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Investor: Thank you. I agree that there will be a class action lawsuit attempt unless the pending data is good or at the very least mixed as you say. I do believe that Missling’s experience from the class action lawsuit filed a few years back and ultimately dismissed is not so distant from his memory that he would risk another lawsuit. Additionally, Anavex has had good and competent legal representation in the past. Presumably, Missling has been in touch with legal counsel leading up to the announcement of this important data, which is to be presented at a significant event, CTAD. It is likely that he has consulted with the same or equally competent counsel because this AD TLD is pivotal. If I am correct about all of this, I think it is likely that the imminent news is, at a minimum, to be good enough to at least avoid another class action lawsuit.
This leaves open another question: What does the market expect? What is the sentiment/expectation regarding the upcoming presentation? Based on AVXL’s current price, it seems that good news is not built into the share price. However, I am not sure about mixed results, but mixed results may be disappointing to some extent thereby causing somewhat of a move down.
Bottom line, if the news is good, we should see a move up in share price. If mixed, there will likely be some drop in share price. If the news is not so good and worse than mixed, the share price, Anavex, and Missling will be in “hot water” as we say, and we will be going through another lawsuit. The wheels of justice grind slowly, as Anavex, Missling and all of us know. So, it would be stunning if Anavex/Missling put us through another class action lawsuit - especially after the class action a few years ago.
But, as Yogi Berra said, “'It's tough to make predictions, especially about the future'”. Yogi also said, “If you see a fork in the road take it”. Hopefully Missling by chance is choosing the right fork in the road that will avoid lawsuits and move the company forward. If not, we should attend Missling’s funeral as Yogi would recommend. Last Yogi quote: “Always go to other people's funerals, otherwise they won't come to yours.”
After more reading and reflection, I think you are right that the license payments do not matter. Relative to the cost of treatment, for whatever it is worth, this is what one commentator had to say:
“Provention along with several advocacy groups is working to expand disease awareness and screening. This will help drive the second wave of sales to the broader at-risk population.
After months of working with key opinion leaders, advocacy groups, payers, doctors, and patients, Provention has settled on a wholesale acquisition cost of $13,850 per vial of TZIELD. Its 14-day treatment regimen is administered to patients through an IV in an outpatient setting to start, and will eventually be available at home too. The total cost of one treatment regimen is $193,900.
This price point reflects the perceived value from all of the stakeholders, including the payers that were receptive to covering it at this cost, that this game-changing medicine brings to patients.”
Also, the drug is licensed from another co. that is due $60 million right now and other payments later.
So, whether this high priced treatment that’s not a cure will be covered by Medicare/insurance is a legitimate concern?
The CNN article said “The treatment comes in a single 14-day course of infusions..”
Drug companies have been manipulating the price of insulin although insulin has been around for many years. This approval may be a step in the direction of some relief away from solely trying to manage type 1 diabetes. It is the first therapy approved for prevention of type 1 diabetes. I assume that the patients undergoing this biologic treatment will not be dependent or solely dependent on insulin? Hopefully, patients prone to type 1 diabetes will avoid all of the debilitating consequences resulting from this disease.
Great news! I wonder if the FDA included some limitations in its approval. The stock is trading again after hours, but it has not jumped like I expected it would upon approval. Anyway, I think it will wind up being broadly prescribed for diabetes patients. Thanks
You are also a smart Vet! AVXL broke through 13.50.
McMagyar: Thank you. I understand. Several drugs seem to candidates to help patients with neurological disorders. These patients do not have the time to wait years for a promising drug to be approved according to the current regulatory systems. Best Choice Medicine is attempting to make drugs available to patients that need, for example, to stop or slow the progression of diseases like Alzheimer’s. Best Choice has a petition in progress. I and others have signed the petition. I hope that you will be able to access either AVXL 2-73 and/or some other drugs in the works that are safe and may help. You might try to contact some of the folks behind the Best Choice movement to obtain ideas about how you may obtain early access.
www.bestchoicemedicine.com/...
Macfarlane believes that by the time Alzheimer’s is diagnosed damage has been done that likely will not be reversed. He thinks that the disease will be treated, but that it will be done with multiple drugs that primarily stop or slow the progression of the disease. If it can be proven that AVXL 2-73 or any other drug slows or stops the progression of the disease in mild Alzheimer’s cases that is a big deal.
Seeking Alpha article
Anavex Life Sciences At A Pivotal Moment
Nov. 08, 2022 7:21 AM ETAnavex Life Sciences Corp. (AVXL)2 Comments
Summary
Anavex will present results from its phase 2b/3 trial for blarcamesine for Alzheimer's disease at the CTAD conference in San Francisco on December 1st.
A past trial suggests that Anavex's blarcamesine modifies mild Alzheimer's disease in some patients at 148 weeks.
At higher concentrations, 4 out of six individuals with mild Alzheimer's disease or mild cognitive impairment improved at 57 weeks.
3 out of these six individuals retained these improvements at 109 weeks.
If these numbers hold up in the larger trial and blarcamesine meets safety requirements, the FDA will likely grant the drug accelerated approval.
Women Backpacking on Exposed Hillside
DanaHenryPhotography/iStock via Getty Images
In the most important moment for the company, Anavex (NASDAQ:AVXL) will be presenting results from its phase 2b/3 trial on blarcamesine/Anavex 2-73 at the Clinical Trials on Alzheimer's Disease conference in San Francisco on December 1st. While it is impossible to tell exactly what these results will be, previous trial results - albeit with a small number of participants - give some clues.
The first and perhaps most important clue is that blarcamesine is likely a disease-modifying treatment for at least some patients with mild Alzheimer's disease:
Alzheimer's Treatments
Disease Modifying (Taiwanese Journal of Psychiatry)
Anavex 2-73 for Mild Alzheimer's disease
Anavex 2-73 at 148 weeks (Anavex Corporate Presentation)
(Note the slope is more important than the specific tests).
Both blarcamesine/Anavex 2-73 and Aricept (an acetylcholinesterase enzyme inhibitor or AchE) are sigma-1 receptor agonists which inhibit the release of intracellular calcium and subsequent oxidative stress. Both may be direct antioxidants. It is possible that blarcamesine is a better sigma-1 receptor agonist and/or better antioxidant than Aricept and that is why in some individuals with mild Alzheimer's disease it can nearly stabilize the disease for almost three years at high concentrations. For moderate Alzheimer's disease, blarcamesine is much less effective because intracellular calcium release decreases after the early stages of the disease (although oxidative stress remains a problem as the result of the influx of calcium) (figure 3).
The second clue as to the effectiveness of blarcamesine for Alzheimer's disease comes from 57 week and 109 week results. Six individuals with mild Alzheimer's disease (sometimes defined as an MMSE of 20 to 24) or mild cognitive impairment showed improvements at 57 weeks. Five out of six of these individuals retained these improvements at 109 weeks (one at a high concentration declined).
Anavex 2-73 at 109 weeks
Anavex 2017 CTAD Presentation
4 out of 6 patients who saw improvements at 57 weeks were at high concentrations (no one in the mid-concentration group improved). The breakdown is as follows:
Two out of nine patients at low concentrations improved (although the improvement in the first patient requires some explanation):
Baseline 57 weeks 109 weeks
1009 20 26 29
1011 20 22 21
Three out of nine patients at high concentrations improved
1014 20 25 25
2006 25 29 28
2010 25 28 28
(charts p. 23, 29)
About two-thirds of those at high concentrations had mild Alzheimer's disease or mild cognitive impairment, so 3 out of 6 individuals in this group improved over the course of 109 weeks. On the other hand, no one with moderate Alzheimer's disease improved on blarcamesine.
To a certain extent the effectiveness of blarcamesine is reduced by genetic mutations that increase intracellular calcium release and oxidative stress in mild Alzheimer's disease, namely mutations in sigma-1 receptor and COMT (Catechol-O-methyltransferase) genes.
Effect size on clinical outcomes at week 5
MMSE
ADCS-ADL
Subjects' characteristics
Mean ? at 57 weeks
Cohen's d
N (%)
Mean ? at 57 weeks
Cohen's d
N (%)
All
-1.52 ± 4.15
0.57 a
21 (100.0%)
-5.24 ± 8.42
0.18
21 (100.0%)
Baseline MMSE ≥ 20
-0.15 ± 4.06
0.94 b
13 (61.9%)
-2.08 ± 5.88
0.66 a
13 (61.9%)
Absence of SIGMAR1 p.Gln2Pro variant
-0.62 ± 4.11
0.81 b
16 (76.2%)
-3.38 ± 7.60
0.43
16 (76.2%)
Absence of COMT p.Leu146fs variant
-0.62 ± 4.05
0.81 b
16 (76.2%)
-2.44 ± 6.93
0.57 a
16 (76.2%)
Absence of SIGMAR1 p.Gln2Pro variant and baseline MMSE ≥ 20
0.27 ± 4.29
1.01 b
11 (52.4%)
-1.36 ± 6.09
0.76 a
11 (52.4%)
Absence of COMT p.Leu146fs variant and baseline MMSE ≥ 20
0.18 ± 4.35
0.98 b
11 (52.4%)
-0.73 ± 5.29
0.89 b
11 (52.4%)
Absence of SIGMAR1 p.Gln2Pro variant and absence of COMT p.Leu146fs variant and baseline MMSE ≥ 20
0.50 ± 4.45
1.05 b
10 (47.6%)
-0.40 ± 5.46
0.93 b
10 (47.6%)
(Table 3)
An MMSE score of 20 or above, though, has a greater impact on the effectiveness of blarcamesine than the absence of variants.
Anavex has now limited its phase 2b/3 trial to those with mild Alzheimer's disease and mild cognitive impairment (i.e. equal to or greater than 20), so the percentage of those with mild Alzheimer's disease or mild cognitive impairment who improve on the highest dose in the current phase 2b/3 clinical trial at 48 weeks could be over sixty percent (four out of six in this category improved in the 57 week trial).
The results are more critical than any other concerns one may have about Anavex's trial. The relatively small size of Anavex's trial (500 participants) and that they had no U.S. sites will probably not be of concern for the FDA. The FDA wants a minimum of 300 participants in a phase 3 clinical trial and it will accept under specified conditions phase 3 trial results from other countries. If then blarcamesine meets both efficacy and safety requirements, the FDA would likely grant it at least accelerated approval (approval for sale while additional trials are conducted). A possible request for an additional 18 month trial to establish whether blarcamesine is indeed a disease modifying drug does not seem unreasonable.
So far at least, Anavex's stock value has not increased very much based on the announcement and anticipation of its CTAD presentation. This may reflect the considerable amount of doubt raised about very small participant numbers and about the data itself. The stock may tick up a bit more as the date draws nearer. I believe the results in this much larger trail will be good, though, and that some form of FDA approval will be forthcoming. Based on that, I rate Anavex as a buy.
Orphan designation, although by no means a guarantee, may to some degree result in drug approval. See below quotes from the article entitled:
Using four decades of FDA orphan drug designations to describe trends in rare disease drug development: substantial growth seen in development of drugs for rare oncologic, neurologic, and pediatric-onset diseases
"Drug sponsors submit a request for designation to the OOPD by presenting evidence that they are developing the drug for a rare disease and demonstrating the scientific rationale of the drug (clinical or preclinical evidence that establishes the medically plausible basis for the use of the drug in that rare disease) [19]...
....There were 5099 orphan drug applications designated between 1983 and 2019. As of December 31, 2019, 724 (14%) of these designations had at least one associated approval, and there were 878 total approvals. For first approvals, 35% occurred within two years of designation, 69% occurred within five years, and 92% occurred within ten years...
Of these orphan products, 59% (3010) were small molecules and 41% (2089) were biologics. This proportion stayed relatively constant when evaluated by decade. Treatments accounted for 92% (4678) of the designations, preventives 7% (332), and diagnostics 2% (89).......
....In just ten years since the last quantitative analysis performed by OOPD, designations and approvals for rare disease drugs have nearly tripled [21]. These recent increases in rare disease drug development have also been observed in the European Union (EU) and Japanese orphan drug programs, indicating that these are international trends [22,23,24]....
This increase in designations also appears to have translated into an increase in approvals, with a similar trend appearing to occur in the EU [4, 24]. However, it is important to note that this may occur on a substantial lag due to the timeline of development: orphan designations may be granted at any stage of the development process, from the preclinical phase up to before a marketing application is submitted [25, 26]. This limits the interpretability of the time from designation to approvals, as well as when designations may translate into approvals in the future. Regardless, the next decade may see a large increase in rare disease drug approvals, if this complementary relationship between designations and approvals persists..... "
https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01901-6#:~:text=There%20were%205099%20orphan%20drug,there%20were%20878%20total%20approvals.
That can be a good strategy too depending on risk suitably that varies with each individual.
Here is an explanation: Steady T seems to be long term bullish, but is thinking that the pending report may not clearly, strongly, or decisively meet bullish expectations. Results may be negative and share price will drop sharply. Results may be positive, but not so positive as to indicate near term approval. Results may be controversial as has happened in the past. Even if positive, share price may surge upwards and then drop. Steady is betting that the calls sold will not likely be exercised because odds are these calls like most calls will expire worthless. If so, he will pocket some cash. He is de-risking to some extent-not altogether. However, in the event the results are spectacular and the options are exercised, Steady will probably be satisfied to gain a large, hopefully long term, capital gain.
We see lots of predictions, but predictions are almost always wrong. We don’t know what will be reported or how the report may be perceived. There is plenty of room for the results, even if seemingly very positive, to be attacked. We don’t know what the market may do or what the price of any stock or thing may be at any future point in time. We don’t know how investors may react to the report. Even if positive, we don’t know what the subsequent investor reaction may be when the report is scrutinized and/or attacked. It’s easier to attack a small biotech that is developing a novel drug. It’s like picking wings off of butterflies. Some delight at doing that. If I may make one prediction, it is that no matter how good the results, AVXL will have its critics. Some of those critics are likely to be vicious as long term investors here have experienced on several past occasions.
Agreed! Thank you.
“Every day thousands of patients die from aging-associated non-communicable diseases (AA-NCDs) that might have otherwise been given new treatments that current regulatory systems have no framework to allow them to try. AA-NCDs have been recognized by the United Nations as a “threat
to global development.” and a mandate has been set to improve the consequences of such diseases. Helping patients get access to new drugs is an imperative of the BCM.” Go to the site. Read about it. Sign the petition if you are so inclined. Best Choice Medicine makes sense for patients suffering from aging associated diseases. By the time a patient is diagnosed, the disease has done irreparable damage, and there is a short window of opportunity to stop the progression of the disease - especially for older patients. Why not allow establish a framework to allow these patients access to new drugs that may help them? Several drugs seem to candidates to help elderly patients with neurological disorders. These patients do not have the time to wait years for a promising drug to be approved according to the current regulatory systems.
https://www.bestchoicemedicine.com/
“Every day thousands of patients die from aging-associated non-communicable diseases (AA-NCDs) that might have otherwise been given new treatments that current regulatory systems have no framework to allow them to try. AA-NCDs have been recognized by the United Nations as a “threat
to global development.” and a mandate has been set to improve the consequences of such diseases. Helping patients get access to new drugs is an imperative of the BCM.” Go to the site. Read about it. Sign the petition if you are so inclined. Best Choice Medicine makes sense for patients suffering from aging associated diseases such as AD. By the time a patient is diagnosed, the disease has done irreparable damage, and there is a short window of opportunity to stop the progression of the disease - especially for older patients. Why not allow establish a framework to allow these patients access to new drugs that may help them? Several drugs seem to candidates to help elderly patients with neurological disorders. These patients do not have the time to wait years for a promising drug to be approved according to the current regulatory systems.
https://www.bestchoicemedicine.com/
“Every day thousands of patients die from aging-associated non-communicable diseases (AA-NCDs) that might have otherwise been given new treatments that current regulatory systems have no framework to allow them to try. AA-NCDs have been recognized by the United Nations as a “threat
to global development.” and a mandate has been set to improve the consequences of such diseases. Helping patients get access to new drugs is an imperative of the BCM.” Go to the site. Read about it. Sign the petition if you are so inclined. Best Choice Medicine makes sense for patients suffering from aging associated diseases such as AD. By the time a patient is diagnosed, the disease has done irreparable damage, and there is a short window of opportunity to stop the progression of the disease - especially for older patients. Why not allow establish a framework to allow these patients access to new drugs that may help them? Several drugs seem to candidates to help elderly patients with neurological disorders. These patients do not have the time to wait years for a promising drug to be approved according to the current regulatory systems.
https://www.bestchoicemedicine.com/
Thank you, Powerwalker. Maybe others here will go to the Best Choice Medicine site and sign the petition if they believe that drugs like AVXL 2-73 show promise to help AD and other patients that otherwise do not have much time to attempt to treat their age related disease.
Here is the site to the white paper on Best Choice Medicine. https://www.bestchoicemedicine.com/general-1
Best Choice Medicine (BCM): “ Every day thousands of
patients die from aging-associated non-communicable diseases (AA-NCDs) that might have otherwise been given new treatments that current regulatory systems have no framework to allow them to try. AA-NCDs have been recognized by the United Nations as a “threat to global development.” and a mandate has been set to improve the consequences of such diseases. Helping patients get access to new drugs is an imperative of the BCM.”
https://www.bestchoicemedicine.com/
Go to the site. Read about it. Sign the petition if you are so inclined.
Best Choice Medicine makes sense for patients suffering from aging associated diseases such as AD. By the time a patient is diagnosed, the disease has done irreparable damage, and there is a short window of opportunity to stop the progression of the disease - especially for older patients. Why not allow establish a framework to allow these patients access to new drugs that may help them? AVXL 2-73 seems to be a candidate to help elderly patients with neurological disorders. These patients do not have the time to wait years for a promising drug to be approved according to the current regulatory systems.
This is what Missling will be speaking about on November 8:
Presentation
Execution of a Clinical Trial Using Precision Medicine in Neurological Diseases
Relevance of biomarkers in clinical studies
What can we learn from oncology
Involving whole blood transcriptomics analysis (RNAseq)
MacFarlane believes that the realistic expectation for AD drug development is to slow the progression of the disease because by the time it becomes known that one has AD irreparable damage has been done to cells. He believes that going forward AD drug development will replicate what we have seen in the treatment of cancer. His opinion is that the most effective treatment for the disease may be a combination of drugs as in the treatment of cancer. Interestingly, he comments that placebo patients in AD trials do better because they receive better treatment and follow up. The latter makes sense because AD trials last years. If you are conducting three years of phases of a clinical trial of a drug you want to keep the participants around to complete the trial phases. The source for the foregoing is a MacFarlane interview in October 2021. Here is the link: https://www.dementiapodcast.com/1268711/9325388
Therefore, if the AVXL 2-73 data we are waiting for shows that the in treated patients AD was slowed significantly, success has been achieved. It may also be that those patients on the placebo did better than AD patients in general, which is what I think past phases of AVXL 2-73’s trials have shown. Of course, data needs to show that treated patients did much better than those on the placebo, but we should not be thrown for a loop just because placebo patients in the trial did better than AD patients in general.
Having said all of the above, we may need to adjust our expectations for whatever it is that Anavex has to report in December if not before. Some patients may likely do better or worse, depending on how long participants have had the disease and the degree of cell damage each patient has incurred. And, some patients may do better or worse depending on gene type or various other factors.
No two individuals in this or any clinical trial are identical depending on duration of the disease, genetic make up, age, health in general, care, mental attitude, etc.
It should be evident that analyzing any AD clinical trial results is highly complex. There is a lot to consider and to explain, including without limitation, why some placebo patients may have performed well compared to those administered the actual drug.
In any event, no one should expect that this or any drug will reverse severe cell damage. The data will not prove that AVXL 2-73 will reverse all aspects of this awful disease, but significantly slowing the progression of the disease is a win, which is what I hope is the case.
Lastly, if it is true that AVXL 2-73, or any other drug, significantly slows the progression of the disease, it may be that this drug or drugs will be prescribed early on to patients that are prone to the disease following the example of what cardiologist have done in prescribing statins to patients believed to be prone to heart disease.
Thank you
Summary of when readouts are expected for AD, PD and Rett (Excellence study) from Seeking Alpha article: Anavex Life Sciences: Upcoming Readouts In Alzheimer's And Parkinson's Disease Dementia
Sep. 19, 2022 5:59 PM ET
"During the call on results for the third quarter of 2022, Anavex mentioned that it is completing finalizing activities to report top-line results of the placebo-controlled Phase 2b/3 study of Anavex 2-73 in early Alzheimer’s disease, expected this coming fall. Data from the 48-week open-label extension of the Parkinson disease dementia Phase 2 study is expected by year-end 2022. Also by year end 2022, Anavex will be reporting on the randomized placebo-controlled Excellence Phase 2/3 study for the treatment of pediatric patients with Rett syndrome."
It is debatable whether Anavex will timely meet its schedule for reporting as stated above, and some here believe that the Excellence data, for example, may not be reported until sometime after the end of this year. However, I agree with frrol that AD and PDD should be reported soon. Hopefully, these reports will be straight forward and not controversial as the past PDD "Proof of Concept" trial.
I believe we will receive the AD readout first. The above article states: "Primary endpoints of interest are Adas-Cog to assess cognition and ADCS-ADL for daily function. Key secondary endpoints are, among others, CDR-SB or Clinical Dementia Rating Sum of Boxes, structural and functional MRI, and both blood and cerebral spinal fluid biomarkers of Abeta40, Abeta42, T-tau, NFL, YKL-40, BACE1 and neurogranin. The most important results for investors will of course come from the primary endpoints Adas-Cog and ADCS-ADL and secondary endpoint CDR-SB.".
The article further states: "To be clear, Anavex has not yet reported Adas-Cog results either in Alzheimer’s or in Parkinson’s Disease Dementia...... Anavex has on several occasions calculated what the results in Adas-Cog would be in light of already existing reporting. It has done so for Alzheimer’s results at week 57, but not at week 148. For the Alzheimer’s patients at week 57, it had mentioned a calculated Adas-Cog score of -3.4 that correlated to a +2.0 points improvement on MMSE at week 57. Of note: the 2016 reporting mentioned a +1.8 point improvement for the total patient group. In Parkinson’s Disease Dementia patients, Anavex has reported calculated Adas-Cog results at week 14."
So, it will be interesting and most important, I think, to see the actual Adas-Cog results from the AD imminent report. However, I am not clear about the actual dosing for this AD trial and the number of patients on each dose. The dosing regimen, I think, is simply labeled as Drug: High dose ANAVEX2-73, Drug: Mid dose ANAVEX2-73, and Drug: Placebo oral capsule. So, how will the results be reported per dosing regimen? Will we receive Adas-Cog scores per high dose and low dose? How many patients are on the high dose, and how many on the low dose? Will the results be controversial regarding the number of patients on each dose and the improvement of patients per dose? If only the high dose patients (by way of only one example) show significant cog improvement, will the number of patients on the high dose be sufficient and meaningful for a clinical trial?
Restoring expression levels of genes associated with Alzheimer's disease seems highly significant in advancing AVXL 2-73's quest for approval.
Quote from today's AAIC Poster:
"Expression levels of dysregulated neurodegenerative genes were restored by the therapeutic effect of ANAVEX 2-73
• Both identified clusters are up-regulated for treated patients compared to placebo: Cluster 2 eigengene expression was significantly increased for patients treated with ANAVEX®2-73 high oral dose compared to placebo (p = 0.021)
• These genes are known to be down-regulated in the pathology of both Alzheimer’s disease1,2 and Parkinson’s disease3,4"
See also: Dysregulated gene-associated biomarkers for Alzheimer’s disease and aging. https://www.degruyter.com/document/doi/10.1515/tnsci-2021-0009/html?lang=en
"...the new crucial biomarkers for the diagnosis and pathogenesis of AD need to be explored further. Here, the common differentially expressed genes (DEGs) were identified through a comprehensive analysis of gene expression profiles from the Gene Expression Omnibus (GEO) database. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these DEGs were mainly associated with biological processes, cellular components, and molecular functions, which are involved in multiple cellular functions. Next, we found that 9 of the 24 genes showed the same regulatory changes in the blood of patients with AD compared to those in the GEO database, and 2 of the 24 genes showed a significant correlation with Montreal Cognitive Assessment scores. Finally, we determined that mice with AD and elderly mice had the same regulatory changes in the identified DEGs in both the blood and hippocampus. Our study identified several potential core biomarkers of AD and aging, which could contribute to the early detection, differential diagnosis, treatment, and pathological analysis of AD."
And, recall the accelerated approval of Aduhelm wherein ... "Instead of direct evidence of a clinical benefit from the trials, the FDA's accelerated approval pathway relies on the use of a biomarker - a biological change prompted by the drug - that could likely predict a patient benefit." https://www.reuters.com/business/healthcare-pharmaceuticals/fda-documents-show-struggle-over-approval-new-alzheimers-drug-biogen-2021-06-22/
Here, AVXL 2-73 seemingly demonstrates a biological change that is associated with aging and onset of Alzheimer's disease as well as some direct evidence of clinical benefit in addition to the fact that that biological change “could likely predict a patient benefit….”
Jaime Kulisevsky, MD, PhD
Prof. Dr. Jaime Kulisevsky is presently Director of the Research Institute of Sant Pau Hospital (IIB-Sant Pau) and director of the Movement Disorders Unit at the Neurology Department of Sant Pau Hospital. He is Full Professor of Neurology and Vice-Dean at the Autonomous University of Barcelona.
Dr Kulisevsky is the PI of the Parkinson’s disease (PD) area of the Spanish Biomedical Network Research Centre for Neurodegenerative Diseases (CIBERNED-Instituto de Salud Carlos III) and is involved in many IP-initiated and Industry-sponsored trials in PD and parkinsonism.
He is the Spanish coordinator of the European Huntington Disease Network (EHDN), Member of the Executive Committee of the EHDN, Coordinator of the Cognitive Phenotype Working Group of the EHDN and the current PI in Spain for the Enroll-HD study.
He has been recipient of several public research grants as well as being involved in a wide range of clinical trials as Principal Investigator. His particular research interest refers to the cognitive and behavioural consequences of Parkinson’s disease, Parkinsonism and other basal ganglia disorders. In this line, Dr. Kulisevsky has authored more than 250 papers in peer-reviewed journals.
https://cony2020.comtecmed.com/jaime-kulisevsky/
Excellent informative post, Investor.
Thank you.
Thank you. Do you have an email for anyone on the BOD or for Missling?
Thank you.
What is Clint’s email address?
Good suggestion.
Investor:
I agree. With or without analyst grilling, Missling needs to explain all of this. It would be best if Missling clarified everything before questions by analyst, but you can bet that analyst will grill him if he does not do so.
I am confused though about the dates that Anavex may have been involved in discussions about the endpoints and any changes to endpoints. As I remember, wasn’t there some sort of contact with the FDA in September of last year? What happened in September versus what happened in December?
I think, however, that the RSBQ AU may be a better endpoint than RSBQ alone, which has been criticized by experts. See https://www.clinicaltrialsarena.com/analysis/rett-syndrome-endpoints/. In pharmacology, the dose response curve shows the relationship between the amount of a drug taken and its effects on the patient. The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration of a dose of the drug. The Clinical Global Impression – Improvement scale (CGI-I) is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. Isn't it best that the clinician assess whether the Rett patient's condition has improved or worsened at points in time in conjunction with the patient's concentration of the drug (AVXL 2-73)? Is this method better than RSBQ alone, which has be criticized by experts as I mention above?
According to some experts, RSBQ on its own may not be reliable; however, I think that it would be best that Anavex “comes clean” and acknowledges what happened, and demonstrates/explains what the original primary endpoints show and how that compares with the primary endpoints as changed. What happened? Who caused it to happen? When did it happen? Why did it happen? Do the changes matter? If so, how? Etc., etc.
I have been thinking that nothing nefarious has taken place and that Missling and Anavex quite simply may not be that adept in making presentations that are clear and understandable. February 9th presents an important opportunity for Anavex to rise to the occasion and right the ship.
Presently, we have retraced approximately 100% from the May 13, 2021 low. A drop to $5 would be about a 124% retracement from that May 13 low. And, a $5 price would be a 100% retracement if you measure from an earlier $5 low to which you refer. Hopefully, $10 support holds. Anavex selling is overdone, but nothing says it can not become even more overdone. I think it is best we just wait and see what happens next week when we hear from Anavex again (November 9).
I think that the RSBQ AU may be a better endpoint than RSBQ alone, which has been criticized by experts. See https://www.clinicaltrialsarena.com/analysis/rett-syndrome-endpoints/. In pharmacology, the dose response curve shows the relationship between the amount of a drug taken and its effects on the patient. The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration of a dose of the drug. The Clinical Global Impression – Improvement scale (CGI-I) is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. Isn't it best that the clinician assess whether the Rett patient's condition has improved or worsened at points in time in conjunction with the patient's concentration of the drug (AVXL 2-73)? Is this method better than RSBQ alone, which has be criticized by experts as I mention above?
The following (excuse any of my typos) is from slide 8 of the conference call that attempted to explain the Avatar data:
.......
"Appropriate Primary End Point for Rett Syndrome
Statistical significance alone not sufficient for determining whether an individual patient has experienced a meaningful clinical benefit
As a standalone caregiver reported primary outcome assessment, RSBQ does not appear optimally suited, on its own, for the determination of a clinical trial outcome (could lead to either type one or type two error)
FDA:
Anchor based responder method - linking of scores from one clinical outcome assessment (RSBQ) with scores from a simple reference "anchor" clinical outcome assessment with a clinically meaningful threshold (CGI-I) to facilitate interpretation of what constitutes a meaningful within and between patient change in clinical outcome assessment scores (RSBQ AUC)"
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So, according to what Anavex indicates above, RSBQ AUC recommended by the FDA was meant to provide a more meaningful outcome assessment than RSBQ on its own, which might lead to errors in interpretation.
See also: Anavex: The First Impression May Not Be The Right Impression
https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwiaisqO9-P1AhVOlWoFHZfDCVgQFnoECAwQAQ&url=https%3A%2F%2Fseekingalpha.com%2Farticle%2F4483849-anavex-the-first-impression-may-not-be-right&usg=AOvVaw0Xrs-NV1fP8s--NvTOLDQT
Of course, this is a difficult subject for me to understand and explain. I have made an attempt to understand this issue and offer bit of an explanation, which may be subject to legitimate criticism. Therefore, I am open to criticism and discussion. Perhaps someone else may find fault with what I say here and may offer a better explanation. In any event, if the FDA did recommend changes in the design of the Avatar clinical trial, it seems to me that, other than the effect on Anavex's share price for the time being, the only things that are important is whether Anavex is providing what the FDA recommended and whether the FDA views the Avatar trial outcome as sufficient to expedite approval of AVXL 2-73 for Rett. In the long run, it does not matter what me, Adam F or anyone else thinks or says.
Following (1-3) is some additional internet research I did in reference to what I have written above.
1.In the field of pharmacokinetics, the area under the curve (AUC) is the definite integral of a curve that describes the variation of a drug concentration in blood plasma as a function of time (this can be done using liquid chromatography–mass spectrometry[1]). In practice, the drug concentration is measured at certain discrete points in time and the trapezoidal rule is used to estimate AUC.
Interpretation and usefulness of AUC values[edit]
The AUC (from zero to infinity) represents the total drug exposure across time. AUC is a useful metric when trying to determine whether two formulations of the same dose (for example a capsule and a tablet) result in equal amounts of tissue or plasma exposure. Another use is in the therapeutic drug monitoring of drugs with a narrow therapeutic index. For example, gentamicin is an antibiotic that can be nephrotoxic (kidney damaging) and ototoxic (hearing damaging); measurement of gentamicin through concentrations in a patient's plasma and calculation of the AUC is used to guide the dosage of this drug.
AUC becomes useful for knowing the average concentration over a time interval, AUC/t. Also, AUC is referenced when talking about elimination. The amount eliminated by the body (mass) = clearance (volume/time) * AUC (mass*time/volume).
AUC and bioavailability[edit]
In pharmacokinetics, bioavailability generally refers to the fraction of drug that is absorbed systemically and is thus available to produce a biological effect....
https://en.wikipedia.org/wiki/Area_under_the_curve_(pharmacokinetics)
2.The area under the curve (AUC) is commonly used to assess the extent of exposure of a drug.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152796/
The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration of a dose of the drug and is expressed in mg*h/L.
This area under the curve is dependant on the rate of elimination of the drug from the body and the dose administered. The total amount of drug eliminated by the body may be assessed by adding up or integrating the amounts eliminated in each time interval, from time zero (time of the administration of the drug) to infinite time. This total amount corresponds to the fraction of the dose administered that reaches the systemic circulation.
The AUC is directly proportional to the dose when the drug follows linear kinetics. The AUC is inversely proportional to the clearance of the drug. That is, the higher the clearance, the less time the drug spends in the systemic circulation and the faster the decline in the plasma drug concentration. Therefore, in such situations, the body exposure to the drug and the area under the concentration-time curve are smaller.
....
3.Clinical implications
During clinical trials, the patient’s plasma drug concentration-time profile can be drawn by measuring the plasma concentration at several time points. The AUC can then be estimated. Knowing the bioavailability and the dose, the clearance of the drug may be calculated by dividing the dose absorbed by the AUC. The clearance calculated is relatively independent on the shape of the concentration-time profile. This method gives precious information on the pharmacokinetic behavior of a drug on trial. It can also be used to study a change in the clearance of a drug in specific clinical conditions, such as disease or concomitant drug administration.
https://sepia2.unil.ch/pharmacology/parameters/areaunderthecurve/#:~:text=The%20area%20under%20the%20plasma,body%20and%20the%20dose%20administered.
Sab: Will a DeMark sequential 13 print today?
Fireman: He sounds like a real lawyer to me. Thanks.