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The Bollinger Band Squeeze occurs when volatility falls to low levels and the Bollinger Bands narrow. According to John Bollinger, periods of low volatility are often followed by periods of high volatility. Therefore, a volatility contraction or narrowing of the bands can foreshadow a significant advance or decline.
One approach (among others) Anavex will seek to use in its discussions with regulators is that Anavex 2-73 restores Protein Homeostasis and reduces Aß (Abeta) induced deficits, which is all connected to the unproven amyloid beta plaque theory. I think Anavex may do this in conjunction achievement of endpoints and other outcome measures such as MRI, blood assessment, and CSF assessment.
Leqembi, which may be less effective, more expensive, and not as safe as AVXL 2-73, was given emergency approval based solely on its Phase 2 data, not phase 3 clinical trial results. Leqembi was approved because it removes amyloid beta plaque which is believed (not proven) to be a critical factor in the disease. Keep in mind that the FDA has allowed accelerated approval of Alzheimer’s drugs although nothing has been clinically proven. It did so based on what it thought was reasonably likely to result in clinical decline of Alzheimer’s disease.
Therefore, it would strike me that it would be ironic for regulators to dismiss any evidence of protein homeostasis and reduction of Aß (Abeta) induced deficits with the administration of Blarcamesine. Below is some of my research references that forms a basis for my thinking.
However, the FDA disapproved Lily's donanemab this past week because Lily did not provide data from at least 100 patients who received a minimum of 12 months of continued treatment. Therefore, Anavex may need to provide data from at least 100 patients who received Blarcamesine for 12 months. One question Lane Simonian raised in a comment on Seeking Alpha is whether 48 weeks is close enough to satisfy the FDA. In any event, Blarcamesine may obtain accelerated approval in Europe, the UK, or Asia without data from 100 patients that received AVXL 2-73 for 12 months.
References:
1. Proteostasis is the dynamic regulation of a balanced, functional proteome. The proteostasis network includes competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of proteins present within and outside the cell.[1][2] Loss of proteostasis is central to understanding the cause of diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes,[3] as well as aggregation-associated degenerative disorders.[4]Therapeutic restoration of proteostasis may treat or resolve these pathologies.[5] Cellular proteostasis is key to ensuring successful development, healthy aging, resistance to environmental stresses, and to minimize homeostatic perturbations from pathogens such as viruses.[2] Cellular mechanisms for maintaining proteostasis include regulated protein translation, chaperone assisted protein folding, and protein degradation pathways. Adjusting each of these mechanisms based on the need for specific proteins is essential to maintain all cellular functions relying on a correctly folded proteome.
Proteostasis
en.wikipedia.org
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2. Proteostasis.
Protein homeostasis or ‘proteostasis’ is the process that regulates proteins within the cell in order to maintain the health of both the cellular proteome and the organism itself. …..
Proteostasis involves a highly complex interconnection of pathways that influence the fate of a protein from synthesis to degradation. As individual components are affected, the others adjust accordingly to maintain normal function. Disruption of one or more of these proteostasis influencers can manifest in pathologies such as Alzheimer’s disease, cancer, and diabetes.
https://www.enzolifesciences.com/platforms/proteostasis/
2a. The loss of proteostasis is one of the reasons we age. The Hallmarks of Aging [1] describes the loss of proteostasis as the failure of the protein building machinery of the cell and the accumulation of misfolded proteins, which is one of the root causes of age-related diseases, including Alzheimer’s disease.
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Why we Age: Loss of Proteostasis
lifespan.io
3. Protein Homeostasis, Aging and Alzheimer’s Disease
Since aging is accompanied by changes in cellular protein homeostasis and an increasing demand for protein degradation, aspects of protein folding, misfolding, refolding and, importantly, protein degradation need to be linked to AD pathogenesis….
…..
Cells permanently encounter the problem to maintain the integrity and functionality of the proteome. Within the crowded cellular environment, the correct conformation of proteins must be controlled and misfolded and irreversibly damaged proteins must be efficiently refolded or removed. Central players of the protein homeostasis system are molecular chaperones that sense misfolded proteins and, when refolding fails, direct them to the protein-degradation pathways. Molecular chaperones are specified as proteins that interact with and participate in folding or refolding of non-native proteins. Therefore, chaperones help unfolded proteins to achieve their functional conformation without being present in the final structure. They exert a multitude of activities, including de novo folding, refolding of denatured proteins, transport to subcellular compartments, oligomeric assembly and disposal by proteolytic degradation…
nlm.nih.gov
3a. Protein Homeostasis, Aging and Alzheimer’s Disease
Alzheimer’s disease (AD) is one key medical challenge of the aging society and despite a great amount of effort and a huge collection of acquired data on molecular mechanisms that are associated with the onset and progression of this devastating disorder, no causal therapy is in sight. The two main hypotheses of AD, the amyloid cascade hypothesis and the Tau hypothesis, are still in the focus of AD research. With aging as the accepted main risk factor of the most important non familial and late onset sporadic forms of AD, it is now mandatory to discuss more intensively aspects of cellular aging and aging biochemistry and its impact on neurodegeneration. Since aging is accompanied by changes in cellular protein homeostasis and an increasing demand for protein degradation, aspects of protein folding, misfolding, refolding and, importantly, protein degradation need to be linked to AD pathogenesis
4. ANAVEX®2-73 activates the Sigma-1 receptor (S1R) protein, which serves as a molecular chaperone and functional modulator involved in restoring homeostasis. S1R activation has demonstrated ability to reduce key pathophysiological signs of Alzheimer’s disease: beta amyloid, hyperphosphorylated tau, and increased inflammation.
https://www.anavex.com/press-releases/anavex-life-sciences-receives-approval-to-initiate-phase-2b%2F3-clinical-trial-of-anavex%C2%AE2-73-for-the-treatment-of-early-alzheimer%E2%80%99s-disease
5. ANAVEX®2-73 (blarcamesine) activates the Sigma-1 receptor (S1R) protein, which serves as a molecular chaperone and functional modulator involved in restoring cellular homeostasis. https://www.anavex.com/post/anavex-life-sciences-announces-completion-of-anavex-2-73-u-s-phase-2-rett-syndrome-clinical-trial
6. Sigma-1 receptor: The novel intracellular target of neuropsychotherapeutic drugs
Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival.
sciencedirect.com
7. The Sigma-1 Receptor at the Crossroad of Proteostasis, Neurodegeneration, and Autophagy
Neurodegenerative diseases are linked to dysfunctional proteostasis and disturbed autophagy.
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The Sigma-1 Receptor at the Crossroad of Proteostasis, Neurodegeneration, and Autophagy - PubMed
nlm.nih.gov
8. Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo
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Sigma-1-Receptor-Activation-Induces-Autophagy-and-Increases-Proteostasis-Capacity-In-Vitro-and-In-Vivo
PDF Document · 2.6 MB
ANAVEX2-72 Positively Regulates Autophagy, Increases Proteostasis Capacity, and Improves Protein Aggregation
9. Protein Homeostasis
Protein homeostasis (proteostasis) refers to an extensive network of components that acts to maintain proteins in the correct concentration, conformation, and subcellular location, to cooperatively achieve the stability and functional features of the proteome…..
… Proteostasis, or protein homeostasis, is essential for all physiological processes of the organism. Cell stress, due either to accumulation of misfolded or aggregated proteins, or exposure to some environmental stimuli, triggers activation of stress sensors and specific response pathways within the cell, leading to transcriptional activation and synthesis of factors that promote proper folding or clearance of defective proteins to restore proteostasis
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/protein-homeostasis achieve the stability and functional features of the proteome.
10. Anavex Life Sciences Announces ANAVEX®2-73 Significantly Prevented Aß (Abeta)-induced Deficits
ANAVEX®2-73 activates the sigma-1 receptor (SIGMAR1). Data suggests that activation of SIGMAR1 results in the restoration of complete housekeeping function within the body and is pivotal to restoring neural cell homeostasis and promoting neuroplasticity.[1] SIGMAR1 also promotes autophagy and results in the degradation of amyloid-beta precursor protein (APP) thereby inhibiting Aß production
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Anavex Life Sciences Announces ANAVEX®2-73 Significantly Prevented Aß (Abeta)-induced Deficits
anavex.com
Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468724/
Thank you, Plexrec
Thank you, Nidan.
Plexrec: What video? Where is the link? Thank you.
I know this does not clinically prove anything, but I experienced dizziness for many years. I have multiple military disabilities. One is damage to my inner ear, which at times caused vertigo. I am deaf, but I hear with cochlear implants. I am 81 years old this month. I exercise daily and experience Orthostatic hypotension when I rise up from doing bench presses. The key is to rise slowly. I take two blood pressure medications in the evening. Both of those medications may cause dizziness.
My point is that dizziness can be dealt with. Since I entered my 80s I don't experience dizziness as much as I once did. In time it has dissipated to the point that I now only experience Orthostatic hypotension when exercising (not when I get up to go to the bathroom during the night ). I have never fallen from being dizzy. Dizziness may be a problem, but it is the least of my worries. It can be dealt with.
Good post. Thank you.
Many drugs approved by the FDA cause dizziness. Medications that get into your brain are more likely to make you dizzy.
MEDICATIONS ASSOCIATED WITH DIZZINES
https://dizziness-and-balance.com/disorders/medical/medication.html
Alzheimer’s drugs side effects includes dizziness.
Does donepezil make you dizzy?
This medicine may cause some people to become dizzy or drowsy, to have blurred vision, or to have problems with clumsiness or unsteadiness.
https://www.mayoclinic.org/drugs-supplements/donepezil-oral-route/side-effects/drg-20063538?p=1
Memantine side effects
The more common side effects that can occur with memantine include:
drowsiness
dizziness
headache
confusion
constipation
If these effects are mild, they may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk to your doctor or pharmacist.
https://www.healthline.com/health/drugs/memantine-oral-tablet#side-effects
Moreover, if one has dementia, dizziness and fainting occurs in any event.
Is dizziness common with dementia?
One of the precursors of dementia has now been identified as an increase in fainting and dizzy spells – something you may have noticed in your loved one before they were diagnosed with a dementia-related illness.May 11, 2021
Dizziness and fainting with dementia
https://www.liftedcare.com/dizziness-and-fainting-with-dementia/
Lastly, Associate Professor Stephen Macfarlane had this to say about side effects of AVXL 2-73:
“We’ve certainly seen individual patients, who both seem to be getting side effects from the drugs and who have shown significant improvements,” Professor Macfarlane told AAA.
“Participants getting side effects, such as dizziness, suggest improvements from the drug, he said.”
“The fact that they’re getting side effects and they were expected side effects based on what we know about the drug, does suggest that the people who are showing the improvements are on the active drug,” Professor Macfarlane said.
https://www.australianageingagenda.com.au/executive/alzheimers-drug-trial-shows-promise/
And did you know drinking too much water can cause death?
https://www.medicalnewstoday.com/articles/318619#:~:text=In%20severe%20cases%2C%20water%20intoxication,in%20severe%20cases%2C%20become%20fatal.
If Blarcamesine works well with APOE3 patients, Anavex will focus on those APOE3 patients. This too would be highly significant in seeking approval in Asia. APOE3 is the most common among all human populations. Interestingly, its frequency varies throughout the world. Most interestingly its frequency in Asia seems to be the highest - 85%. ! APOE4 is relatively high in Australia, but highest in Central Africa.
“The world-wide frequency of human APOE alleles varies considerably (Figure 1). APOE3 is the most common among all human populations and its frequency ranges from 85% (Asia) to 69% (Africa) (Singh et al., 2006). APOE4 allele frequency varies considerably in native populations of Central Africa (40%), Oceania (37%), and Australia (26%) (Corbo and Scacchi, 1999). The distribution across Europe and Asia follows an apparent gradient from north to south, with low APOE4 allele frequencies in the Mediterranean or South China and higher frequencies in northern regions (up to 25%) (Egert et al., 2012). APOE2 is the least common allele with a global prevalence of 7.3% and is absent in many indigenous people without any clear regional pattern”.
https://www.frontiersin.org/articles/10.3389/fnins.2021.630502/full
Good observations. Thank you.
As slide 18 points out, the patients in the AVXL 2-73 trial were more advanced in the disease than the patients in the Lecanemab trial. See also Seeking Alpha article published in December: “The patients in Anavex's Blarcamesine trial were substantially more cognitively impaired than those in Biogen's Lecanemab trial.” How Well Does Anavex's New Alzheimer's Drug Compare Against Biogen's New Drug? That SA article also states: “The patients in the Anavex Phase 2b/3 trial started the trial with an ADAS-Cog of around 29; this is a serious level of cognitive impairment, and this group typically gets worse by about 4.5 points in a year's time.” However, at 24 to 36 weeks as shown on slide 18, the once daily oral Blarcamesine begins to compare favorably compared to 12 weeks. Blarcamesine at 36 weeks, one half the time period of the 72 week Lecanemab trial, begin to perform more favorably compared to the placebo and even more so at 48 weeks.
In comparing Blarcamesine to Lecanemab the above SA article also had this to say:
“…the Blarcamesine patients started off their drug trial with a good deal more cognitive dysfunction than the Lecanemab patients. The average ADAS-Cog scores of the Lecanemab trial was 24.45. The average ADAS-Cog scores of the people being administered Blarcamesine was 28.75. That's a 4.3 point difference, a very substantial difference in starting points.
Blarcamesine is 40% more effective than Lecanemab at 48 weeks, and on patients who are significantly more cognitively impaired. To be fair Lecanemab's trial continued for another 7 months and continued to slow impairment. Blarcamesine's trial ended at 48 weeks, and patients have the option to continue treatment in another study; will Blarcamesine continue to hold its 40% lead over Lecanemab? It is unclear, but it seems one's first year of Alzheimer's treatment should be on Blarcamesine.
Regarding the CDR-SB. The Blarcamesine patients were suffering from greater global impairment than the Lecanemab patients, as measured by the CDR-SB. At BASELINE (at the start of each study) the Blarcamesine patients had an average CDR-SB score of 3.81 versus Lecanemab's 3.17, representing significantly more impairment among the Blarcamesine group.
The Blarcamesine patients at baseline were suffering from Very Mild Dementia or Mild Dementia, while patients in the Lecanemab trial were suffering from Very Mild Dementia, Mild Dementia, but also "Questionable Impairment" (very little impairment, if any). See this link for a full discussion.
In this context, it is quite remarkable that the Blarcamesine patients reduced their cognitive decline by 27% over 48 weeks, while Lecanemab produced a similar 27% reduction in cognitive decline, except it took Lecanemab over 78 weeks (18 months). What would Blarcamesine accomplish given another 7 months?
Anavex hints that the drug would continue to reduce decline such that by 78 weeks, Blarcamesine would have a healthy lead over Lecanemab. The suggested logic is, if Blarcamesine at 11 months is equal to Lecanemab at 18 months, then given an equal amount of time to work, Blarcamesine should stretch to at least a 50% lead over Lecanemab.
Regarding ADCS-ADL. It is on the ADCS-MCI-ADL that Biogen's Lecanemab produced its best results. Those who took the drug saw a 37% reduction of decline compared to placebo over the course of over 78 weeks. Some strange numbers hang over the results. Men reduced their decline by almost 3x what women did. And Hispanics reduced their decline by about 3x-8x what non-Hispanics did (3x in the US and 8x outside of the US). Hispanics made up a major portion of their trial population, while Blacks did not.
In their initial readout, Anavex did not present much data on its ADCS-ADL results, one of their main endpoints. The company will release the full data set, including all the ADCS numbers before they submit a paper for publication in a peer-reviewed journal and before they meet with the FDA to discuss approval.
Perhaps the results of the ADCS were disappointing. This possibility is contradicted by a statistic the company did report: those who took Blarcamesine were 167% more likely to improve their ADCS-ADL score by 3.5 points than placebo.
Alzheimer's patients, especially those as deteriorated as the ones in the Blarcamesine trial were, are expected to get worse over the course of 48 weeks unless they are given a placebo or medication. In this case, I would expect very reasonably that maybe 12% of the placebo group improved 3.5 points on a measure that has far more to do with morale and mood than the ADAS-Cog. For instance, one question asks the caregiver how much help does the patient need in eating? The more optimistic one feels, the more likely one will refuse help and find a way to eat even if it requires a great deal of effort. Placebos provide optimism.
So, if 12% of the placebo arm improved by 3.5 points, then more than 32% of those who took Blarcamesine improved by 3.5 points or more. If that is the case, then a major portion performed magnificently with the help of Blarcamesine.
What about the other two-thirds? The ADCS is a questionnaire taken by the caregiver regarding the previous four weeks of helping the patient. In a trial that lasted only 48 weeks and for a psychotropic medication that may take numerous weeks to ramp up, the 44th week may not have been so pretty as the 47th week. Plus the caregiver may have their own biases. I would consider the ADCS scores to be the least reliable of the three measures that Anavex used as endpoints.”
A simple comparison of the Lecanemab trial with the Blarcamesine trial is not an apples to apples comparison. Clearly, the differences between the two trials, and in particular the differences in the disease condition of the patients in the two trials needs to somehow be taken into consideration. Note also that the above article says that “…a psychotropic medication … may take numerous weeks to ramp up…”. See for example: “Antidepressant and antipsychotic medications may take 6 weeks or more to fully work.” https://www.nami.org/About-Mental-Illness/Treatment/Mental-Health-Medications/What-to-Expect-From-Your-Medications
Frankly, I believe that making comparisons between Lecanemab and Blarcamesine is more complicated than many of us here seem to think. However, I also believe that regulators in Europe, Asia and the USA, are equipped to fairly and adequately make comparisons between the two drugs by taking into consideration the differences between the the two clinical trials and differences between the two drugs.
I believe neither drug (neither trial) has produced enough evidence to obtain final approval. Thus, the conditional approval of Lecanemab. Only time will tell how all of this will play out. I think that MacFarlane is correct in saying that it will take a combination of drugs to treat AD. Perhaps Lecanemab and Blarcamesine will play a part in that combination. Or, perhaps other drugs may be added to produce an Alzheimer’s “cocktail” form of treatment.
It will also be interesting to see how the EU regulators may react to Lecanemab given the failure of EU approval of Aduhelm. The EU said in its refusal to approve Adu, along with Adu’s side effects, noted this: “The European Medicines Agency noted that although Aduhelm reduces amyloid beta in the brain, the link between this effect and clinical improvement had not been established.” See: https://www.ema.europa.eu/en/documents/medicine-qa/questions-answers-refusal-marketing-authorisation-aduhelm-aducanumab_en.pdf
With Adu, the benefit was extremely slight. The drug failed in earlier clinical trials, and squeezed by later using different measures. Further, there was no Adu responder group with a therapeutic benefit like Blarcamesine. Of course, everything was controversial about Adu before and after approval, and I don't think it is a good model for approval. However, the precedent, good or bad, has to be dealt with.
All in all, Blarcamesine in comparison with Adu is a better choice for treatment. It is more likely to predict a clinical benefit - more so for the responder group and likely a benefit for some other patients not in the responder group that is more beneficial than Adu. The safety comparison is better as well.
Having said all of that, there is much more that we do not know as you and others point out. Investor gives the odds of an accelerated approval 25%, but I think the odds for approval in the EU may be higher than that - maybe 50/50 at this point. It could be higher depending on what we learn going forward. The EU rejected the approval of Aduhelm, but I think the EU’s Guideline for Alzheimer’s provides a better chance for early approval.
If not early approval, the case seems solid for a Phase 3 Precision Medicine trial. So, my question is: May a precision medicine trial be designed to facilitate a fast approval based on a small Phase 3 trial ? If so, how small and for what duration? See: Precision Medicines Have Faster Approvals Based On Fewer And Smaller Trials Than Other Medicines. https://www.healthaffairs.org/doi/10.1377/hlthaff.2017.1580
You may be correct, what I think I said was that the EMA may be open to new biomarkers. See part 6 of the EMA Alzheimer’s Guidelines, it says this:
“While biomarkers for the most part still require validation for many of these particular purposes, cerebrospinal fluid markers as well as MRI and PET imaging markers are qualified for the enrichment of study populations (see Qualification opinionsfor specific populations in Annex 1). Context of use of these biomarkers remains to be qualified in preclinical AD
….
Qualification of biomarkers for any of the above mentioned use requires to test both biomarker positive and negative patients.
Many activities are underway on new biomarkers that may emerge in the future, e.g. tau PET imaging, biomarkers for neuroinflammation, blood or metabolic signatures.”
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicines-treatment-alzheimers-disease-revision-2_en.pdf
The SIGMAR1-RNA biomarker would have to be qualified/validated:
Validation of a biomarker:
Test sensitivity and specificity
Test sensitivity and specificity are usually considered together because they are essentially two sides of the same coin. A test is specific if it gives a positive result only if the biomarker is present and gives a negative result when the biomarker is not present. A test is sensitive if it gives a positive result every time the biomarker is present.
Analytical validity
Analytical validity refers to how well the test measures what it is supposed to measure. Test sensitivity and specificity are essential components of analytic validity. Any test, whether it be for a cancer biomarker, driving ability, assessing intelligence, or determining pregnancy, must show analytical validity in order to be useful. The analytical validity of a newly developed test is often judged by comparing the results to those obtained from the best available test, sometimes referred to as the “gold standard.”
Clinical validity
Clinical validity is another important aspect of biomarker validation. Clinical validity refers to the ability of the test to accurately predict a clinically important outcome. Often, a clinically valid test will correlate with improvement in patient care…..
A good biomarker test must have both analytical and clinical validity. A biomarker test that has high analytic specificity and sensitivity is no good if the result doesn’t tell us something important about our health status.
Test Reliability
Test reliability is a concept that is often discussed along with test validity. Test reliability means that the results of the test are repeatable……
Clinical Utility
Another important concept in the area of biomarker development has to do with the benefits and drawbacks of a test in the context of clinical use. This is known as clinical utility. Biomarker tests should provide some sort of benefit to patients in order to have clinical utility. For example, they must aid in diagnosis, treatment selection, outcome prediction, or another medically important variable…..However, in order for a biomarker test to show clinical utility, demonstration of benefit is not enough—the benefits of the test must also outweigh its drawbacks.
https://researchadvocacy.org/sites/default/files/resources/BiomarkerValidationFinal-vDownload.pdf
Lastly, other outcome measures may possibly be used for biomarkers in addition to SIGMAR1-mRNA such as MRI, blood, CSF, etc.
Anavex will most likely attempt to use the SIGMAR1-mRNA biomarker for approval of Blarcamesine as pointed out by Dr. Oph on this board. I assume that there may be 30-50 in the 50 mg responder group. Is this a sufficient number according to what 12X posted? Moreover, what is the CDR-SB score for the 30-50 in this group?
See: Anavex Announces First Entire Clinical Alzheimer’s Gene Pathway Data of ANAVEX®2-73 at AAIC 2022 https://www.anavex.com/post/anavex-announces-first-entire-clinical-alzheimer-s-gene-pathway-data-of-anavex-2-73-at-aaic-2022
“Expression levels of pathological dysregulated neurodegenerative genes of both Alzheimer’s and Parkinson’s disease were significantly restored by the therapeutic effect of ANAVEX®2-73 (p<0.005).
These findings will facilitate contextualization of upcoming readout of ANAVEX®2-73 Phase 2b/3 Alzheimer’s disease clinical trial”
In referring to the PDD study Anavex said: “The study found that ANAVEX®2-73 was well tolerated in oral doses up to 50 mg once daily. The results showed clinically meaningful, dose dependent, and statistically significant improvements in the Cognitive Drug Research (CDR) computerized assessment system analysis. The study validated the precision medicine approach of targeting SIGMAR1 as a genetic biomarker of response to ANAVEX®2-73, confirming that ANAVEX®2-73 acts through SIGMAR1 activation. “
Anavex is trying to correlate SIGMAR1 mRNA expression increase in ANAVEX®2-73-treated patients (maybe 30-50 patients?) as the biomarker to support approval of its drug for Alzheimer’s. If this biomarker correlates to clinical improvement from administering the drug to patients, than Anavex may legitimately seek approval in Great Britain, the EU, the U.S. or elsewhere. However, this treatment effect will have to be corroborated in an additional study whether that is conditional approval with a Phase 4 study or simply another Phase 3 study. Let’s see what Mayo’s upcoming report reveals about the possibility of approval in the EU or possibly Great Britain.
What are the various scores for the 30-50 patients that may correlate with the SIGMAR1 gene expression in these patients? For example, what are the Cog, ADL, CDR-SB scores and other outcome measures of these patients? However, I do think, from reading the EMA guideline for Alzheimer’s, that the EMA may likely entertain the use of the SIGMAR1 mRNA biomarker. It seems to be pretty open to the use of any pre specified biomarker that can be connected with a treatment effect of the drug in question. Probably, the more important score for the EMA at least is CDR-SB, which has been pointed out to be a combination of Cog and function.
Gene expression is the process by which the information encoded in a gene is turned into a function. This mostly occurs via the transcription of RNA molecules that code for proteins or non-coding RNA molecules that serve other functions. Gene expression be thought of as an “on/off switch” to control when and where RNA molecules and proteins are made and as a “volume control” to determine how much of those products are made. The process of gene expression is carefully regulated, changing substantially under different conditions and cell types. The RNA and protein products of many genes serve to regulate the expression of other genes. Where, when, and how much a gene is expressed can also be assessed by measuring the functional activity of a gene product or observing a phenotype associated with a gene.
With current technologies, we have the ability to measure mRNA expression of every gene in the entire genome. Sometimes, we can do that in individual cells. This is a really powerful tool to help us measure which genes are turned on, how much and where. Classically, we can also measure gene expression by observing a phenotype or a trait. Examples of those would be to measure a protein activity. If a protein activity can be measured, the gene that encodes for that protein is probably turned on or we can define it as turned on. We can also look for patterns and traits. So for example, if a beautiful butterfly wing with multiple colors is the result of different genes being turned on in different places in the butterfly wing, then we can measure that gene expression simply by observing the wing of the butterfly and marking the locations of the colors.
https://www.genome.gov/genetics-glossary/Gene-Expression
What does mRNA expression tell us?
The quantity of mRNA transcript for a single gene directly reflects how much transcription of that gene has occurred. Tracking of that quantity will therefore indicate how vigorously a gene is transcribed, or expressed.
Gene Expression Is Analyzed by Tracking RNA - Naturehttps://www.nature.com › scitable › topicpage › gene-exp...
What is meant by gene expression?
The process by which a gene gets turned on in a cell to make RNA and proteins. Gene expression may be measured by looking at the RNA, or the protein made from the RNA, or what the protein does in a cell.
Definition of gene expression - NCI Dictionary of Cancer Terms
Why is the mRNA important?
An mRNA can teach the body how to make a specific protein that can help your immune system prevent or treat certain diseases.
Science of mRNA - Modernahttps://www.modernatx.com › en-US › power-of-mrna › s...
Is gene expression and mRNA Expression same?
Gene expression has been defined as the “production of an observable phenotype by a gene — usually by directing the synthesis of a protein”16. By contrast, most gene expression studies exclusively report mRNA data. The term 'gene expression' is often used synonymously with mRNA measurements.
What is the difference between mRNA and RNA?
One type of RNA is known as mRNA, which stands for “messenger RNA.” mRNA is RNA that is read by ribosomes to build proteins. While all types of RNA are involved in building proteins, mRNA is the one that actually acts as the messenger. It is mRNA specifically that has the recipe for a protein.Jan 8, 2021
"DNA" vs. "RNA" vs. "mRNA": The Differences Are Vital - Dictionary.com
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect.
https://en.wikipedia.org/wiki/Gene_expression
Now, that’s funny!
That is good to know, thank you.
Thank you, Dr. Oph.
At least in the Blarcamesine Parkinson’s study Anavex previously reported (Aug. 2022) that “SIGMAR1 mRNA expression significantly increased in ANAVEX®2-73-treated patients vs placebo (p=0.035) over the course of treatment and was significantly associated with improvements of MDS-UPDRS scores and cognitive efficacy endpoints CDR system.”
Anavex said then that: “These findings will facilitate contextualization of upcoming readout of ANAVEX®2-73 Phase 2b/3 Alzheimer’s disease clinical trial”
ANAVEX®2-73 transcriptomics analysis (RNAseq) identified a gene network that is differentially expressed in Parkinson’s disease dementia (PDD) patients treated with ANAVEX®2-73 compared to placebo after 14 weeks of treatment. The expression of 14,150 genes were analyzed from both placebo and ANAVEX®2-73 treated patients. Biological relevance of this gene network was assessed through pathway analysis and confirmed the impact of ANAVEX®2-73 treatment on pathways involved in neurodegenerative diseases, especially Alzheimer’s disease and Parkinson’s disease.
While genes are known to be down-regulated in Alzheimer’s disease1 and Parkinson’s disease2, representing pathology for these diseases, ANAVEX®2-73 singularly impacted expression levels of these genes in multiple pathways by countering the pathological down-regulation of genes in both Alzheimer’s (p<0.005) and Parkinson’s disease (p<0.005) and other degenerative diseases (p<0.005).
The scope of these detected gene expressions identified through ANAVEX®2-73 effect may represent additional potential biomarkers of disease pathology and response.
Previously, this study demonstrated dose-dependent, statistically significant improvement of dementia assessment, Quality of Episodic Memory with ANAVEX®2-73 (p=0.003) as well as significant improvement of Parkinson’s assessment, MDS-UPDRS Total score (p=0.034), in patients treated with ANAVEX®2-73 high oral dose once daily during the 14-week trial. SIGMAR1 mRNA expression significantly increased in ANAVEX®2-73-treated patients vs placebo (p=0.035) over the course of treatment and was significantly associated with improvements of MDS-UPDRS scores and cognitive efficacy endpoints CDR system.3
https://www.rna-seqblog.com/rna-seq-identifies-treatment-impact-of-neurodegenerative-drug-anavex2-73/
So, Anavex is trying to correlate SIGMAR1 mRNA expression increase in ANAVEX®2-73-treated patients (maybe 30-50 patients?) as the biomarker to support approval of its drug for Alzheimer’s? If so, do you have any idea what the CDR-SB score may be for the 30-50 patients? Did anyone at CTAD have any opinion about that?
12X: Thank you for your excellent work. It continues to be very helpful.
Yes, as Investor and Abe point out, the lawsuit was dismissed with prejudice. The judge granted Anavex’s motion to dismiss and did so with prejudice. A motion to dismiss is a procedural device that enables a defendant to dispose of a plaintiff's claims at the beginning of a case. In other words, the plaintiffs were zeroed once and for all early on because the lawsuit did not have a leg to stand on - putting it in plain language.
It does indeed go hand in hand as you say. Thank you.
APOE and other biomarkers relevant to AD approval in the EU.
See my earlier post this morning wherein I referenced the EMA guideline article specific to Alzheimer’s. At # 6 of the guideline it discusses the role of biomarkers and mentions APOE, among others. See the whole section in re biomarkers, but here is the mention of APOE.
“….. While biomarkers for the most part still require validation for many of these particular purposes, cerebrospinal fluid markers as well as MRI and PET imaging markers are qualified for the enrichment of study populations (see Qualification opinions for specific populations in Annex 1). Context of use of these biomarkers remains to be qualified in preclinical AD…..
The role and type of biomarkers ……. APOE is the major genotype associated with the risk of developing AD.APOE e4 homozygotes constitute 2–3% of the general Caucasian population and have a particularly high risk of developing symptoms of late onset AD, more so in the presence of AD pathology. APOE e4 status may be used as one of themeans of enrichment in a clinical trial population. However, generalizability will have to be justified if only patients with this specific genotype are included without any data in non-carriers……..
…. Downstream topographical markers of brain regional structural and metabolic changes (e.g. hippocampal atrophy assessed by MRI, cortical hypometabolism by FDG PET) while having insufficient pathological specificity may be particularly valuable for detection and quantification of disease progression.
So far, one specific biomarker cannot be endorsed over other alternatives for the purpose of identifying those patients who may progress more rapidly. The trajectory of cognitive decline may further be modified by cognitive reserve, medical comorbidities, lifestyle factors and cognitive training (see section 9). Hence increasing clinical trial efficiency and qualification opinion procedures are encouraged.
Qualification of biomarkers for any of the above mentioned use requires to test both biomarker positive and negative patients.
Many activities are underway on new biomarkers that may emerge in the future, e.g. tau PET imaging, biomarkers for neuroinflammation, blood or metabolic signatures.”
Anavex’s recent AD trial should produce quite a bit of data related to biomarkers that may be acceptable to the EMA in connection with an application for approval of Blarcamesine. See other outcome measures of the Phase 2b/3 AD Anavex trial:
Number of participants with change of brain volume assessed by MRI [ Time Frame: 48 weeks ]
To evaluate the effect of ANAVEX2–73 on structural and Arterial Spin Labeling (ASL) MRI scan assessments characteristic for AD pathophysiology compared to placebo over a 48-week treatment duration
Blood assessment [ Time Frame: 48 weeks ]
Blood assessment from baseline and compared to placebo at +48 weeks: Abeta40, Abeta42, T-tau, NFL, YKL-40, BACE1 concentration
CSF assessment [ Time Frame: 48 weeks ]
Changes in CSF parameters (Abeta40, Abeta42, T-tau, P-tau, NFL, YKL-40, neurogranin, BACE1 concentration) characteristic for AD pathophysiology from baseline and compared to placebo at +48 weeks treatment differences within subgroups will be performed
Number of participants with pre-specified genetic variants [ Time Frame: 48 weeks ]
AD relevant pre-specified genetic variants will be assessed. Statistical testing of treatment differences within subgroups will be performed
https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-aduhelm-information
The EU is likely a good choice for seeking accelerated approval of Aavex’s Alzheimer’s drug. The EU and Australia cooperate in the exchange of drug development information.
“The European Medicines Agency and the European Commission have had confidentiality arrangements with the Therapeutic Goods Administration (TGA) of the Australian Government Department of Health and Ageing since 2012, to allow the exchange of information between the parties as part of their regulatory and scientific processes. The European Union (EU) and Australia also have a mutual recognition agreement (MRA) in place on good manufacturing practice (GMP) compliance.” https://www.ema.europa.eu/en/partners-networks/international-activities/bilateral-interactions-non-eu-regulators/australia
It will be good to see Mayo’s report on approval potential with the EMA. I am sure his report will be well done. In the meantime, for anyone that cares to study this rather lengthy article entitled “Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s disease” you will learn in detail how Blarcamesine may be considered for approval in the EU. You will find the entire text here: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicines-treatment-alzheimers-disease-revision-2_en.pdf
There has been much speculation here about Anavex’s recent study and how regulatory agencies may handle Anavex’s request for approval of its drug. However, much of the speculation, I think, is irrelevant because it is not based on how regulatory agencies specifically handle proposed treatments for Alzheimer’s and how regulatory agencies in different countries may approach the approval or disapproval of an Alzheimer’s drug that potentially treats the disease. By way of only one example, the above guideline points out that:“The handling of missing data, particularly resulting from patients who discontinue from the trial, is of particular concern in Alzheimer’s disease trials as several approaches that have been used regularly in other conditions present problems in conditions with a deteriorating clinical course.” The guideline goes on to say that in regard to missing data “last observation carried forward (LOCF) and baseline observation carried forward (BOCF) are inappropriate” and the “mixed model for repeated measures (MMRM) approach is also questionable.” Other approaches may be suitable for addressing missing data.
In reading the EMA guideline, keep in mind that patients have been administered Blarcamesine since 2015 - 2018. See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167374/ .The EMA may look at treatment data over a minimum of 18 months:
“Trial duration should be relevant to the treatment goal. The minimum duration of confirmatory trials depends on the expected progression rate and the assumed activity of the experimental compound, e.g. in patients with mild to moderate and prodromal AD/MCI due to AD, minimum duration of 18 months has been assumed to be sufficient, in some trials, even longer studies might be necessary. Depending on the product’s mechanism of action, the timing of the intervention might be critical to the outcome. If efficacy is demonstrated in prodromal/MCI due to AD patients in a disease modifying trial, it would be difficult to extrapolate information on treatment initiated at a later stage of the disease course (moderate or severe dementia).Ideally, efficacy should be demonstrated in two trials at two different stages along the AD continuum.”
Anavex has conducted 3 AD clinical trials since 2015 to date and patients in these trials have continued with treatment.
The EMA “Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s disease” requires a great deal of study. The effort may be more than many here are willing to undertake; however, I think it is necessary that any Anavex investor make that effort if you think that Anavex may chose to seek approval of Blarcamesine in the EU first and foremost.
Merry Christmas! I hope everyone has at least a little peace and more goodwill toward all during this holiday season, and may we soon have a new drug approval that will contribute to the benefit of humanity.
Sab:
Thank you. Merry Christmas!
Sab:
Check out the positive divergence between on balance volume and AVXL’s stock price. I think it indicates that AVXL is highly likely being accumulated at low prices, which is likely to be followed by a big move up in the stock price. The market works in mysterious ways. Is it likely that smart money is taking advantage of the contentious situation surrounding Anavex’s AD trial data to accumulate low shares at low prices. If so, smart money is actually voting that Anavex’s Phase 2b/3 AD trial is quite positive!
One more quote from today’s Seeking Alpha article:
“The patients in the Anavex Phase 2b/3 trial started the trial with an ADAS-Cog of around 29; this is a serious level of cognitive impairment, and this group typically gets worse by about 4.5 points in a year's time. So, the 2.26 point decline among those treated with Blarcamesine represents about a halving of decline compared to the untreated.”
From Some interesting comparison’s from today’s Seeking Alpha article: How Well Does Anavex's New Alzheimer's Drug Compare Against Biogen's New Drug?
“In both studies, the placebo arm deteriorated in cognition at a faster rate than the treatment arm. Blarcamesine reduced deterioration by 40% more than Lecanemab at 48 weeks.
Furthermore, the Blarcamesine patients started off their drug trial with a good deal more cognitive dysfunction than the Lecanemab patients. The average ADAS-Cog scores of the Lecanemab trial was 24.45. The average ADAS-Cog scores of the people being administered Blarcamesine was 28.75. That's a 4.3 point difference, a very substantial difference in starting points.
Blarcamesine is 40% more effective than Lecanemab at 48 weeks, and on patients who are significantly more cognitively impaired. To be fair Lecanemab's trial continued for another 7 months and continued to slow impairment. Blarcamesine's trial ended at 48 weeks, and patients have the option to continue treatment in another study; will Blarcamesine continue to hold its 40% lead over Lecanemab? It is unclear, but it seems one's first year of Alzheimer's treatment should be on Blarcamesine.
Regarding the CDR-SB. The Blarcamesine patients were suffering from greater global impairment than the Lecanemab patients, as measured by the CDR-SB. At BASELINE (at the start of each study) the Blarcamesine patients had an average CDR-SB score of 3.81 versus Lecanemab's 3.17, representing significantly more impairment among the Blarcamesine group.
The Blarcamesine patients at baseline were suffering from Very Mild Dementia or Mild Dementia, while patients in the Lecanemab trial were suffering from Very Mild Dementia, Mild Dementia, but also "Questionable Impairment" (very little impairment, if any). See this link for a full discussion.
In this context, it is quite remarkable that the Blarcamesine patients reduced their cognitive decline by 27% over 48 weeks, while Lecanemab produced a similar 27% reduction in cognitive decline, except it took Lecanemab over 78 weeks (18 months). What would Blarcamesine accomplish given another 7 months?
Anavex hints that the drug would continue to reduce decline such that by 78 weeks, Blarcamesine would have a healthy lead over Lecanemab. The suggested logic is, if Blarcamesine at 11 months is equal to Lecanemab at 18 months, then given an equal amount of time to work, Blarcamesine should stretch to at least a 50% lead over Lecanemab.
Regarding ADCS-ADL. It is on the ADCS-MCI-ADL that Biogen's Lecanemab produced its best results. Those who took the drug saw a 37% reduction of decline compared to placebo over the course of over 78 weeks. Some strange numbers hang over the results. Men reduced their decline by almost 3x what women did. And Hispanics reduced their decline by about 3x-8x what non-Hispanics did (3x in the US and 8x outside of the US). Hispanics made up a major portion of their trial population, while Blacks did not.”
*************************************
And, the article gives a different perspective regarding the lack of data and information provided by Anavex regarding ADCS-ADL results from the Phase 2b/3 Anavex AD trial:
“In their initial readout, Anavex did not present much data on its ADCS-ADL results, one of their main endpoints. The company will release the full data set, including all the ADCS numbers before they submit a paper for publication in a peer-reviewed journal and before they meet with the FDA to discuss approval.
Perhaps the results of the ADCS were disappointing. This possibility is contradicted by a statistic the company did report: those who took Blarcamesine were 167% more likely to improve their ADCS-ADL score by 3.5 points than placebo.
Alzheimer's patients, especially those as deteriorated as the ones in the Blarcamesine trial were, are expected to get worse over the course of 48 weeks unless they are given a placebo or medication. In this case, I would expect very reasonably that maybe 12% of the placebo group improved 3.5 points on a measure that has far more to do with morale and mood than the ADAS-Cog. For instance, one question asks the caregiver how much help does the patient need in eating? The more optimistic one feels, the more likely one will refuse help and find a way to eat even if it requires a great deal of effort. Placebos provide optimism.
So, if 12% of the placebo arm improved by 3.5 points, then more than 32% of those who took Blarcamesine improved by 3.5 points or more. If that is the case, then a major portion performed magnificently with the help of Blarcamesine.
What about the other two-thirds? The ADCS is a questionnaire taken by the caregiver regarding the previous four weeks of helping the patient. In a trial that lasted only 48 weeks and for a psychotropic medication that may take numerous weeks to ramp up, the 44th week may not have been so pretty as the 47th week. Plus the caregiver may have their own biases. I would consider the ADCS scores to be the least reliable of the three measures that Anavex used as endpoints.”
********
Lastly, relative to side effects the article says:
“Regarding Side Effects. Blarcamesine trounces Lecanemab. About 3% of those who took Biogen's drug suffered from symptomatic brain hemorrhaging. Many more suffered asymptomatic brain hemorrhaging as well as noticeable brain swelling. Such symptoms may not prevent millions of desperate people from taking Biogen's Lecanemab, if it is approved and if there is no other alternative.
But 3% of one million is 30,000 people who must get treated or examined for brain hemorrhaging at an advanced age.”
Participants getting side effects, such as dizziness, suggest improvements from the drug, he (MacFarlane) said.
“The fact that they’re getting side effects and they were expected side effects based on what we know about the drug, does suggest that the people who are showing the improvements are on the active drug,” Professor Macfarlane said.
https://www.australianageingagenda.com.au/executive/alzheimers-drug-trial-shows-promise/
Thank you, Plexrec. I think and hope you are right.
Yep, it was Amstock
Msg 3745 of 3752 at 12/12/2022 11:16:16 AM by
amstocks82
Thank you. That helps. Have a good rest of the weekend, and I hope we all get more and good news from Anavex soon. That is my Christmas wish.
IV? Please tell me who on IV posted what you quoted and when it was posted. Thank you.
Thank you. It would be good if you gave us references and citations so that we do not have to dig and guess who the well informed person is that said what I think you quote - maybe verbatim? Like Plexrec, I and others would like to know who that well informed investors is?
Right. Thank you.
No, I am looking for Anavex’s reply to the short’s (Harrier Captial’s negative-short article). Anavex did reply to refute the article, and I am trying to find the full text of that reply - may be some new good stuff in Anavex’s reply.
Harrier Capital on Seeking Alpha quoted portions of Anavex’s response to Harrier’s initial negative article about Anavex’s Phase 2b/3 AD trial. Does anyone have the entire response by Anavex to the initial Harrier article? It would be nice to read Anavex’s entire response versus portions of Anavex’s response and Harrier’s remarks to the various or selected parts of Anavex’s response to Harrier’s initial article.
Of course, I don’t believe him.
Ronjohn_stockguru
1:13 PM
$COSM $AVXL
LEAKING that Roche is buying Anavex for $3.2 Billion.
(This is some stocktwits person playing games.)