic analysis of our Phase 2a study.”...
”The use of machine learning rather than a commonly used hypothesis driven method, in which you select a hypothesis, which is then tested against data, has several advantages.”
....
”The machine learning methods are objective and purely data driven. ”
....
”That means there is no need for an prior hypothesis. So, it is more like just let the pure data speak.”
....
”It is note worthy that using this same unbiased data driven approach, the inclusion baseline MMSE score of greater of 20 as well as the concentration of the drug as the main driver of response was identified using this same objective ranking approach.”
.....
"In order to identify any biomarkers, we have taken a completely unbiased data driven hypothesis free approach to the systematic analysis of our Phase 2a study."
...
"Using the artificial intelligence technology KEM from Ariana Pharma, the relation between all parameters both clinical and genomic and the impact on outcome was ranked in an entirely unbiased way."
I repeat this part from the above: "....the main driver of response was identified using this same objective ranking approach.” Now what do you suppose was the main driver of the response?
Frankly, the older apporach of first coming up with an hypothesis is by its nature biased. Bias has been involved in older and existing AD clinical trials wherein it was determined beforehand that amyloid was the sole AD culprit so that is what we pursue, which is exactly what has been pursued time and time and time again without any success. Biogen's AD clinical trials, among many others, are biased.
KEM analysis is new and is acceptable to the FDA. If we succeed in any of the three Anavex trials, all using the same approach, the FDA will approve those trials.
Most everyone has been hoping for a commercial BP. We already have some partners such as Australia, Rett Foundation, and Fox Foundation, but that is not enough for some although it is fine with me for now. If we need a commercial partner, we will obtain one if and when it appears that any of the newly designed Anavex trials are about to be a success. BIG PHARMA DOES NOT INNOVATE. THEY SIT BACK, WAIT, AND SEE IF THE RISK TAKERS ARE ABOUT TO SUCCEED, AND THAT IS WHEN THEY MOVE. This is the way our "system" is designed. HOWEVER, ”TIMES ARE A CHANGIN”. THE RISK BIG PHARMA WILL EXPERIENCE AT SOME POINT IS TO MISS OUT ALTOGETHER on something really big simply because of 1. Precision medicine 2. Advances in technology (AI).
Think about the affect of change and advances of technology. What happens? Companies thought to be dominant and remain dominant have become extinct. One of many examples: Kodax. It did not accept change, and it rejected technology that replaced it.
Let’s review this quote again:
”The machine learning methods are objective and purely data. They enable the analysis of very small cohorts of patients, which systematically ranks biomarkers without any bias. And explores the discrimination and patient effect. That means there is no need for an prior hypothesis. So, it is more like just let the pure data speak.”
NEW TECNONOLGY AND PRECISOIN MEDICINE EMBRACED BY THE FDA allow for smaller, less expensive and faster clinical trials. ISN’T THAT WHAT WE (OR SHOULD) ALL DESIRE?
MY GOD, IS CIVILIZATION ADVANCING OR DECLINING? I think it is gradually advancing although it may sometimes be two steps forward and one step backwards.
”Times are a changin”.... Either you get it or you don't. If you don't get it, you become extinct. To put it on another level, what happens when a steamroller is approaching in your direction. If you think doing nothing and standing your ground is eliminating risks, you may become part of the pavement. Everything is a risk. Getting out of bed in the morning is a risk. The relevant question is, what is the right risk? For treating AD and numerous other CNS diseases, I think Anavex is pursuing the right risk.
The question asked by Robert LeBoyer from Roth Capital on the recent conference call is very important because it seems that the KEM analysis is further indication that heretofore the focus for treatment of AD has been on the wrong gene (ApoE4) or factors (APP factors) and that we are on the correct path. If the KEM analysis has validity, and I think it does, this question and the answer should attract much attention. Anavex remains a speculative investment, but with the KEM analysis this stock is not as speculative as it once was. We have come a long way. Perhaps there is light at the end of the tunnel? Here is the Q & A:
"Operator
Our next question comes from Robert LeBoyer from Roth Capital Partners. Robert, your line is now open.
Robert LeBoyer
Thank you and congratulations for on all of this progress. The question I have is related to the genomic studies. And the description that you just gave, Christopher, was very thorough and complete. The only other questions I would have on top of those things were whether you found any other correlations with other genes that have been associated with Alzheimer's such as ApoE4 or presenilin or any of the APP processing factors that have been preliminarily tied to Alzheimer's or if there’s any kind of information there?
Christopher Missling
Very good question and obviously the KEM analysis is exactly meant to find if there is a correlation to identify such a correlation. And we did not find any one for ApoE4 predominant genes are not – and I think the way to explain this is that the ApoE4 seemed to be indicating a risk factor of the Alzheimer's pathology.
So it is a correlation with the fact that you will likely become pathologic with Alzheimer's disease. But what we're looking at is the response with our drug. And the good news is that independently if you have ApoE4 gene carrying or if you do not have that gene – only have ApoE3 or ApoE2 that seem to be indicate you will have the same beneficial effect of the drug treatment independently of the fact that if you are likely getting Alzheimer's disease or not. So the drug seems to be responding in the same way independently of any risk factors of getting Alzheimer's disease in the first place. And that is right now our current understanding based on the analysis.
Robert LeBoyer
Okay, great. That's an important point. Thank you very much.
Christopher Missling
Thank you.”
Theodore Roosevelt was gifted in writing and speaking skills. I admire what he overcame in life, and what he accomplished dispite his afflictions. "Teddy" wrot this:
“It is not the critic who counts; not the man who points out how the strong man stumbles, or where the doer of deeds could have done them better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood; who strives valiantly; who errs, who comes short again and again, because there is no effort without error and shortcoming; but who does actually strive to do the deeds; who knows great enthusiasms, the great devotions; who spends himself in a worthy cause; who at the best knows in the end the triumph of high achievement, and who at the worst, if he fails, at least fails while daring greatly, so that his place shall never be with those cold and timid souls who neither know victory nor defeat.”
Christopher is striving. He dares to accomplish something great. Something that no person or entity has ever accomplished before. If he/Anavex fails at least they failed while daring greatly so that their "place shall never be with those cold and timid souls who neither know victory nor defeat".
So, let "those cold and timid souls" continue as critics. They do not count in my opinion.
A positive PR tomorrow is highly likely. I cannot think of any reason why it would not be. On the positve side our AAIC 2018 presentation was a plus whereas Biogen's was not as we all know. We should be in a fairly decent position financially for the time being, and we have an additional avenue in place to raise more capital on our own with Cantor. I do not want to speculate about news on the clinical trial front. However, again, I cannot think of any reason why we may have any negative news emerge at this point whereas there is room for positive news with enrollment on the continuing trial in Australia and the new PD trial in Spain. Hopefully, we will have some news on Rett. Christopher Missling is a "Trusted Member of Industry" when it comes to rare diseases. Why in the world would the FDA and everyone else not desire to see an AVXL 2-73 trial take place with Rett? I have thought about the FDA being concerned and, rightfully so, about looking closely at the safety issue in the Rett trial because by its nature it involves some young children, but the Rett organizaion has endorsed this trial, there is no cure for Rett, and I believe parents of Rett patients must be desperate for something that may help. I can imagine how desperate they may be because my sister died at the age of 22 after suffering for many years -- not from Rett but from complications from Spinal Meningitis. That was a long time ago, but she suffered for many years before she died. I was six years old, and she was two years old when the disease hit her. I remember that day seventy years ago. I was with her when she collapsed with her first seizure while watching me play a game of jacks. My family would have tried anything for a cure. This is one of the reasons why I hope Anavex has some success, and why I feel good about my investment in Anavex, which for me is substantial.
Bio:
Those are good true life stories. I am old enough to relate to the PT Barnum story for sure.
If I may, I will add to your post another element that may be illustrated by analogies of what goes on in nature. A Puffer Fish blows itself up to protect itself when it is threatened or frieghtened. Some animals protect themslves by making themselves look bigger by fluffing up their fur. Bears do this plus they stand up on their hind legs to make themselves look bigger and more powerful. When agnry they growl, pound the ground and sometimes they charge whatever is bothering. They may charge and retreat.
The way Biogen has been acting is strange as you surmised prior to AAIC 2018 and as you continue to do so now. It may be that Biogen feels threatened. It may be that it is desperate about its Alzheimer's pipeline. As you observe, we do not know the exact reason why Biogen did what it did relative to its Alzheimer drug on the eve of AAIC 2018, but we do know that it was an embarrassing flop. Much evidence shows that what Biogen published was sketchy, hurried, and plainly sloppy. Biogen opened itself and its drug up to criticism and it got it from experts and others. That cannot go unnoticed by the FDA and regulatory authorities in other parts of the world.
So, what we do know is that Biogen's ploy failed. Biogen attempted to use AAIC 2018 as an opportunity to make its Alzheimer's drug look like a big deal through a lot of huff, puff and fluff, but it failed. Perhaps its failure is a good thing -- for the benefit of patients and others such as Anavex and Christopher Missling. It does make Christopher look even more like a "Trusted Member of Industry".
I second that, Nidan. I am encouraged as well. Thank you, and thank Bio too.
Mycroft: Thank you.
Do not be the least bit dissuaded by the usual critics who may be suffering from the Semmelweis effect. There will continue to be opposition to Anavex no matter what. Unfortunately, the Semmelweis reflex is a like a disease in itself that is not quickly cured.
Robert Anton Wilson refered to this effect in his book, The Game of Life. In that book Timothy Leary made reference to the Semmelweis reflex as "Mob behavior found among primates and larval hominids on undeveloped planets, in which a discovery of important scientific fact is punished".
The amyloid plaque theory remains entrenched despite failure after failure. Despite these failures, the tendency will be to reject any new theory about how to treat Alzheimer's. It is unfortunate, but this effect to reject new evidence or new discoveries has existed throughout history.
A study OFP has cited is entitled ”Sigma-1 Receptor Agonists Induce Oxidative Stress in Mitochondria and EnhanceComplexIActivityinPhysiological Condition but Protect Against Pathological Oxidative Stress”. OFP mistakenly cites a small part of this article as evidence that AVXL 2-73 is altogether ineffective. Therefore, I encourage everyone to read the entire article - not just what I, OFP or others say. Unfortunately, you must pay approximately $40 as I did to obtain the entire article. Here is where the article may be located.
https://www.ncbi.nlm.nih.gov/pubmed/29127580
This study OFP cited actually concludes that AVXL 2-73 is neuroprotective. Tangui Maurice, an Anavex SAB member, participated in the study, but OFP cited part of this study without giving the title or naming any authors to argue that AVXL 2-73 is ineffective in treating AD disease. OFP is mistaken.
Sigma 1 is an s1R agonist as you all know. ”The study ..confirmed that s1R activityis closely related to mitochondrial physiopathology. In physiological conditions, s1R agonists are able to generate a moderate oxidative stress, through ROS production involving complex I activity. In pathological conditions, such as Aß-induced stress, s1R activity may help to contribute to a rapid restoration of mitochondrial physiology. ”
Apparently, the authors of the above study, Tangui Maurice Included, observed that some agonists like donepezil increase beneficial and non-beneficial oxidative stress. However, AVXL 2-73 may not increase the non-beneficial type of stress. The way I, and maybe others, such as our good friend and brilliant poster Bio, understand it, some degree of physiological oxidative stress is beneficial and other oxidative stress such as pathological oxidative stress is not.
If I may too quote from Wikipedia:
”In humans, oxidative stress is thought to be involved in the development of ADHD,[2] cancer,[3] Parkinson's disease,[4] Lafora disease,[5] Alzheimer's disease,[6] atherosclerosis,[7] heart failure,[8] myocardial infarction,[9][10] fragile X syndrome,[11] sickle-cell disease,[12] lichen planus,[13] vitiligo,[14] autism,[15] infection, chronic fatigue syndrome,[16] and depression[17] and seems to be characteristic of individuals with Asperger syndrome.[18] However, reactive oxygen species can be beneficial, as they are used by the immune system as a way to attack and kill pathogens.[19] Short-term oxidative stress may also be important in prevention of aging by induction of a process named mitohormesis.[20”
”Low-level oxidative stress induces an adaptive response commonly defined as hormesis; this type of stress is often related to reactive oxygen species (ROS) originating from the mitochondrial respiratory chain (mitochondrial hormesis or mitohormesis). The accumulation of transient low doses of ROS either through chronic physical activity or caloric restriction influences signaling from the mitochondrial compartment to the cell, reduces glucose metabolism, induces mitochondrial metabolism, increases stress resistance and ultimately, increases lifespan. ”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940498/
”Hormesis is a biological phenomenon whereby a beneficial effect (improved health, stress tolerance, growth or longevity) results from exposure to low doses of an agent that is otherwise toxic or lethal when given at higher doses. ”
https://gettingstronger.org/hormesis/
As Lane Simonian has pointed out in the comments section of his SA article about the above article cited by OFP:
”As always, there is another way to look at this. 4 out of 5 individuals at the highest dose of Anavex 2-73 either showed improvements or stabilized over two years.”
’The conclusion in your (OFP’s) linked article is an important one: "s1R (sigma 1 receptor) activity in mitochondria therefore results in a Ying-Yang effect, by triggering moderate ROS increase acting as a physiological signal and promoting a marked anti-oxidant effect in pathological (Aß) conditions." The means by which sigma 1 receptor agonists such as Aricept (donepezil) and Anavex 2-73 do so is by inhibiting intracellular calcium release invoked by amyloid oliogmers and dozens of other "toxins" (loosely defined). However both anti-amyloid antibodies and sigma 1 agonists such as Aricept only slow the further production of oxidants; they do not scavenge or reverse the damage done by oxidants. Korean red ginseng, various herbs in conjunction with conventional therapy, and Anavex 2-73 may limit the production of oxidants, scavenge oxidants, and reverse part of their damage. And the combination of doing all three appears to keep Alzheimer's disease from progressing early in the disease.’
Again, the study cited above confirmed that s1Ractivityis closely related to mitochondrial physiopathology. ...s1R activity may help to contribute to a rapid restoration of mitochondrial physiology, which I interpret as enabling the body to heal itself.
Again, as the title of the above OFP cited article indicates ”Sigma-1 Receptor Agonists Induce Oxidative Stress in Mitochondria and EnhanceComplexIActivityinPhysiological Condition but Protect Against Pathological Oxidative Stress”, sigma-1 receptor agonists -- especially AVXL 2-73, which may provide the right kind and degree of stress to help contribute to restoration of mitochondrial physiology that ignites the spark so to speak.
The OFP dited article says: ”The s1Ragonists(PRE-084,AN1-41,andtoalesserextent AN3-71)decreased Aß1–42 - (Aß1–42 - Amyloid) induced increase in mitochondrial ROS. s1R antagonists did not affect Aß1–42-induced increase in mitochondrial ROS. This observation confirmed that, in pathological conditions, s1R agonists have direct antioxidant potential in mitochondria. In order to determine whether this effect was due to a restoration of ETC, we analyzed the oxidative respiration and observed that PRE-084, AN1-41, and AN2-73 attenuated or significantly prevented the Aß1–42-induced decrease in RCR, indicating that the ETC worked more efficiently. Indeed, Aß1–42 altered in the same concentration range, both complex I and complex IV activities. These effects were significantly prevented by PRE-084 for complex I and IV activities and the ANAVEX compounds for complex IV activity. The s1R antagonists remained without effect. These data confirmed the direct mitochondria protective effect of s1R agonists. The mechanism of action may combine a general effect on TCA cycle efficacy and up-regulation of cellular anti-oxidant pathways.”
(Aß1–42 - Amyloid)
The electron transport chain (ETC) was indicated to work more efficiently, but this 2017 article cited indicated that more work was needed.
The above is a beginning of my effort to understand why donepezil may not be very beneficial or even harmful, and that AVXL 2-73 may be beneficial. I do not claim that I have the answer or that everything I say in this post is correct, but perhaps this will encourage a discussion that may lead to a better and more useful understanding.
Real money. We know what the AD market is worth simply based on the billions Biogen share price surged this year and in 2015 when it made its optimistic announcements about its drugs. Biogen made enthusiastic statements about Aducanumab in 2015, and about BAN2401 this year as we all know.
I purchased some Anavex shares about 4 years ago for 19 cents a share. Since that time, I have accumulated more shares at higher prices, averaging $2.99 in one account and $4.18 in another account. I have, however, in the interim traded quite a number of shares, sold covered options, and even sold puts all at a profit. I know how discouraging it can be to stick with a biotech like this, but I am comfortable with my Anavex positions in the two accounts averaging $4.18 and $2.99.
I have seen quite a number of ups and downs in this stock. I think it is likely that we may see the share price bottom tomorrow and a swing upward begin next week. I say this rather casually, but I base this on experience and a number of indications I follow. However, these shorter term moves are pretty much irrelevant to me. I am holding as many shares as possible — my long term core position for what I hope will be the huge move if and when efficacy is established. If it doesn’t happen I am prepared to face my loss. Anavex is one of a number of promising biotech stocks I own because biotech is one of the few places where real money may be made even if you win a few and lose a few. It just takes an awful lot of time and work.
More importantly, I like Anavex and the other biotech stocks I own because I hope for a better future for treatments and cures for diseases that have caused much misery and pain. Alzheimer's, Parkinson's and many other CNS diseases are cruel diseases that I have witnessed first hand.
Yes, Donepezil was developed by Eisai and Pfizer, but presently it is sold as a generic by multiple suppliers.
A brief respite, but potentially more danger ahead.
Biogen shares traded at 50 cents (+ or -) a share in the 1990s. I had a position in Biogen once, but not now. Of course, I am long Anavex and a number of other biotech stocks. It is does not bother me that someone refers to any of my share holdings as penny stocks. Frankly, I try to buy biotechs on the cheap and sell them at very high prices. Thanks to all of those that remind me that I am accumulating Anavex shares at the penny stock price level. That's great! Maybe I will succeed once again in buying extremely low and selling extremely high. That's what I always try to do. That's the only way real money can be made.
Yes, thanks.
I-Hub news wire (see above) : ”AVXL is another stock we like a lot because it is oversold in our opinion, and could be ready to breakout towards it’s 52 week high at anytime now.”
Yes, let's discuss this. I will be offline but available tomorrow after an early morning engagement sometime around 10:30 EST - 9:30 CST.
The AVXL 2-73 stories about responders needs to be spread as the Anavex clinical trials progress.
Agreed! Let's brainstorm about now to do that.
The Us Against Alzheimer’a website briefly mentions Anavex citing the LA Times article.
https://www.usagainstalzheimers.org/news/july-27-2018
The Alzheimer’a Association constantly raises money, and its website says many millions of dollars goes for ”research toward treatment, prevention and, ultimately, a cure.” http://act.alz.org/site/PageServer?pagename=walk_money
However, what do you think the odds are that Anavex has or will ever receive a dime? I believe instead funds are going to major pharmaceutical companies like Janssen, for example:
https://www.janssen.com/update-janssens-bace-inhibitor-program-regarding-DIAN-TU
Read both of the webpages I post above, and you will see what I mean.
Unfortunately, the Alzheimer’a Association appears to be brainwashed on the amyloid plaque hypothesis. As the below article discusses, it is time to change the focus, but it will probably be a cold day in hell before the AA comes around to doing that.
See https://www.nature.com/articles/d41586-018-05719-4
”The amyloid hypothesis on trial
As the development of treatments for Alzheimer’s disease continues to stumble, is it time for researchers to broaden their list of the condition’s potential causes?”
As the Nature article points out: ”The amyloid hypothesis has never been universally accepted...”
Most clinical trials are conducted outside the United States. The total in the U.S. 98,011 represent 35%. The total clinical trials in the world is 279,151 (100%). Conducting a clinical trial outside the United States is not a stigma any more than conducting a clinical trial in the United States is a stigma.
https://clinicaltrials.gov/ct2/resources/trends#RegisteredStudiesOverTimePostedResults
We are all humans, and we all live in the same world. If something works on a human outside the United States, why should it not work on a human in the United States?
What's more, based on your logic, you can no more assume that something is a fact any more than you can assume that something is not a fact.