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It appears that 2020 may be the big year for Anavex and AVXL 2-73!
AVXL 2-73's Chances of Approval:
Numerous Scientific Publications are Supportive for AVXL 2-73
AVXL 2-73 Animal Studies Confirm the Scienific Liturature
AVXL 2-73 Human Clinical Trials Confirm the Science and Show Promise
Real World Evidence is Supportive
The Anavex and Ariana Comparitave Study of Patients from Anavex’s AD trials and AD Patients from the ADNI Data Base is Positive.
As of the end of 2019, around 400 or so patients will have participated in AVXL 2-73 clinical trials for AD, PDD and Rett. Some of those patients are placebo patients. It may be that this time next year there will be 600 or more patients participating in Anavex’s clinical trials. However, Anavex may be expanding the clinical trials. PDD clinical trial results may be available mid 2020.
Slides from Anavex's most recent presentation:
“FDA’s new Real World Evidence Program Likely to have a Profound Impact on the Biopharma Industry” was the first slide in the most recent Anavex presentation wherein Anavex and Ariana did a comparitave placebo mimic study using patients from Anavex’s AD trials and patients from the ADNI data base.
The slide entitled “Use of Real World Evidence in Regulatory Settings is Gaining Momentum” from Anavex’s recent presentation mentions one drug, Blinatumomab, approved by the FDA with supporing Real World Evidence. That slide lists reasons and benefits for using Real World Evidence together with results from clinical trials:
• Collection of real-world data is not new
• May provide access to patients that may not have been considered in a clinical trial
• Ethical question of unnecessarily exposing patients to placebo
• Reducing size, duration and costs of trials
• Accelerating regulatory path
See the slide "ANAVEX®2-73 Selective Sigma-1 Receptor (SIGMAR1) Agonist Demonstrated Improved MMSE1 and ADCS-ADL2 Scores in Phase 2a AD Study through 148 Weeks" If this and other type of improvement (such as improved gut microbiota*, etc.) continues into 2020 with significant numbers of AVXL 2-73 treated patients, 2020 could be the big year for Anavex.
* "Communication between gut microbiota and the brain has been shown to be a critical requirement of a healthy brain function. The reduction in gut microbiota diversity has become one of the hallmarks of aging, and disturbances in its composition are associated with several age-related neurological conditions, including Alzheimer’s disease....”
Giau, V.V.; Wu, S.Y.; Jamerlan, A.; An, S.S.A.; Kim, S.; Hulme, J. Gut Microbiota and Their Neuroinflammatory Implications in Alzheimer’s Disease. Nutrients 2018, 10,
1765
https://www.anavex.com/anavex-life-sciences-presents-new-clinical-data-identifying-gut-microbiota-biomarkers-associated-with-improved-clinical-response-in-patients-treated-with-anavex2-73-at-2019-alzheimers-a/
As of the end of 2019, around 400 or so patients will have participated in AVXL 2-73 clinical trials for AD, PDD and Rett. Some of those patients are placebo patients. It may be that this time next year there will be 600 or more patients participating in Anavex’s clinical trials. PDD clinical trial results may be available mid 2020. “FDA’s new Real World Evidence Program Likely to have a Profound Impact on
the Biopharma Industry” was the first slide in the most recent Anavex presentation wherein Anavex and Ariana did a comparitave placebo mimic study using patients from Anavex’s AD trials and patients from the ADNI data base.
The slide entitled “Use of Real World Evidence in Regulatory Settings is Gaining Momentum” from Anavex’s recent presentation mentions one drug, Blinatumomab, approved by the FDA with supporing Real World Evidence. That slide lists reasons and benefits for using Real World Evidence together with results from clinical trials:
• Collection of real-world data is not new
• May provide access to patients that may not have been considered in a clinical trial
• Ethical question of unnecessarily exposing patients to placebo
• Reducing size, duration and costs of trials
• Accelerating regulatory path
It appears to me that 2020 may be the big year for Anavex and AVXL 2-73!
Xena is correct and therefore Anavex is investigating this as part of its ongoing clinical trials. See these references:
“...the microbiota is closely related to neurological dysfunction and plays a significant role in neuroinflammation through the secretion of pro-inflammatory cytokines. Changes in the homeostatic state of the microbiota leads to increased intestinal permeability, which may promote the translocation of bacteria and endotoxins across the epithelial barrier, inducing an immunological response associated with the production of pro-inflammatory cytokines. The activation of both enteric neurons and glia cells may result in various neurological disorders.”
Gut Microbiota and Their Neuroinflammatory Implications in Alzheimer’s Disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266223/pdf/
nutrients-10-01765.pdf
For example, "In a susceptible individual, inflammatory triggers (1) initiate immune responses in the gut that deleteriously impact the microbiota, increase intestinal permeability, and induce increased expression and aggregation of aSYN (2). Synucleinopathy may be transmitted from the gut to the brain via the vagus nerve (3b), and chronic intestinal inflammation and permeability promote systemic inflammation, which, among other things, can increase blood-brain barrier permeability (3a). Intestinal inflammation, systemic inflammation, and synuclein pathology in the brain all promote neuroinflammation (4) which drives the neurodegeneration that characterizes PD."
The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445611/
https://www.anavex.com/anavex-life-sciences-presents-new-clinical-data-identifying-gut-microbiota-biomarkers-associated-with-improved-clinical-response-in-patients-treated-with-anavex2-73-at-2019-alzheimers-a/
"Communication between gut microbiota and the brain has been shown to be a critical requirement of a healthy brain function. The reduction in gut microbiota diversity has become one of the hallmarks of aging, and disturbances in its composition are associated with several age-related neurological conditions, including Alzheimer’s disease. These changes in the gut microbiota composition induce increased permeability of the gut barrier and immune activation leading to systemic inflammation, which in turn may impair the blood-brain barrier and promote neuroinflammation, neural injury, and ultimately neurodegeneration.[4]" Giau, V.V.; Wu, S.Y.; Jamerlan, A.; An, S.S.A.; Kim, S.; Hulme, J. Gut Microbiota and Their Neuroinflammatory Implications in Alzheimer’s Disease. Nutrients 2018, 10,
1765
https://www.anavex.com/anavex-life-sciences-presents-new-clinical-data-identifying-gut-microbiota-biomarkers-associated-with-improved-clinical-response-in-patients-treated-with-anavex2-73-at-2019-alzheimers-a/
"The data, presented at the Alzheimer’s Association International Conference, represent the first microbiome measurements reported in a clinical trial of an investigational Alzheimer’s therapy. Because they come from a single sample taken from a small group in an extension study, without a baseline comparator, it’s impossible to know what these associations mean. But the findings are enough to nudge Anavex Life Sciences into adding microbiome changes to its new study of Anavex 2-73, according to Christopher Missling, PhD, president and chief executive officer of the company."
"Things shifted dramatically in 2017, with a seminal paper finding that germ-free mice inoculated with stool from Parkinson’s patients developed Parkinson’s symptoms. This study was widely heralded as a breakthrough in the field—the first time any neurodegenerative disease had been conclusively linked to dysregulations in the human microbiome."
Dr. Missling said ..... "It’s something of great interest, we think, and deserves to be investigated."
https://www.neurologyreviews-digital.com/neurologyreviews/nr_november_2019/MobilePagedArticle.action?articleId=1535393#articleId1535393
Yes, Anavex has this information, but is keeping this and much more close to the vest.
See https://www.anavex.com/anavex-life-sciences-presents-new-clinical-data-identifying-gut-microbiota-biomarkers-associated-with-improved-clinical-response-in-patients-treated-with-anavex2-73-at-2019-alzheimers-a/
"Communication between gut microbiota and the brain has been shown to be a critical requirement of a healthy brain function. The reduction in gut microbiota diversity has become one of the hallmarks of aging, and disturbances in its composition are associated with several age-related neurological conditions, including Alzheimer’s disease. These changes in the gut microbiota composition induce increased permeability of the gut barrier and immune activation leading to systemic inflammation, which in turn may impair the blood-brain barrier and promote neuroinflammation, neural injury, and ultimately neurodegeneration.[4]" Giau, V.V.; Wu, S.Y.; Jamerlan, A.; An, S.S.A.; Kim, S.; Hulme, J. Gut Microbiota and Their Neuroinflammatory Implications in Alzheimer’s Disease. Nutrients 2018, 10, 1765
See also:
Gut Microbiota and Their Neuroinflammatory
Implications in Alzheimer’s Disease
https://res.mdpi.com/d_attachment/nutrients/nutrients-10-01765/article_deploy/nutrients-10-01765-v3.pdf
"...chronic gut inflammation may increase the breakdown of blood–brain barrier, LPS permeability, and the generation of pro-inflammatory cytokines. Elevated levels of LPS were found in the plasma of AD patients compared to healthy controls [82]. In an animal study, peripheral administration of LPS led to neuroinflammation with an increase in levels of IL-6. Moreover, overexpression of IL-1ß resulted in a robust increase in tau phosphorylation in the triple transgenic mouse model of AD [121,135]. Furthermore, recent studies suggested that increased concentrations of circulating LPS, promoted by changes in intestinal permeability, may play a pivotal role in insulin resistance. Neuronal insulin resistance can increase the risk of developing AD, and insulin treatment may enhance memory function. Carvalho et al. found that antibiotic treatment greatly modifies the gut microbiota by reducing levels of Bacteroidetes and Firmicutes and circulating LPS levels. This modulation consequently improved glucose and insulin tolerance and activity in metabolically
active tissues [138]."
And again, this: Sigma-1 receptor activation alleviates blood-brain barrier dysfunction in vascular dementia mice
https://www.sciencedirect.com/science/article/abs/pii/S0014488618302085
Sigma-1 receptor activation alleviates blood-brain barrier dysfunction in vascular dementia mice
Author links open overlay panelDan-YangLiua1Tian-YanChia1Xue-FeiJiaPengLiuaXiao-XiaoQiaLinZhuaZi-QiWangaLinLicLingChenbLi-BoZoua
Show more
https://doi.org/10.1016/j.expneurol.2018.07.002Get rights and content
Highlights
•
Sigma-1 receptor agonist reduces BBB damage after brain ischemia reperfusion.
•
The neuroprotective and BBB protection functions of Sigma-1 receptor agonist are blocked by its antagonist.
•
BBB protective effect of agonist is lost when sigma 1 receptor knockout mice.
•
Agonist increases the expression and translocation of Sigma-1 receptor.
Abstract
Sigma-1 receptor (Sig-1R) activation has been shown to decrease infarct volume and enhance neuronal survival after brain ischemia-reperfusion (IR) in rodent models. The present study aims to investigate first the effect of Sig-1R activation on blood-brain barrier (BBB) disruption during experimental stroke. Male C57BL/6 mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 15?min, and the worst BBB leakage was observed on the 7th day after brain IR. To confirm the BBB protective role of Sig-1R, mice were divided into five groups (sham group, BCCAO group, PRE084 group, BD1047 group, PRE084 and BD1047 group; 29–35 mice for each group), and treated with agonist PRE084 (1?mg/kg) and/or antagonist BD1047 (1?mg/kg) for 7?days intraperitoneally once a day after BCCAO. Interestingly, PRE084 administration significantly improved neurobehavioral performance as well as healing of neuron damage and white matter lesions. PRE084 also reduced the leakage of Evans blue and IgG and attenuated the disassembly of BBB structural proteins, while the neuroprotective and BBB protective functions of PRE084 were blocked by BD1047. Furthermore, in Sig-1R knockout (Sig-1R KO) mice, brain IR produced more serious IgG leakage and degradation of BBB structural proteins than in wild-type model mice. In addition, the protective effect of PRE084 against the BBB was lost in Sig-1R KO mice after brain IR. Finally, treatment with PRE084 significantly increased the expression of Sig-1R in brain microvascular endothelial cells of mice that were subjected to brain IR and increased translocation of Sig-1R to the cell plasmalemma. Thus, we identified a previously unexplored role of Sig-1R in alleviating BBB disruption in stroke processes and have demonstrated that reversing BBB rupture through Sig-1R activation may be another promising method for cerebral protection against IR injury.
https://www.sciencedirect.com/science/article/abs/pii/S0014488618302085
Note: I could not download the full article.
Brain-Gut-Microbiota Axis in Alzheimer’s Disease
Karol Kowalski and Agata Mulak
Additional article information
Abstract
Disturbances along the brain-gut-microbiota axis may significantly contribute to the pathogenesis of neurodegenerative disorders. Alzheimer’s disease (AD) is the most frequent cause of dementia characterized by a progressive decline in cognitive function associated with the formation of amyloid beta (Aß) plaques and neurofibrillary tangles. Alterations in the gut microbiota composition induce increased permeability of the gut barrier and immune activation leading to systemic inflammation, which in turn may impair the blood-brain barrier and promote neuroinflammation, neural injury, and ultimately neurodegeneration. Recently, Aß has also been recognized as an antimicrobial peptide participating in the innate immune response. However, in the dysregulated state, Aß may reveal harmful properties. Importantly, bacterial amyloids through molecular mimicry may elicit cross-seeding of misfolding and induce microglial priming. The Aß seeding and propagation may occur at different levels of the brain-gut-microbiota axis. The potential mechanisms of amyloid spreading include neuron-to-neuron or distal neuron spreading, direct blood-brain barrier crossing or via other cells as astrocytes, fibroblasts, microglia, and immune system cells. A growing body of experimental and clinical data confirms a key role of gut dysbiosis and gut microbiota-host interactions in neurodegeneration. The convergence of gut-derived inflammatory response together with aging and poor diet in the elderly contribute to the pathogenesis of AD. Modification of the gut microbiota composition by food-based therapy or by probiotic supplementation may create new preventive and therapeutic options in AD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326209/#__sec1title
This Slide 9, with the Hampel 2019 reference, is entitled: ANAVEX®2-73 Selective Sigma-1 Receptor (SIGMAR1) Agonist Demonstrated Improved MMSE1 and ADCS-ADL2 Scores in Phase 2a AD Study through 148 Weeks
Slide 9 shows:
Adjusted change in MMSE1 (±SE) - p-value < 0.0001 and Adjusted change in ADCS-AD
2 (±SE) - p-value < 0.0008
Encouraging.
FDA Approving Drugs at Breakneck Speed, Raising Alarm
By Michelle Cortez and Cristin Flanagan
December 6, 2019, 9:00 AM CST Corrected December 6, 2019, 3:09 PM CST
The U.S. is approving new drugs so fast that companies are now preparing for a green light months in advance of the scheduled decision date, a pace that’s helping patients with rare or untreatable diseases but raising alarm among consumer advocates.
Global Blood Therapeutics Inc., maker of a new sickle cell disease drug called Oxbryta, built a booth to showcase the medicine at the annual meeting of the American Society of Hematology that begins this weekend -- even though the Food and Drug Administration’s deadline for approval was Feb. 26.
The move paid off: Oxbryta was given the go-ahead by the FDA on Nov. 25, almost three months ahead of schedule, and the branded booth will make its debut at the ASH conference in Orlando, Florida, on Saturday.
“It’s very much a change,” said Alethia Young, a biotechnology analyst at Cantor Fitzgerald in New York. “It has happened over the past five years, and it’s probably here to stay. In areas of high unmet need, FDA seems to be committed to getting medicines to these people as fast as possible.”
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Oxbryta’s approval added to a growing number of breakthrough products that have beaten their FDA deadlines by weeks and sometimes months. For normal medicines, the agency typically has 10 months to issue a ruling. For those with exceptional benefits, or that treat conditions with few existing therapies, it offers a priority review that takes just six months. From mid-October to mid-November, the agency approved five medicines in as little as eight weeks.
The shift is emerging as the FDA is approving new drugs at a record pace, and breakthroughs in biotechnology and genetics are enabling drug companies and their scientists to provide more specific data to federal regulators.
“It isn’t that we changed our policies and are saying we are going to approve drugs faster,” said Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, who joined the agency under President Ronald Reagan. “The difference now is we are going to see more of those because of the science. If there are people out there with no options and they have terrible diseases, we are going to get those drugs to them as fast as feasible.”
But even as drugmakers, investors and patients cheer on the agency’s pace, patient-safety advocates argue that speed comes at a price. Studies show medicines approved on a faster time line are more likely to have safety problems emerge after they become broadly available, while other treatments offer fewer benefits than anticipated.....
I am posting an excerpt from the article. For the entire article, see this: https://www.bloomberg.com/news/articles/2019-12-06/fda-is-green-lighting-drugs-at-breakneck-speed-and-raising-alarm
Thank you, amstock82 for your excellent post.
Yes, there is much we do not know.
F1ash: Thank you. Your post is helpful.
I have a question about this calculation you provided: ‘By my math the “high dose” group probably consists of 4 people’. My question is: How likely is it that the dosage of all the other patients remaining in the Anavex study would continue to remain on a lower dose if a higher dose was demonstrating results?
I think that sometime ago Anavex disclosed that the higher dose, whatever that dose is, was showing better results. Is it likely that all patients in the study that could tolerate a higher dose would at some point be switched to the higher dose if the higher dosed patients were experiencing a better benefit? I say this too because I think that more than 4 patients voluntarily continued to be dosed beyond the original clinical trial date or dates.
This was not in your post, F1ash, but another poster commented on yesterday’s announcement about the analysis where Blarcamesine treated patients in Anavex’s 104 week were compared to to propensity corrected patients from the ADNI data base by saying that the study included only 32 patients when actually the 32 patients from the Anavex 104 week study were compared to patients from the ADNI data base. I remember people on this board contending that the original 32 patient clinical trial would be more meaningful if the 32 patients administered AVXL 2-73 were compared to patients treated with a placebo. One may take issue with the use of the ADNI data base patients to make the comparison made, but it is the only measure available that may be used as an indication of whether AVXL 2-73 patients fair better than patients not treated with AVXL 2-73 although the latter patients may have been treated with a cholinesterase inhibitor (Aricept) as Doc pointed out.
Lastly, another post indicated that if the other patients from the ADNI data base were being treated with a cholinesterase inhibitor that may be a negative reflection on this study because cholinesterase inhibitor patients are actually worse off in the long run. This may have some ring of truth, but I find it difficult to believe that a regulator would say that this ADNI comparative study is invalid because patients in the ADNI data base were using a drug we approved that actually harms patients. Additionally, we do not know whether the ADNI patients were administered a cholinesterase inhibitor for a limited or extended time - meaning the use of the cholinesterase inhibitor may have been terminated because it was no longer effective.
Nidan:
Yes, data from all AD studies I believe is relevant whether it be evidence from past Anavex studies or evidence from other studies that may be used for comparison.
This analysis announced this morning where AD patients in the Phase 2a ANAVEX®2-73 (blarcamesine) cohort and AD patients from the ADNI control cohort were compared is certainly relevant and another meaningful piece of evidence. If this and all other evidence compares favorably with what will be revealed once data is analyzed and available from the ongoing Anavex trials, that will confirm the benefit of AVXL 2-73, buttress this study announced today, and will be unsurpassed any AD drug thus far.
One question that I would like to know is whether the patients selected from the ADNI data base were treated with any approved AD drug. If those patients were treated with any AD approved drugs, this could make the comparison to AVXL 2-73 even more significant.
Possibly. See the below article August 2018 article reposted by Xena entitled:
Fast-tracking of new drugs: getting the balance right
https://www.nps.org.au/australian-prescriber/articles/fast-tracking-of-new-drugs-getting-the-balance-right
“..... The traditional approach in the assessment of a new drug involves a sequence of clinical trials (phase I–III). Accumulated evidence of dose justification, efficacy and safety in specified treatment indications and target populations then enables the drug’s sponsor to apply for registration of the drug. However, in the last 20 years, several regulatory bodies have tried to develop and test fast-track approval processes for drugs to treat severe diseases for which the options are limited.
Following a review1 the TGA consulted about expedited approvals2 and has introduced a priority review pathway. This aims to assess new drugs within 150 days.3 The European Medicines Agency (EMA) introduced its PRIME (Priority Medicines) program of accelerated approval and priority review in 2016. The FDA already had such programs, and in 2017 new molecule drug approvals were at a 20-year record of 46 (more than double the 22 approved in 2016). Of the 46 new molecular entities, 18 (more than half for oncology indications) received approval through the fast-track pathway.4
In these programs drugs for serious illnesses are rapidly approved on the basis of limited clinical trial data or data reliant on surrogate outcome measures.......”
Therefore, I suppose the analysis I described in my earlier post to Nidan could be considered a surrogate or substitute for a real placebo controlled trial, but it would be best if Anavex is also able to provide supporting trial data from the existing placebo controlled trials. I cannot say that any submission for PA or fast track has been made although it seems that Anavex and Ariana may have taken a step in that direction. Otherwise, why do such an analysis as I describe? I think either in preparation of a submission or to attract a partner. In any event, I have to think that the analysis to be presented later this week is positive. The big question I have though is how does or how will this analysis stack up in comparison with data that will emerge from the ongoing randomized clinical trials.
Nidan:
What is Real-World data?:
Real world data (RWD) in medicine is data derived from a number of sources that are associated with outcomes in a heterogeneous patient population in real-world settings, such as patient surveys, clinical trials, and observational cohort studies. Real-world data refer to observational data as opposed to data gathered in an experimental setting such as a randomized controlled trial (RCT). They are derived from electronic health records (EHRs), claims and billing activities, product and disease registries. Real world data includes evidence, real world evidence, gathered by Anavex over many months - 104 + months.
If I correctly understand the title of Anavex’s presentation, what Anavex and its team has done is to compare the Blarcamesine treated patients in their 104 week study to propensity corrected patients from the ADNI that were not treated with Blarcamesine to mimic a randomized study. In other words, they used information from the ADNI database to find nontreated patients (AD patients that were not teated with Blarcamesine) that were otherwise comparable to patients that were administered Blarcamesine for 104 weeks. And, I assume that the presentation will show how comparable non-treated propensity corrected patients from the ADNI database compare to treated patients in the 104 week Blarcamesine study.
So, you may also want to know what propensity corrected patients means. See this article:
An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies
Peter C. Austin
“ The propensity score is the probability of treatment assignment conditional on observed baseline characteristics. The propensity score allows one to design and analyze an observational (nonrandomized) study so that it mimics some of the particular characteristics of a randomized controlled trial. In particular, the propensity score is a balancing score: conditional on the propensity score, the distribution of observed baseline covariates will be similar between treated and untreated subjects. I describe 4 different propensity score methods: matching on the propensity score, stratification on the propensity score, inverse probability of treatment weighting using the propensity score, and covariate adjustment using the propensity score. I describe balance diagnostics for examining whether the propensity score model has been adequately specified.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144483/
Of course we are familiar with the ADNI:
“The Alzheimer’s Disease Neuroimaging Initiative (ADNI) unites researchers with study data as they work to define the progression of Alzheimer’s disease (AD). ADNI researchers collect, validate and utilize data, including MRI and PET images, genetics, cognitive tests, CSF and blood biomarkers as predictors of the disease. Study resources and data from the North American ADNI study are available through this website, including Alzheimer’s disease patients, mild cognitive impairment subjects, and elderly controls.”
http://adni.loni.usc.edu/
The Anavex presentation is entitled:
LB19 - Novel analytics framework for augmenting single-arm Phase 2a open label trials with Real-World external control data: Application to the Blarcamesine (ANAVEX®2-73) study in Alzheimer’s disease matched with propensity corrected patients from Alzheimer’s Disease Neuroimaging Initiative (ADNI) exploring treatment effect on cognition at Interim two-year (104-Week)
timepoint
Mohammad AFSHAR (1), Coralie WILLIAMS (1), Nanthara SRITHARAN (1), Frederic PARMENTIER (1), Federico GOODSAID (2), Christopher MISSLING (3)
(1) Ariana Pharma, France, (2) Regulatory Pathfinders, United States, (3) Anavex, United States
In conclusion, I surmise that this presentation late Friday of this week is about a study/analysis Anavex did with Ariana, et al. using data from its clinical trials over 104 months and comparing that with data from ADNI to mimic a randomized trial - a virtual randomized trial. Of course, as you know, Anavex is also in the process of conducting actual randomized clinical trials with AVXL 2-73 as we speak, and I think it is important to wait and see what those trials reveal.
Yes Xena, and please note this from the article: “In these programs drugs for serious illnesses are rapidly approved on the basis of limited clinical trial data or data reliant on surrogate outcome measures ...... rather than clinical.”
And, consider the upcoming presentation by Anavex at CTAD on Friday, December 6 at 5:30 p.m. entitled: “LB19 - Novel analytics framework for augmenting single-arm Phase 2a open label trials with Real-World external control data: Application to the Blarcamesine (ANAVEX®2-73) study in Alzheimer’s disease matched with propensity corrected patients from Alzheimer’s Disease Neuroimaging Initiative (ADNI) exploring treatment effect on cognition at Interim two-year (104-Week) time-point.” To be presented by Mohammad AFSHAR (1), Coralie WILLIAMS (1), Nanthara SRITHARAN (1), Frederic PARMENTIER (1), Federico GOODSAID (2), Christopher MISSLING (3)
(1) Ariana Pharma, France, (2) Regulatory Pathfinders, United States, (3) Anavex, United States.
The terms used in describing this presentation such as “Real-World external control data”, “propensity corrected patients” may be revealing. For example, see this article:
An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies
- Peter C. Austin
“ The propensity score is the probability of treatment assignment conditional on observed baseline characteristics. The propensity score allows one to design and analyze an observational (nonrandomized) study so that it mimics some of the particular characteristics of a randomized controlled trial. In particular, the propensity score is a balancing score: conditional on the propensity score, the distribution of observed baseline covariates will be similar between treated and untreated subjects. I describe 4 different propensity score methods: matching on the propensity score, stratification on the propensity score, inverse probability of treatment weighting using the propensity score, and covariate adjustment using the propensity score. I describe balance diagnostics for examining whether the propensity score model has been adequately specified.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144483/
I believe it may be that Anavex and its team has compared the Blarcamesine treated patients in their 104 week study to propensity corrected patients from the ADNI that were not treated with Blarcamesine to mimic a randomized study. In other words, they used information from the ADNI database to find nontreated patients (AD patients that were not teated with Blarcamesine) that were otherwise comparable to patients that were administered Blarcamesine for 104 weeks. And, I assume that the presentation will show how comparable non-treated propensity corrected patients from the ADNI database compare to treated patients in the 104 week Blarcamesine study - a surrogate outcome measure so to speak that mimics a randomized trial.
Of course, Anavex is also conducting randomized clinical trials of AVXL 2-73 as we all know, and it is important that those clinical trials are demonstrating positive results. Hopefully, the ongoing clinical trial results compares favorably with what Anavex will reveal at the CTAD presentation this coming Friday in San Diego at 5:30 p.m. - 8:30 p.m. E.T. - 7:30 p.m. CST - 6:30 p.m M.T. However, I doubt that we will have much in the way of information about the ongoing clinical trials at the time of this CTAD presentation. In any event, it will be interesting to see what it is that Anavex presents at CTAD 2019.
Oxidative stress, aging, and diseases
Reactive oxygen and nitrogen species (RONS) are produced by several endogenous and exogenous processes, and their negative effects are neutralized by antioxidant defenses. Oxidative stress occurs from the imbalance between RONS production and these antioxidant defenses. Aging is a process characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is based on the hypothesis that age-associated functional losses are due to the accumulation of RONS-induced damages. At the same time, oxidative stress is involved in several age-related conditions (ie, cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, and cancer), including sarcopenia and frailty. Different types of oxidative stress biomarkers have been identified and may provide important information about the efficacy of the treatment, guiding the selection of the most effective drugs/dose regimens for patients and, if particularly relevant from a pathophysiological point of view, acting on a specific therapeutic target. Given the important role of oxidative stress in the pathogenesis of many clinical conditions and aging, antioxidant therapy could positively affect the natural history of several diseases, but further investigation is needed to evaluate the real efficacy of these therapeutic interventions. The purpose of this paper is to provide a review of literature on this complex topic of ever increasing interest.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927356/
The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314091/
Yes, I bought some today. Demark sequential gave a 9 and 13 buy count today. However, as you indicate, if selling is not exhausted for now it is close to that stage - just sense how down people are on this board. We have been here before. Possibly, the SP will decline further and form a double bottom along with the August $2.21 low, which may complete the C leg of an Elliott Wave ABC downward correction if that has not already occurred. Despite the science, positive pre-clinical trials conducted with new and better predictive heterozygous MECP2 mice, successful clinical trials that have progressed long term and are indicative of fruition, no one is paying attention because Anavex has no earnings and the old-line pundits have not told anyone to buy — yet.
Thank you. I commented on the article, but George found it. I replied to jimmy’s post about this article George found. It is a good article.
As Charles H. Dow used to say: “The public rarely sees values until they are pointed out,”—which means that the public does not lead, but is led in speculation. It rarely acts until it is told to act, or until action of some sort is suggested by a bit of verbal information, a market letter, etc.
It’s times like these that remind me “that the public does not lead but is led ... It rarely acts until it is told to act, or until action of some sort is suggested... The public rarely sees values...”, and so I continue to be different because I chose to find and recognize value. But to do that I must ignore the madness of the crowds that buy at the tops and sell at the bottoms. And I must remember that history repeats itself, but I must be patient and let it happen. Tomorrow will be another day... Have a good evening all!
This article supports Missling’s hypothesis that activating SR-1 results in homeostasis that, in turn, should lead one to believe that SR-1 agonist, AVXL 2-73 et al, may indeed benefit multiple CNS diseases as well as other disorders.
“Thus, the new finding of Tsai et al. suggests that the Sig-1R apparently provides the myristic acid, by means of myristic acid “hitchhiking” on the Sig-1R that allows p35 to bind to the lipid membrane where p35 can accomplish the balanced or homeostatic activation of cdk5. This ultimately results in the regulation of normal axonal growth and maintenance......
Neurodegenerative diseases are linked to tauopathy as a result of cyclin dependent kinase 5 (cdk5) binding to its p25 activator instead of its p35 activator and becoming over-activated. The overactive complex stimulates the hyperphosphorylation of tau proteins, leading to neurofibrillary tangles (NFTs) and stunting axon growth and development. It is known that the sigma-1 receptor (Sig-1R), an endoplasmic reticulum chaperone, can be involved in axon growth by promoting neurite sprouting through nerve growth factor (NGF) and tropomyosin receptor kinase B (TrkB)[1, 2]. It has also been previously demonstrated that a Sig-1R deficiency impairs the process of neurogenesis by causing a down-regulation of N-methyl-D-aspartate receptors (NMDARs)[3]. The recent study by Tsai et al. sought to understand the relationship between Sig-1R and tauopathy[4]. It was discovered that the Sig-1R helps maintain proper tau phosphorylation and axon development by facilitating p35 myristoylation and promoting p35 turnover. Neurons that had the Sig-1R knocked down exhibited shortened axons and higher levels of phosphorylated tau proteins compared to control neurons. Here we discuss these recent findings on the role of Sig-1R in tauopathy and highlight the newly presented physiological consequences of the Sig-1R-lipid interaction, helping to understand the close relationship between lipids and neurodegeneration.....
Neurodegenerative and CNS diseases, such as Alzheimer’s disease and Parkinson’s disease, are in part caused by disturbances in proper axonal maintenance and can be recognized by a decrease in axonal length[5–7]. ...”
Activation of Sig-1R “...ultimately results in the regulation of normal axonal growth and maintenance......
AVXL 2-73 may benefit a variety of CNS diseases. Additionally, AVXL 2-73 could very well be a homeostatic anti-aging drug. Neurodegenerative diseases are associated with aging.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827442/
Trading some Anavex shares has obviously been a good, wise and decent strategy, but holding some shares may where you make the most money. However, holding these shares long term requires patience and persistence to make real money in a promising biotech - especially a biotech in the CNS field even though the AVXL science as well as the preclinical and clinical trials to date have all been positive. Too many of us do not have the patience and persistence to prevail over the long term.
New and better mouse models. The mice used in the AVXL 2-73 Rett pre-clinical trial were "heterozygous MECP2 mice, a validated animal model for the disease". These mice are more predictive of success or failure. Better mouse models are now available for a number of diseases. Numerous scientific articles are are available to any one that is interested that discuss MECP2 mice for use in Rett clinical studies.
In general"
"There is a silver lining that, now, a better mouse model is available to confirm or refute promising results in traditional lab mice."
—Franck Carbonero, Washington State University
https://www.the-scientist.com/news-opinion/new-mouse-model-predicts-two-clinical-trial-failures-in-humans--66223
Anavex Life Sciences Announces Publication of Foundational Data for ANAVEX®2-73 (blarcamesine) in Rett Syndrome
"heterozygous MECP2 mice, a validated animal model for the disease" were used in the AVXL 2-73 study. Therefore, a comparison of the use of these specific mice to the predictive value of other mice is an apples and oranges comparison.
All prescription drugs have side effects. The active ingredients of drugs must be potent to treat diseases. Aricept (donepezil hydrochloride) has side effects. Side effects may be avoided by gradually increasing dosage. Some (not all) of donepezil side effects are listed below, some of which you refer in your response to Falconer’s post:
“Dosage is based on your medical condition and response to treatment. To reduce your risk of side effects (such as nausea and diarrhea), your doctor will start this medication at a low dose and gradually increase your dose over weeks to months. Follow your doctor's instructions carefully. Do not increase your dose or use this drug more often than prescribed.”
https://www.webmd.com/drugs/2/drug-14334-9218/donepezil-oral/donepezil-oral/details
“Aricept (donepezil hydrochloride) is a cholinesterase inhibitor that reduces or prevents acetylcholinebreakdown in brain tissue. Aricept is used to treat mild to moderate dementia like that found in patients with Alzheimer's disease. Aricept is not a cure; it reduces symptoms. Aricept is available as a generic. Common side effects of Aricept include
feeling unwell (malaise),
appetite loss,
weight loss,
sleep problems (insomnia),
muscle cramps,
tiredness,
drowsiness,
dizziness,
weakness,
shakiness (tremor),
itchy skin,
nausea,
vomiting, or
diarrhea.
Tell your doctor if you experience serious side effects of Aricept including painful urination, seizures, chest pain, and GI symptoms of tarry or bloody stools and vomiting blood or material that resembles "coffee grounds."
Aricept (donepezil hydrochloride) is available for oral administration in film-coated tablets in doses of 5, 10, or 23 mg of donepezil hydrochloride. Aricept may interact with many drugs; tell the physician if you have a history of breathing problems, heart disease, fainting, seizures, GI diseases or urinary problems because they may get worst with this drug. Aricept is not recommended for use in pregnant or breastfeeding women. Aricept safety and effectiveness has not been studied in the pediatric population.
Our Aricept Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur.”
https://www.rxlist.com/aricept-side-effects-drug-center.htm
It may be the 150 days runs from acceptance of a formal application. However, see this:
"The timeframe is calculated from acceptance for evaluation through to the delegate's decision."
https://www.tga.gov.au/publication/priority-registration-process
Dranesthesia:
The author of this article, Paul Kubler, does not agree with your statement that "Until they have a large appropriately powered study that confirms their thesis than they have nothing." https://www.nps.org.au/australian-prescriber/articles/fast-tracking-of-new-drugs-getting-the-balance-right
Paul Kubler that wrote the article has received sponsorship from Bristol-Myers Squibb to attend the 2017 EULAR Annual European Congress of Rheumatology and has acted as a consultant to Abbvie, Eli Lilly and Reckitt Benckhiser.
Read the article, but I summarize the article below:
I. Patients and their doctors have a growing desire to access new drugs as soon as possible.
2. A traditional drug regulatory framework may no longer be the most appropriate assessment process for dealing with quickly evolving scientific advances.
3. In the last 20 years, several regulatory bodies have tried to develop and test fast-track approval processes for drugs to treat severe diseases for which the options are limited.
4. That, as advocates maintain, targeted treatments such as modern immunotherapies do not fit current regulatory processes.
5. Novel immuno-oncology drugs are clinically tested in trials with small patient numbers and often in the setting of knowing the patient’s genetic profile.
6. These attributes may allow for better prediction of response with fewer significant adverse events.
7. Advances in digital technology, remote monitoring, patient sensors and data analytics are allowing for improved recording of reliable and validated patient-related outcomes in studies with smaller sample sizes.
8. Making a drug available early with temporary authorisation is not a new concept, particularly for patients with life-threatening or seriously disabling conditions for which there is a clear unmet therapeutic need.
AVXL 2-73 is unquestionably a candidate for fast track provisional approval for one or all of the CNS indications involved in its existing multiple clinal trials.
Those that argue against AVXL 2-73 obtaining a fast or provisional approval in Australia are using traditional drug regulatory processes for approval of a drug in support of their arguments. Those arguments do not fit here, and are clearly outdated. In March 2018, Australia adopted a new provisional pathway as discussed below, and it definitely encompasses faster non-traditional approval for drugs for serious diseases with an unmet need, including dementia.
The eligibility criteria are (a) a new prescription medicine or new indications medicine, (b) treating a serious condition with a favorable comparison against existing therapeutic goods, (d) a major therapeutic advance and (f) evidence of a plan to submit comprehensive clinical data. https://www.tga.gov.au/provisional-approval-pathway-prescription-medicines#what
Provisional approval in Australia recognizes that:
I. Patients and their doctors have a growing desire to access new drugs as soon as possible.
2. A traditional drug regulatory framework may no longer be the most appropriate assessment process for dealing with quickly evolving scientific advances.
3. In the last 20 years, several regulatory bodies have tried to develop and test fast-track approval processes for drugs to treat severe diseases for which the options are limited.
4. That, as advocates maintain, targeted treatments such as modern immunotherapies do not fit current regulatory processes.
5. Novel immuno-oncology drugs are clinically tested in trials with small patient numbers and often in the setting of knowing the patient’s genetic profile.
6. These attributes may allow for better prediction of response with fewer significant adverse events.
7. Advances in digital technology, remote monitoring, patient sensors and data analytics are allowing for improved recording of reliable and validated patient-related outcomes in studies with smaller sample sizes.
8. Making a drug available early with temporary authorisation is not a new concept, particularly for patients with life-threatening or seriously disabling conditions for which there is a clear unmet therapeutic need.
''In Australia, like the rest of the world, patients and their doctors have a growing desire to access new drugs as soon as possible. They hope to make an impact on conditions with limited pharmacotherapeutic options, such as cystic fibrosis and rare cancers like mesothelioma. New approaches to more common diseases, such as lung cancer and dementia, may offer greater efficacy or less toxicity than current therapies. The pharmaceutical industry is also hungry for expedited drug approvals as a vehicle to reward and encourage innovation. Faster approvals may increase company profits as products get to the market more rapidly....
...a traditional drug regulatory framework may no longer be the most appropriate assessment process for dealing with quickly evolving scientific advances.
The traditional approach in the assessment of a new drug involves a sequence of clinical trials (phase I–III). Accumulated evidence of dose justification, efficacy and safety in specified treatment indications and target populations then enables the drug’s sponsor to apply for registration of the drug. However, in the last 20 years, several regulatory bodies have tried to develop and test fast-track approval processes for drugs to treat severe diseases for which the options are limited.
Following a review1 the TGA consulted about expedited approvals and has introduced a priority review pathway. This aims to assess new drugs within 150 days....
In these programs drugs for serious illnesses are rapidly approved on the basis of limited clinical trial data or data reliant on surrogate outcome measures, some of which are biochemical, for example glycated haemoglobin (HbA1c), rather than clinical. Anticancer drugs may be approved on response rates, often measured over relatively short time frames, rather than on improved survival.....
Advocates of rapid access to new therapies claim that targeted treatments such as modern immunotherapies do not fit current regulatory processes. With an enhanced contemporary understanding of disease pathogenesis pre-study, novel immuno-oncology drugs are clinically tested in trials with small patient numbers and often in the setting of knowing the patient’s genetic profile. It is claimed that these attributes allow for better prediction of response with fewer significant adverse events. Furthermore, advances in digital technology, remote monitoring, patient sensors and data analytics are allowing for improved recording of reliable and validated patient-related outcomes in studies with smaller sample sizes.
In March 2018, the TGA announced a provisional approval pathway. This will allow drugs to be available for up to six years based on preliminary data.9 The anticancer drug olaratumab is the first drug to be considered for provisional approval in Australia.
Access to new therapies is a balance between evidence (determining the risk of acceptable adverse effects versus efficacy) and the speed of availability, intersected by the issue of affordability. Making a drug available early with temporary authorisation is not a new concept, particularly for patients with life-threatening or seriously disabling conditions for which there is a clear unmet therapeutic need. Temporary access is akin to a learner driver receiving their provisional licence – a full licence is only granted after more experience. Rapidly approved drugs should receive provisional registration for a period of three years and the drug company should be required to provide annual data on the postmarketing experience.''
https://www.nps.org.au/australian-prescriber/articles/fast-tracking-of-new-drugs-getting-the-balance-right
No patient taking any drug is going to stay the same and/or get better with time. Furthermore, none of us will remain the same, and we will all decline as time goes by whether we take prescription drugs or not. We are all going to demise and die at some point. But, to put this in another perspective, cancer drugs are approved that merely extend a patient’s life for a matter of months. This will be my last post for the near future. I will not read or reply to any replies. Have a good day, a good remainder of the summer, and good luck, etc., etc.
Excellent news that the indication is that AVXL 2-73 positively impacts the gut, which is a critical component of a healthy brain function.
The following is from the AAIC July 14 - 18, 2019 presentation entitled Exploring Gut Microbiota as a Source of Potential Biomarkers: Initial Results from the ANAVEX ® 2Alzheimer’s Disease Clinical Study:
•Communication between gut microbiota and the brain is a critical component of a healthy brain function–identified in studies in the last decade [1,2,3]
1.Giau, V., Wu, S., Jamerlan, A., An, S., Kim, S., & Hulme, J. (2018). Gut microbiota and their neuroinflammatoryimplications in Alzheimer’s disease. Nutrients, 10(11), 1765.2.Calvani, R., Picca, A., Lo Monaco, M. R., Landi, F., Bernabei, R., & Marzetti, E. (2018). Of microbes and minds: a narrative review on the second brain aging. Frontiers in medicine, 5, 53.3.Kowalski, K., & Mulak, A. (2019). Brain-Gut-Microbiota Axis in Alzheimer’s Disease. Journal of neurogastroenterologyand motility, 25(1), 48.
•Higher levels of microbiota families i.e. Ruminococcaceaeand Porphyromonadaceae–associated with improvedANAVEX®2-73 response at week 148 (p<0.01 and 0<0.04, respectively)
ANAVEX®2-73 may have beneficial homeostatic effect on brain-gut-microbiota axis
Everything I have seen remains positive for Anavex and its trials, including the news this morning. Although clinical trials designed or based on the precision the medicine approach may hold the hope to expedite the approval of drugs, these trials take time and need to show safety and efficacy for a number of patients over a reasonable period of time. On one hand Anavex has been criticized for reporting positive results for a small number of trial participants over a relatively short period of time, and it is also criticized for not reporting positive results for patients over a relatively short period of time. I think that even if Anavex reported positive results for some patients enrolled earlier than others, it would be criticized for jumping to conclusions about its drug before it has been tested on a greater numbers of patients for longer periods of time. Let's wait for the trials to be completed and for the results to be analyzed. In the meantime, I do not know of any sound basis to be negative about what Anavex has reported to date.
Yes, I suppose NFLX swing trades may be good opportunities if timed right. I also think that NFLX bearish option spreads are good from time to time. Recently, I have made some money on bear put spreads.
Yes. This best explains the announcement.
I agree. I think this NFLX bounce most likely will not last for too long. It may close that gap down from July 17th - 18th before it makes another move down.
I agree. I am expecting a market correction between now and the end of the year. It could happen soon. Possibly in August?
Man, that answer by Michael, is a good example of a bureaucratic non-answer. Biogen, has been successful overall, but it is clearly failing in its struggle when it comes to treating AD. It may very likely be that Biogen is saving face while pursing another AD strategy through and with the help of Eisai as its partner in crime. Actually, given what has transpired, that is not a good strategy for Biogen.
NFLX -
Very little, if anything, to gain and a tremendous amount to lose on any long position in this stock.
Fundamentally and technically, there is no reason for me to own this stock. In fact, I think it is foolish and down right dangerous for me to own NFLX based on enormous competition, the disruption of its model (content availability at a cheap cost) and enormous investments of capital to attempt to replace content as well as the substantial lack of experience do so.
NFLlX hopes to compete with numerous others much more capable and experienced to produce content- not to mention the price competition of the likes of Disney, which is cheaper, as well as the numerous other competitors that chip away its subscriber base and more ...
Analyst that stick with it must have a vested interest for doing so. The valuation models of these analyst will in time fail because they argue and assume that NFLX will maintain, and continue to increase its revenue and market position, but we already have evidence to expect further subscriber loss -decline of revenue - while NFLX takes on cosmic debt in its attempt to do so. This tree, like all others, will not continue to grow to the sky. It is being disrupted by the former disrupted. It is Disney and others opportunity to be the disruptor, and NFLX’s turn to be disrupted.
Anavex remains relatively undiscovered and disrespected at this point. Ironically, Biogen and others that have failed in pursuing the amyloid removal hypothesis for treating AD maintain respect. Most investors I think are lazy. They wait for someone on WS to tell them what is a good deal and what to do. They are not willing to spend the time or make the effort to learn new scinece or theories even when the old ones have failed. It is simply too difficult for them to do so.
Instead, most investors will react emotionally without making an effort to understand the potential of Anavex's drugs. They simply react as part of a herd mentality, but that is what makes Anavex a good deal with a low price with a potentially high return. This, I think, is where real money may be made - not by investing in the established Biogens of the world.
Therefore, my inclination is to ignore comments made about the day to day price of this or any stock. Many comments are based on greed, fear, frustration, euphoria or some other emotion and self serving cryptic messages repeated day after day without any substance or fundamental support. Nothing that I have heard gives me any reason to change my mind about my long term investment in Anavex. I will not be running with the herd.
THIS WEEKS NEWS IS GOOD NEWS. AVXL 2-73 MAY INFLUENCE THE BODY TO CURE ITSELF AS HAS BEEN THE HYPOTHESIS ALL ALONG.
Mind-body connection:
"For example, neurological pathways connect parts of the brain that process emotions with the spinal cord, muscles, cardiovascular system, and digestive tract. This allows major life events, stressors, or emotions to trigger physical symptoms. You may have experienced this aspect of the mind-body connection when you feel butterflies in your stomach when you feel nervous, or when you heart feels like it is pounding out of your chest when you are under intense stress.
These intersecting systems help to establish the mind-body connection that influences the maintenance of health or the development of disease. For example, emotions like anxiety can trigger increased stress hormones, which may suppress the immune system and set the stage for the development of infections or cancer."
https://chopra.com/articles/mind-body-connection-understanding-the-psycho-emotional-roots-of-disease
The Brain Mind Body Connection with Dr. Rudy Tanzi
https://www.pbs.org/video/brain-mind-body-connection-dr-rudy-tanzi-wsvlfg/
''The Alzheimer’s disease puzzle Part 2: Clues from the microbiome
July 16, 2018
|
Madeline West & Dr Amy Loughman
In the previous article, we discussed limitations of current drug treatment approaches for Alzheimer’s disease (AD) and the growing understanding about the importance of lifestyle and health behaviours. This is where the gut microbiome comes in.
How could the microbiome be involved?
The bidirectional communication that takes place between the gut microbiota and the central nervous system has been coined the now popular term “gut-brain axis” that we write about here often. Our knowledge of this phenomenon has increased rapidly over recent years with the gut now associated with mental health and neurological conditions including depression, Parkinson’s disease, Huntington’s disease, and autism spectrum disorders. A small but convincing body of research also suggests a critical role of the microbiome in AD. Animal studies have shown that the microbiome and its metabolites play a causal role in AD by modulating blood-brain barrier permeability and amyloid levels. Additionally, preliminary data also show microbiome differences in people with early AD. ''
https://www.mindbodymicrobiome.com/single-post/2018/07/17/The-Alzheimer%E2%80%99s-disease-puzzle-Part-2-Clues-from-the-microbiome
Think Twice: How the Gut's "Second Brain" Influences Mood and Well-Being
The emerging and surprising view of how the enteric nervous system in our bellies goes far beyond just processing the food we eat
https://www.scientificamerican.com/article/gut-second-brain/
Anavex Life Sciences Presents New Clinical Data Identifying Gut Microbiota Biomarkers Associated with Improved Clinical Responses:
''The analysis was conducted using Ariana Pharma’s KEM® Artificial Intelligence, an FDA-tested technology to systematically explore combinations of biomarkers. Results revealed that patients treated with ANAVEX®2-73 had high levels of two gut microbiota families, Ruminococcaceae and Porphyromonadaceae, which were associated with improved activities of daily living (ADCS-ADL) at week 148 (p<0.01 and p<0.04, respectively).
Communication between gut microbiota and the brain has been shown to be a critical requirement of a healthy brain function. The reduction in gut microbiota diversity has become one of the hallmarks of aging, and disturbances in its composition are associated with several age-related neurological conditions, including Alzheimer’s disease. These changes in the gut microbiota composition induce increased permeability of the gut barrier and immune activation leading to systemic inflammation, which in turn may impair the blood-brain barrier and promote neuroinflammation, neural injury, and ultimately neurodegeneration.4
Numerous pre-clinical studies demonstrate beneficial effects of SIGMAR1 (S1R) agonists on neuroinflammation, including with ANAVEX®2-735. The effect might potentially be reversal of the microbiota imbalances and might have a homeostatic effect on the brain-gut-microbiota axis.''
Anavex Life Sciences Presents New Clinical Data Identifying Gut Microbiota Biomarkers Associated with Improved Clinical Response...
https://www.globenewswire.com/news-release/2019/07/17/1884144/0/en/Anavex-Life-Sciences-Presents-New-Clinical-Data-Identifying-Gut-Microbiota-Biomarkers-Associated-with-Improved-Clinical-Response-in-Patients-Treated-with-ANAVEX-2-73-at-2019-Alzhei.html
CHECK OUT THE MIND BODY CONNECTION AND SPECIFICALLY THE GUT'S CONNECTION WITH THE BRAIN. IT IS EASY RESEARCH FOR ANYONE THAT DESIRES TO LEARN. YOU CAN EASILY FIND NUMEROUS REFERENCES RELATED TO THIS SUBJECT.
The Anavex news this week was indeed good news. All one needs to do is research the mind-body connection to appreciate it. However, that is what AVXL 2-73 is all about.
Is Targeting Brain Inflammation The Key To Beating Alzheimer's? | NBC Nightly News
Yes, it will probably continue to move up for now. Like John Maynard Keynes said: “The market can remain irritional for longer than you can remain solvent.”
Autophagy – One way AVXL 2-73 may work.
AVXL 2-73 induces autophagy. “Based on the data presented here, the use of available Sig-1R agonists to stabilize protein homeostasis by promoting autophagy may represent an added value for such a treatment approach and strongly supports further clinical studies for prevention and treatment of neurodegeneration.” https://www.mdpi.com/2073-4409/8/3/211/htm.
Autophagy fights disease through cellular self-digestion
''Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.''
https://www.nature.com/articles/nature06639
Chaperones in autophagy
Author links open overlay panelSusmitaKaushikAna MariaCuervo
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https://doi.org/10.1016/j.phrs.2012.10.002Get rights and content
Abstract
Cells continuously turn over proteins through cycles of synthesis and degradation in order to maintain a functional proteome and to exert a tight control in the levels of regulatory proteins. Selective degradation of proteins was initially thought to be an exclusive function of the ubiquitin–proteasome system, however, over the years, the contribution of lysosomes to this selective degradation, through the process of autophagy, has become consolidated. In this context, molecular chaperones, classically associated with protein folding, unfolding and assembling have been revealed as important modulators of selectivity during the autophagic process. Here, we review this relatively new role of chaperones in mediating selective autophagy and comment on how alterations of this function can lead to human pathologies associated to proteotoxicity.
https://www.sciencedirect.com/science/article/abs/pii/S1043661812001880
ANAVEX®2-73 activates the Sigma-1 receptor (S1R) protein, which serves as a molecular chaperone and functional modulator involved in restoring homeostasis.
See: https://www.globenewswire.com/news-release/2019/03/11/1751068/0/en/Anavex-Life-Sciences-Reaches-50-Enrollment-Threshold-in-ANAVEX-2-73-Parkinson-s-Disease-Dementia-PDD-Phase-2-Study-Ahead-of-Schedule.html
Chemical Inducers of Autophagy That Enhance the Clearance of Mutant Proteins in Neurodegenerative Diseases*
Abstract
Many of the neurodegenerative diseases that afflict people are caused by intracytoplasmic aggregate-prone proteins. These include Parkinson disease, tauopathies, and polyglutamine expansion diseases such as Huntington disease. In Mendelian forms of these diseases, the mutations generally confer toxic novel functions on the relevant proteins. Thus, one potential strategy for dealing with these mutant proteins is to enhance their degradation. This can be achieved by up-regulating macroautophagy, which we will henceforth call autophagy. In this minireview, we will consider the reasons why autophagy up-regulation may be a powerful strategy for these diseases. In addition, we will consider some of the drugs and associated signaling pathways that can be used to induce autophagy with these therapeutic aims in mind.
Intracellular protein misfolding and aggregation are features of many late-onset neurodegenerative diseases called proteinopathies. These include Alzheimer disease, Parkinson disease, tauopathies, and polyQ3 expansion diseases such as HD and various SCAs such as SCA3 (1, 2). Currently, there are no effective strategies to slow or prevent the neurodegeneration resulting from these diseases in humans.
https://www.ncbi.nlm.nih.gov/pubmed/20147746