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Not sure about your question. I was replying to this sentence from Investor’s post: “After September 30, 2022, FDA may not award any rare pediatric disease priority review vouchers.”
Investor: Yes, I understand, and I can see how it is misleading. I suppose the bottom line is that we do not know what the FDA may do about the so-called “deadline”.
Yes, but while we are at it - placing emphasis on “may qualify” - : “After September 30, 2022, FDA MAY NOT (emphasis added) award any rare pediatric disease priority review vouchers.” Therefore, the FDA may or may not award a voucher after September 30, 2022, and Anavex may or may not qualify. Additionally, Anavex may or may not otherwise meet the September 30, 2022, deadline. I think too that the exceptions may be made for drug trials that may have been delayed by the C-virus.
Could be. Thank you.
The chart has been forming a downward sloping flag - bullish according to stock chart analyst. Price tends to pause before continuing the direction of the trend. Supposedly indicates a period of consolidation before moving in the direction of the trend. Let’s see how that works out, and if the 150,000 buy orders near the end of the day turn out to be profitable.
Effectiveness of Drugs - It’s Complicated But..
I have provided references below that show that many drugs are approved even though the drugs benefit a small percentage of people that take them. "The top ten highest-grossing drugs in the United States help between 1 in 25 and 1 in 4 of the people who take them .... For some drugs, such as statins — routinely used to lower cholesterol — as few as 1 in 50 may benefit1. " See references below.
If Anavex can approve safety and efficacy for a certain class of patients based on — genetic and environmental factors, among others — that shows a response to treatment.... it may obtain approval of AVXL 2-73.
1. How effective are common medications: a perspective based on meta-analyses of major drugs
''We found that some of the medications have relatively low effect sizes with only 11 out of 17 of them showing a minimal clinically important difference. Efficacy was often established based on surrogate outcomes and not the more relevant patient-oriented outcomes. As the interpretation of the efficacy of medication is complex, more training for physicians might be needed to get a more realistic view of drug efficacy. ''
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-015-0494-1
2. ''The effectiveness of a drug is closely linked to its safety. It is for this reason that the legal approval for the administration of a particular drug is assessed on a risk/benefit analysis. If a drug is known to generate significant side effects in a consumer, it will have a reduced effectiveness, notwithstanding the drug's ability to counter a particular physical condition.''
https://www.encyclopedia.com/sports/sports-fitness-recreation-and-leisure-magazines/drug-effectiveness
3. Personalized medicine: Time for one-person trials
''Precision medicine requires a different type of clinical trial that focuses on individual, not average, responses to therapy, says Nicholas J. Schork....
...Every day, millions of people are taking medications that will not help them. The top ten highest-grossing drugs in the United States help between 1 in 25 and 1 in 4 of the people who take them (see 'Imprecision medicine'). For some drugs, such as statins — routinely used to lower cholesterol — as few as 1 in 50 may benefit1. There are even drugs that are harmful to certain ethnic groups because of the bias towards white Western participants in classical clinical trials2....
....Classical clinical trials harvest a handful of measurements from thousands of people. Precision medicine requires different ways of testing interventions. Researchers need to probe the myriad factors — genetic and environmental, among others — that shape a person's response to a particular treatment....
...Discovering that an intervention works well in certain groups happens relatively rarely and often by chance. Researchers typically get disappointing results with a drug in large, population-based trials. This leads them to conduct ad hoc post-trial analyses, to try to identify the factors that cause some of the people in the trial to seem to be responsive3.
For instance, the drug Gleevec (imatinib) was found to double survival rates of leukaemia patients4 with a chromosomal abnormality in their tumours called the Philadelphia translocation. Similarly, it turns out that Erbitux (cetuximab) improves the survival of people with colorectal cancer whose tumour cells carry a mutated EGFR gene but not a mutated KRAS gene5.
This approach to discovery is inefficient at best. Conventional phase III trials involve thousands of people. The intervention being tested is often given at random to one group while another group receives a sham treatment, such as a sugar pill or the standard treatment that physicians would give such patients. Because scant data are collected on factors such as genetics, lifestyles and diets, the results of these trials often indicate the need for yet another study to validate the effectiveness of the intervention among the apparent responders and to establish the underlying mechanisms....
https://www.nature.com/news/personalized-medicine-time-for-one-person-trials-1.17411
TrendH2O2 and Nidan: Semper Fi!
Bio and Steady: Good points. Let’s see what the trials say. “Then you will know the truth, and the truth will set you (us) free.”
The securities litigation against Anavex was dismissed by the Court after Anavex’s attorney filed a motion to dismiss stating this:
“The Court will not dismiss any claims pursuant to Rule 12(b)(6) unless the plaintiff has failed to plead sufficient facts to state a claim to relief that is facially plausible, see Bell Atlantic Corp. v. Twombly, 550 U.S. 544, 570 (2007), that is, one that contains "factual content that allows the court to draw the reasonable inference that the defendant is liable for the misconduct alleged," Ashcroft v. Iqbal, 556 U.S. 662, 678 (2009). (Court granted the motion to dismiss, and would not allow the suit to be amended).
“... The Court declines to grant Plaintiffs' request (to amend) for a combination of three reasons. First, amendment here would likely be futile. Indeed, given the various grounds for the Court's decision, there is nothing to suggest that Plaintiffs would be able to state a valid claim should the Court grant them leave to amend. See, e.g., Ruffolo v. Oppenheimer & Co., 987 F.2d 129, 131 (2d Cir. 1993) ("Where it appears that granting leave to amend is unlikely to be productive .”
https://casetext.com/case/cortina-v-anavex-life-scis-corp-1
Therefore, the lawsuit was not factual, but I do agree that Missling has been gun shy to lawsuits since then. I think that is the reason we are not getting much in the way of updates.
I also wonder about the relationship between Parkinson’s and motor function diseases? This is may be where AVXL 2-73, a mixed agonists, may be postulated to have an effect. Therefore, see this:
1. https://www.genecards.org/cgi-bin/carddisp.pl?gene=SIGMAR1
UniProtKB/Swiss-Prot Summary for SIGMAR1 Gene
(Among other functions - including motor function it)....... Plays a role in several other cell functions including proliferation, survival and death. Originally identified for its ability to bind various psychoactive drugs it is involved in learning processes, memory and mood alteration (PubMed:16472803, PubMed:9341151). Necessary for proper mitochondrial axonal transport in motor neurons, in particular the retrograde movement of mitochondria. Plays a role in protecting cells against oxidative stress-induced cell death via its interaction with RNF112 (By similarity). SGMR1_HUMAN,Q99720
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269748/
Disruption of Axonal Transport in Motor Neuron Diseases
Motor neurons typically have very long axons, and fine-tuning axonal transport is crucial for their survival. The obstruction of axonal transport is gaining attention as a cause of neuronal dysfunction in a variety of neurodegenerative motor neuron diseases. .....Disruption of axonal transport also underlies the pathogenesis of spinal muscular atrophy and hereditary spastic paraplegias. These observations suggest that the impairment of axonal transport is a key event in the pathological processes of motor neuron degeneration and an important target of therapy development for motor neuron diseases.
Comment 1: Parkinson's, I think, is not currently identified as a motor neuron disease, but maybe it has some overlap with those diseases.
3. What are the four types of motor neuron disorders?
The disease can be classified into four main types depending on the pattern of motor neurone involvement and the part of the body where the symptoms begin.
Amyotrophic lateral sclerosis (ALS) ...
Progressive bulbar palsy (PBP) ...
Progressive muscular atrophy (PMA) ...
Primary lateral sclerosis (PLS)
SEE: https://www.mndnsw.asn.au/index.php?option=com_content&view=article&id=44:mndforms&catid=34:what-is-mnd
Comment 2: AVXL 2-73 has been mentioned for possible treatment of ALS, etc.
Yes, muscarinic receptors do play a role as you say, and with Parkinson’s as well. There is a need to explore and know more about this, and Anavex may be taking one of the first steps in doing so with the PDD study. If I may add, this:
AVXL 2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. It is a mixed ligand for sigma1/muscarinic receptors. SEE: https://www.alzforum.org/therapeutics/blarcamesine
I have located a couple of references, but only about M1.
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286317/
Roles of the M1 Muscarinic Acetylcholine Receptor Subtype in the Regulation of Basal Ganglia Function and Implications for the Treatment of Parkinson's Disease
2. https://www.michaeljfox.org/grant/highly-selective-m1-muscarinic-receptor-positive-allosteric-modulators-treatment-parkinsons
Hypothesis:
We believe that small molecules that affect the function of the M1 mAChR in a highly selective manner have the potential to deliver novel, well-tolerated and efficacious drugs to treat learning and memory deficits in individuals with PDD.
Study Design:
We have generated small molecules of novel chemical classes that are positive allosteric modulators of the M1 mAChR and have a good understanding of the structure-activity relationship of these molecules. Based on this knowledge, we will synthesize these molecules and optimize them for target engagement in the brain and safety.
“While heading the profit of my counsel, avail yourself also of any helpful circumstances over and beyond the ordinary rules. According as circumstances are favorable, one should modify one's plans.”
Excerpt From
The Art of War
Sun Tzu
If Anavex had followed the ordinary rules, it would have been over and done with. However, it has not, and it has modified its plans according to the circumstances. It has followed what it believes to be the most favorable routes to prevail. In these unusually trying times, it takes a warrior to succeed at achieving innovation while our government is too busy protecting and bailing out the status quo with trillions of stimulus and corporate bond purchases.
Agree. Thanks
Nidan: Yes, thank you.
Anavex “has surpassed by 50% the company’s original enrollment target for the ANAVEX®2-73 (blarcamesine) U.S. Phase 2 study in Rett syndrome.” So, Anavex has more patients in the study in the United States than it originally planned to enroll here in the U.S.? Exceeding its goal in enrollment is a newsworthy event, but I am not sure what this means. Where do we stand on Rett enrollment elsewhere?
Bio: Good to hear it has not “boiled over and exploded”. Thank you for posting that. I hear there’s a lot of great things going on in Pittsburgh these days. It sounds like it is a center for transformational technology.
What is COMT? Why is COMT important for the AVXL 2-72 AD and PDD clinical trials? The COMT gene and/or variants thereof play a role in Alzheimer's and Parkinson's. Here's a number of articles about that including articles about AVXL 2-73 and COMT variants.
1. https://parkinsonsnewstoday.com/2019/01/11/genetic-variant-predetermine-cognitive-decline-parkinsons/
Genetic Variant Predetermines Risk of Cognitive Decline in Parkinson’s, Research Suggests
Researchers have found that Parkinson’s patients whose cognitive ability is intact, but who have a specific genetic variant, have significantly less gray matter in the regions of their brain that are related to dementia.
The study with that finding, “Reduced gray matter volume in cognitively preserved COMTÂ 158Val/Val Parkinson’s disease patients and its association with cognitive decline,” was published in Brain Imaging and Behavior.
Several mutations in the COMT gene have been associated with the risk of developing Parkinson’s disease. This gene provides instructions for making catechol-O-methyltransferase (COMT), an enzyme that helps break down certain chemical messengers like dopamine.
https://parkinsonsnewstoday.com/2019/01/11/genetic-variant-predetermine-cognitive-decline-parkinsons/
2. https://www.ptcommunity.com/wire/anavex-life-sciences-presents-new-data-identifying-treatment-response-biomarkers-alzheimer-s
Several genetic variants that impacted response to ANAVEX®2-73 were identified in the study analysis including the Sigma-1 receptor (SIGMAR1), the target for ANAVEX®2-73, and the Catechol-O-methyltransferase (COMT) gene, produced by nerve cells and involved in memory function. Results showed that study participants with SIGMAR1 (rs1800866) or COMT (rs113895332/rs61143203) variants were less likely to benefit from treatment with ANAVEX®2-73. In the study population, when participants with these variants (approximately 20 percent) were excluded, the remaining study participants (approximately 80 percent) showed improved scores on gold-standard tests of cognition (MMSE) and activities of daily living (ADCS-ADL) (p<0.05).
Including participants with milder disease (baseline MMSE ≥20) and excluding those with a SIGMAR1 variant resulted in an average improvement of +1.7 MMSE and +3.9 ADCS-ADL at week 57 compared to baseline. The additional exclusion of participants with the COMT variant resulted in a score improvement of +2.0 MMSE and +4.9 ADCS-ADL at week 57 compared to baseline.
3. https://www.neurologylive.com/conferences/aaic-2018/harald-hampel-md-phd-ma-msc-genomic-analysis-of-anavex-273-in-alzheimer-disease-study
Anavex identified several genetic variants that impacted the response to ANAVEX 2-73, a selective sigma-1 receptor (SIGMAR1) agonist, which include SIGMAR1, ANAVEX 2-73’s target, and the Catechol-O-methyltransferase (COMT), a gene involved in memory function.
Harald Hampel, MD, PhD, MA, MSc: Genomic Analysis of ANAVEX 2-73 in Alzheimer Disease Study
4. https://ghr.nlm.nih.gov/gene/COMT
What is COMT?
Catechol-O-Methyltransferase (COMT) is one of several enzymes that degrade dopamine, epinephrine, and norepinephrine. COMT breaks down dopamine mostly in the part of the brain responsible for higher cognitive and executive function (prefrontal cortex) [1].
The COMT gene provides instructions for making an enzyme called catechol-O-methyltransferase. Two versions of this enzyme are made from the gene. The longer form, called membrane-bound catechol-O-methyltransferase (MB-COMT), is chiefly produced by nerve cells in the brain. Other tissues, including the liver, kidneys, and blood, produce a shorter form of the enzyme called soluble catechol-O-methyltransferase (S-COMT). This form of the enzyme helps control the levels of certain hormones.
In the brain, catechol-O-methyltransferase helps break down certain chemical messengers called neurotransmitters. These chemicals conduct signals from one nerve cell to another. Catechol-O-methyltransferase is particularly important in an area at the front of the brain called the prefrontal cortex, which organizes and coordinates information from other parts of the brain. This region is involved with personality, planning, inhibition of behaviors, abstract thinking, emotion, and working (short-term) memory. To function efficiently, the prefrontal cortex requires signaling by neurotransmitters such as dopamine and norepinephrine. Catechol-O-methyltransferase helps maintain appropriate levels of these neurotransmitters in this part of the brain.
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966542/
Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum
A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the COMT Val158 allele) has been found to associate with poorer cognitive performance and increased susceptibility to develop psychiatric disorders. It is generally assumed that this increase in COMT activity influences cognitive function and psychiatric disease risk by increasing dopamine turnover in cortical synapses, though this cannot be directly measured in humans.
6. https://pubmed.ncbi.nlm.nih.gov/29439855/
Catechol-O-methyltransferase (COMT) Genetic Variants Are Associated With Cognitive Decline in Patients With Parkinson's Disease
7. https://parkinsonsnewstoday.com/2019/01/11/genetic-variant-predetermine-cognitive-decline-parkinsons/
Genetic Variant Predetermines Risk of Cognitive Decline in Parkinson’s, Research Suggests
Several mutations in the COMT gene have been associated with the risk of developing Parkinson’s disease. This gene provides instructions for making catechol-O-methyltransferase (COMT), an enzyme that helps break down certain chemical messengers like dopamine.
The most common alteration in the DNA sequence that makes up the COMT gene is the Val158Met mutation in which a valine (Val) is replaced by a methionine (Met) at position 158. Val and Met are both amino acids, also known as the protein’s building blocks.
...
The Val158Met mutation in the COMT gene has been associated with an increased risk of cognitive decline in Parkinson’s disease, particularly in people with greater COMT activity. When this happens, there is too much neurotransmitter degradation, thus leading to reduced levels of dopamine and affecting basic brain functions such as motor coordination and memory.
Evidence suggests a correlation between cognitive impairment, one of Parkinson’s non-motor features, and reduced gray matter volume.
...
A Spanish team of researchers used magnetic resonance imaging (MRI), a non-invasive imaging technology, to investigate a possible structural brain compromise in Parkinson’s patients with highly active COMT activity that could explain their increased risk for subsequent cognitive impairment.
The study included 120 newly diagnosed Parkinson’s patients with normal cognition (who were not previously treated for the disease) and 48 healthy controls from the Parkinson’s Progression Markers Initiative database.
Results showed that there was a widespread, significant reduction in cerebral gray matter volume in patients with the Val/Val genotype. They observed alterations in the fronto-subcortical and posterior-cortical brain regions, where motor and cognitive functions originate.
8. https://pubmed.ncbi.nlm.nih.gov/22483294/
...Catechol-O-mehyltransferase (COMT) is surfacing with a prominent role in AD pathophysiology by affecting the metabolism of catecholamine neurotransmitters and estrogen. COMT gene regulates dopamine levels in the prefrontal cortex which are involved in working memory and executive functioning. Impaired executive functioning is reported in a subgroup of AD patients and is associated with a more severe disorder, a more rapid disease progression and a shorter survival. .......... COMT inhibitors, that are adjunctive drugs in Parkinson's disease treatment, lower homocysteine levels and improve executive memory processes in normal subjects. A preliminary study, which needs replication, demonstrates that COMT inhibitors block beta-amyloid fibrils in vitro. Taken together, these findings suggest that research should focus on the role of COMT in AD pathogenesis and on the feasibility of targeting COMT activity in AD treatment.
Bio is right. Short Interest Shows Sentiment. ” It is anticipation of results coupled with acknowledgement that dilution has stopped, game is tied, and it’s late innings.” (Bio quote). Investor sentiment believes that the stock price is likely to go higher because short interest is decreasing.
Anavex Biomarker and Adapative Trial Design
The adaptive clinical trial design and bio marker- guided design (mostly used in cancer trials) has been adopted by Anavex. So, I am trying to learn about that. Here is a bit of what I have read:
1.
“..... It has been hypothesized and demonstrated that using molecular markers to stratify patients into appropriate clinical trials can improve success rates of trials. While a study analyzing clinical trial drug development in breast cancer from 1998 to 2012 found that only 14% of drugs in clinical development for advanced disease were approved, when patients were selected based on HER2 status, the success rate increased to 23%. Using HER2 status to stratify patients also led to a 27% decrease in costs (Parker, 2012).
Similarly, clinical trial success rates in NSCLC during the same time period were six times higher for biomarker-targeted therapies and three times higher for receptor-targeted therapies than for trials that were not molecularly guided. The risk-adjusted cost for NSCLC clinical drug development was estimated to be nearly $2 billion (Parker, 2014).
Over the past few years, two new trial methodologies have emerged in order to address this growing need for a new clinical trial approach:
The adaptive design and
The biomarker-guided design.
The goals of these two methods are three-fold:
More effectively match drugs to the populations most likely to benefit based on an individual patient’s molecular profile
Decrease trial costs
Decrease the time to drug approval.
The strategies involved within these new designs include interim trial analyses of individual patient data, as well as pre-trial biomarker screening combined with a deeper analysis of the molecular variability within individual patient tumors. The FDA has drafted industry guidance outlining the use and importance of adaptive trials, and various biomarker status initiatives are underway or are being developed.”
....
“The Adaptive Design Clinical Trial
The purpose of the adaptive trial design is both to increase the likelihood of a study’s success as well as to deliver more in-depth data concerning the treatment’s effects. The FDA defines an adaptive trial as “a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study.”
A key feature of this trial design is the use of interim analyses, which permit researchers to customize the trial, for example, by adjusting the randomization process or treatment dose or schedule, based on results from earlier participants in the study. This allows for potentially ineffective parameters within the trial to be minimized, instead of being locked into the study’s original design (FDA, 2010).”
https://obroncology.com/article/new-clinical-trials-designed-to-better-leverage-precision-medicine-2/
2.
“Precision medicine is positioned to revolutionize the healthcare landscape, and the utilization of advanced clinical development technologies is key to supporting precision medicine trials. These technologies can harness a variety of disparate data sources at richer and greater volumes to build more accurate predictive models for different patient subsets. We discuss briefly the nature of precision medicine, the FDA’s initiatives encouraging the development of targeted therapies and the importance of the revolution in genomics for precision medicine. We describe the five Vs of big data and the pivotal role of big data in precision medicine. We present four clinical trial technologies that provide essential capabilities for precision medicine:
(1) Continuous collection, aggregation, and integration of myriad data sources; (2) Adaptive and iterative study design and execution as new information becomes available; (3) Maintenance and management of data throughout the study life cycle; and (4) Advanced analytics for research discovery. Precision medicine shows great promise for developing exploratory hypotheses from its broad variety of data and iterative approach, evaluating these hypotheses, and producing safer, more effective treatments for targeted patient subgroups with advantageous benefit-risk profiles. The complexities of precision medicine study designs require substantial planning, investment, and commitment from all stakeholders.”
https://www.thejournalofprecisionmedicine.com/wp-content/uploads/2017/12/DAVI.pdf
Comment: Anavex is collecting its own data, and it is accessing and using the data from the Alzheimer’s Initiatives, etc.
Don’t all drug companies go for approval anywhere they can? My experience with big pharma is that they sell their drugs globally - everywhere. Why not go for approval in these countries if Anavex feels, for some reason, that it will be difficult or longer in obtaining approval in the U.S. If you do the research you will find numerous antitrust cases involving instances where major pharma has blocked competition in the U.S. Just Google “pharmaceutical antitrust litigation blocking competition” or “pharmaceutical antitrust litigation blocking generic competition” or “pharmaceutical antitrust litigation blocking drug entry by filing baseless Citizen Petition with the FDA” or “blocking drug entry or approval by sham listing of patents in the FDA’s Orange Book, etc., etc. What’s more, I find it difficult to deny that the FDA is not or never has been influnenced by major pharma when so many from big pharma serve in positions with the FDA past, present, and future. I find it difficult to believe that in the real world companies do not try to defeat competition from other companies and that major pharma does not try to protect their drug pipelines when in fact they do. Bias exists everywhere. Agencies are sometimes biased. Judges are sometimes biased. We do not live in a perfet world. I am biased. This board is biased and everyone on it is biased to some extent one way or another. It may be that it is easier for a small biotech to get approval elsewhere than in the U.S. Also, once approved elsewhere, that company has a better chance of approval in the U.S. Major pharma sells their drugs everywhere at different prices in different coutries. That’s why folks travel to Mexico and Canada to buy drugs.
Certainly, it indicates at the very least that Anavex is not planning to crash and burn. We will see what happens, but I am wondering what advantages/incentives are present for Anavex to expand to the UK and Canada. I know there are advantages but to what extent? Also, does the UK and Canada provide any incentives such as funding or other aid or assistance? Obviously, this expansion entails more capital, but whose capital? It also means more hands on deck because Anavex is conducting studies in more countries/locations. As an investors, I think we need to do more work, study, research and seek to know and understand why this small company is expanding and how it will do that?
I think that is the key point to look for right there “... all the trials have a set of objective biomarkers that are subject to pre-specified analysis. This is important because if it can be shown that the group patients in each those trials that did best also correspond to those with the hypothesised biomarkers for response to A2-73 Anavex will likely be able to show convincing statistical significance in those subgroups.” Quoting Investor.
Thank you all for your responses. Very helpful.
Frrol and Bio:
It could be that I am confused and/or do not understand the discussions about biomarkers. If so, please let me know.
My understanding is that a predictive biomarker is usually measured before treatment and provides information on the probability of response to a particular therapy. Therefore, for example, if predictive biomarkers are identified in patients in both groups, the placebo group and in the drug group, and the patients identified with predictive biomarkers respond favorably in the group that receive the drug with some of the patients identified in the placebo group having a mixed response, some with a placebo response and some with no response, may that be of any use in addressing the placebo issue.
I ask that question because not everyone, including those with identified biomarkers, that receive the placebo will necessarily have an effect, correct? Some patients with identified predictive biomarkers in the placebo group may have no response during the 14 week trial period. However, those very same patients may receive the drug in the OLE after 14 weeks, and they may have a response. I am assuming that patients with predictive biomarkers will respond favorably if AVXL 2-73 has efficacy. Therefore, it would be relevant to know how patients with predictive biomarkers faired during the 14 week trial and afterwards in the OLE, right?
It may also be that the placebo response, if any, may be greater or less in placebo patients than the response by those receiving the drug. That information, may be relevant as well.
Am I making any sense? Perhaps I am not because I really do not understand biomarkers and their use in clinical trials. Or, perhaps any analysis along the lines I have described is of no use in disproving or proving anything when it comes to the placebo effect.
I have questions for Doc, frroll, Investor, Bio and others.
Puttting aside the dosing question, I have questions about the placebo effect relative to identification and confirmation of genomic biomarkers. Can the placebo effect have different effects in patients that have different genetic variants? Can the genetic variants and gene expression of patients in this trial be used to detemine the effect of AVXL 2-73 versus the placebo effect? Can the placebo effect correspond with each patients different genetic profile?
See below where Missiling says “... the analysis platform described in this work opens the possibility of using big data-driven unbiased genome-wide patient selection marker identification early on in the drug development process...”. I am not sure what Missling means, but it seems to me that the analysis of the trial results will involve making comparisons between groups (actual drug group - placebo group) on the basis of the genetic profiles of patients in each group?
My questions may not be worded that well, but I think you may understand what I am seeking to know. I do think the placebo effect is a valid concern with the clinical trials that Anavex has conducted, but I am trying to determine if genetic profiles may be used to address the placebo concern.
My questions relate to comments to the peer-reviewed journal, Alzheimer's & Dementia: Translational Research & Clinical Interventions, entitled, “A precision medicine framework using Artificial Intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer’s disease therapy: Analysis of the Blarcamesine (ANAVEX2-73) Phase 2a clinical study.“
"This study highlights the relevance of phenotypic and genotypic precision medicine analyses of Whole Exome Sequencing (WES) and gene expression (RNAseq) data in drug development and in particular the potential to identify patients’ genetic variants and gene expression changes that may predict increased chances of success of Alzheimer’s disease treatments,” said Dr. Harald Hampel, M.D., Ph.D., M.A., M.Sc., Founding President of the Alzheimer Precision Medicine Initiative (APMI)1 and lead author of the paper."
"...We believe that the analysis platform described in this work opens the possibility of using big data-driven unbiased genome-wide patient selection marker identification early on in the drug development process of CNS diseases, including Alzheimer’s disease, which is currently applied more routinely in the field of oncology,” said Christopher U. Missling"
https://www.globenewswire.com/news-release/2020/04/23/2020772/0/en/Anavex-Life-Sciences-Announces-Publication-of-Clinical-Data-for-ANAVEX-2-73-blarcamesine-in-Alzheimer-s-Disease.html
Bio: Thank you. Your post, not mine, set the standard of excellence. I think the board also has many other intelligent and knowledgeable contributors, and I learn by reading what you and they write.
Why the 2-73 PDD results may be positive.
Autophagy is involved in maintaining cellular homeostasis and that may be key to treating PDD.
"As brain changes caused by Parkinson’s gradually spread, they often begin to affect mental functions, including memory and the ability to pay attention, make sound judgments and plan the steps needed to complete a task....
The key brain changes linked to Parkinson’s disease and Parkinson’s disease dementia are abnormal microscopic deposits composed chiefly of alpha-synuclein, a protein found widely in the brain with a normal function not yet known. The deposits are called “Lewy bodies” after Frederick H. Lewy, M.D., the neurologist who discovered them while working in Dr. Alois Alzheimer’s laboratory during the early 1900s...."
https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/parkinson-s-disease-dementia#about
"Alpha-synuclein is normally a wavy-like structure and in Parkinson's, the alpha-synuclein protein misfolds forming a toxic clump or aggregate.....They also go on to accumulate in large masses termed 'Lewy bodies' and these clumps are now associated with brain cell death; the process involved in the aggregation of these misfolded proteins may be a trigger for PD...Alpha-synuclein, like all other proteins produced in the cells of the body is subject to regulation and recycling and sometimes it is the failure of this process that may lead to aggregation....
Although scientists do not know exactly what causes the protein to misfold and clump together, many believe that if we find a way to prevent its accumulation or reduce alpha-synuclein gene expression or promote its removal and or recycling , we may be able to stop and potentially reverse the damage these deposits may cause to the brain. It is not surprising then that alpha-synuclein has now become a major target for potential PD therapies."
https://www.cureparkinsons.org.uk/why-alpha-synuclein
"....Autophagy is involved in maintaining cellular homeostasis......". See Regulation and Function of Autophagy during Cell Survival and Cell Death
https://cshperspectives.cshlp.org/content/4/6/a008813.full
"...ANAVEX®2-73 can selectively induce the autophagy process and increase protein homeostasis in both in vitro and in vivo models...
Autophagy is a cellular process that cleans cells of defective proteins and is part of a set of mechanisms that participate in proteostasis, or the balance of the protein network. Loss of proteostasis and dysfunction of the autophagy process, has been closely linked to the pathogenesis of human neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and ALS1.
“There is a great amount of data linking dysfunction and malfunction of autophagy to neurodegenerative disease and, consistent with its role in proteostasis, to the accumulation of protein aggregates. Thus, the modulation of autophagy has become one key pharmacological target in neurodegeneration,” the researchers reported. “In fact, there are multiple overlaps of autophagy and pathogenesis pathways in Alzheimer’s disease, Parkinson’s disease, and ALS. Recently different alternative views and new pharmacological targets towards Alzheimer’s prevention and treatment are evolving and include a strong focus on the autophagy process.
The Cells paper also noted that this is the ?rst report to show that Sig-1R activation enhances the autophagic ?ux in human cells and in C. elegans with positive effects on proteostasis in vitro and in vivo, an important concept towards the stabilization of neuronal survival and function that may help to prevent age-associated neurodegeneration."
https://www.globenewswire.com/news-release/2019/03/04/1745838/0/en/Anavex-Life-Sciences-Reports-Publication-of-New-Data-that-Show-ANAVEX-2-73-Induces-Cellular-Recycling-Process-Linked-to-the-Prevention-and-Treatment-of-Age-Associated-Diseases.html
See also my post: How may AVXL 2-73 benefit patients with Parkinson's dementia? https://investorshub.advfn.com/boards/read_msg.aspx?message_id=149155921
Lastly, AVXL 2-73 as a Muscarinic agonist affects short term memory (paying attention, etc.) and long term memory whereas Sigma 1 may only be involved in long term memory.
Yes, Missling describes it as: “ANAVEX®2-73 (blarcamesine) is an orally available, small-molecule activator of the sigma-1 receptor which, data suggest, is pivotal to restoring neural cell homeostasis and promoting neuroplasticity.”
https://www.anavex.com/anavex-life-sciences-issued-new-u-s-patent-for-composition-of-matter-covering-anavex2-73-for-the-treatment-of-alzheimers-disease/
“Living organisms need to maintain homeostasis constantly in order to properly grow, work, and survive. In general, homeostasis is essential for normal cell function, and overall balance.”
https://www.bioexplorer.net/importance-of-homeostatis-examples.html/#Importance_of_Homeostasis
“Homeostasis is the process through which an organism regulates its internal environment, keeping critical parameters within acceptable limits. Aging affects the ability to maintain and restore homeostasis because some of the mechanisms used by the organism are no longer as effective as in a young body.
In many cases the inability to restore homeostasis can affect the body's activities and can result in reduced capabilities and disease....”
https://sciencing.com/aging-affect-ability-restore-homeostasis-22809.html
A simple explanation of what Anavex believes that AVXL 2-73 does is to activate or stimulate the Sigma 1 receptor to attempt to put one’s body back in a state to heal itself. It is a Sigma-1 receptor agonist that restores endoplasmic reticulum mitochondria, which in turn sets off a chain reaction throughout the central nervous system or the body that hopefully repairs the damage resulting from aging or oxidative stress. My simplistic way of thinking tells me that the affect that AVXL 2-73 may have on any particular person in restoring homeostasis and helping that person’s body to heal itself will depend on many factors, including genetic make up, age, severity of the central nervous disease or damage in question, general state of health, diet, environment, physical condition, activity, etc.
It seems to me that the more damage that has been done to one’s body the more difficult it will be for that body to restore homeostasis and heal itself. Each individual is different, and the effect that of restoring homeostasis may vary. I think that if the drug is effective in prolonging life of a person with AD, it may be even more effective if that person is able to make an effort to engage in things that will add to that benefit. Of course, we should not forget too that AVXL 2-73 is a dual agonist - a Muscarinic agonist as well as a sigma agonist. Therefore, the drug may also have health benefits as a Muscarinic agonist such as treating blood pressure.
Lastly, Alzheimer’s News Today says this:
“Anavex 2-73 is a small molecule that activates the sigma-1 receptor, which is known to modulate cellular processes relevant to neurodegeneration. Specifically, Anavex 2-73 is thought to help restore cellular balance by targeting protein misfolding (when proteins fail to fold correctly, into a normal configuration, they do not work as intended), oxidative stress (which damages cells due oxygen molecules with free radicals, or unpaired electrons), mitochondrial dysfunction, inflammation, and cellular stress.
The sigma-1 receptor is a small transmembrane protein, a stress-reducing survival protein, mainly located on the endoplasmic reticulum membrane of cells. This receptor also is present on the surface of some nerve cells and multiple other central nervous system cells and tissues. As sigma-1 receptors are present in various sites, different physiological and pathological processes may be influenced by Anavex 2-73 treatment.
The brain of a person with Alzheimer’s disease has fewer sigma-1 receptors than that of healthy people of the same age. That’s why the activation of these receptors could improve the clinical symptoms of the disease and protect against neurologic changes.”
https://alzheimersnewstoday.com/anavex-2-73/
Patients with Rett syndrome (RTT) may demonstrate parkinsonian features.
https://www.cambridge.org/core/journals/canadian-journal-of-neurological-sciences/article/incidence-and-evolution-of-parkinsonian-rigidity-in-rett-syndrome-a-pilot-study/6B08C671ADFFA5692A1EA73C6D916625
Dopamine is implicated in both Parkinson’s and Rett.
https://www.spectrumnews.org/news/molecular-mechanisms-dopamine-implicated-in-rett-syndrome/
A Tsunami of Dementia Could Be On the Way
Read in Scientific American: https://apple.news/AqjWK6HJJQF25IGe8ihxqpA
Trump appointed a person close to big pharmaceutical companies who just happens to be on the Moderna Board, Moncef Slaoui, Ph.D. Moderna’s claim is based on a few healthy participants from its first trial, which was only a safety trial. I think Moderna has never had a successful vaccine. I’m not confident we will get the best vaccine available assuming any of the 100 vaccine candidates actually work.
Gernee:
Thank you.
If we do not meet the endpoints (even if motor function is improved), the initial reaction is likely to be that the stock price moves down considerably. We should not necessarily sell if that happens.
Some large funds employ AI/Algos to trade stocks. In other words, machines trade large volumes of stock. These machines or programs are developed based on the past or what is known from the past - not what may known in the future. For example, these programs did not know that a C-virus pandemic would occur, but they were programmed to sell once the selling commenced. They contribute to big swings in the market. We are now witnessing a big swing up, but they could just as easily facilitate another big move down again. I certainly can envision that their systems may be programmed to automatically sell if endpoints in a clinical trial are not met or for any influence that a failure may have. These funds do not necessarily get hurt because they can, upon reflection, buy back at lower prices. Or, they get out early with smaller losses. Many individual investors though may get crushed. We do not react as quickly.
I have been involved with at least one biotech that missed end points in a trial, but otherwise had encouraging results because of other factors. The stock dropped precipitously. However, if one took the time to examine the results instead of automatically selling they would have realized that a segment of those in the study otherwise benefited and that segment represented a large percentage of patients with the disease in question.
If we get any type of mixed results, we could see a drop in share price because that will not meet with expectations of most investors in this clinical stage biotech. However, mixed results in this one trial (PDD) too does not mean it is all over and done.
Of course, if it is a complete failure, we know what will happen, but, to be clear, that is certainly not my expectation. I have researched this company for a number of years. Based on my research, I believe it is highly likely that AVXL 2-72 and 3-71 show promise to treat multiple CNS diseases. I believe that conclusion is reasonable based on the science and studies thus far. I am willing to wait and see. If I am wrong, there will be no meaningful impact on my life style. If I am right, .... I will just leave it at that.
Yes, good point about it being a bit strange. It will be interesting to see what this leads to. Thank you.
Yes, you are correct about plans being in place before the pandemic. My opaque comment, not worded as such, was made in response to the lack of numbers or dates in the announcement. It occurred to me that Missling may have pushed this out there faster than previously planned. Therefore, I suppose I am guilty as charged of connecting dots. I am not very smart as many on this board, and I was not aware I may have been connecting dots. I throw myself at the mercy of the court.
Bio - Keen observation. The 3-71 safety will be conducted in Australia with lower cost and very likely some governmental funding as was the case with 2-73. A-73 is safe and has shots at treating mulitple CNS diseases. 3-71, if safe, will be a candidate to treat multiple diseases as well. I was scheduled to travel to attend an investment conference this month. It was initially cancelled, but it was held online within the past two weeks. Many topics were covered including discussions about the new normal. One comment was that we moved forward three to four years in one week due to the C-virus. The world is moving faster than ever, and that will continue. We will see exponential change. Anyone thinking linear will be left behind. Drug approval will happen faster along with everything else. We will not be going back to “normal”. I think Missling is smart. If we prove safety for 3-71 now at very little cost to the company, that drug will be another horse running out front in the race to treat deadly and costly diseases that are a drag on the world economy.
Understand. Thank you for the explanation.
“The stock has not seen $6 in years ...”???
I’m sorry, but the February 2020 high for Anavex was $6.31! Check your facts.
Bio: Brilliant research and analysis. I never would have made all of the connections, including the statement by Missling about being in good company with Lilly. You demonstrae too that Missling knows what he is doing although we sometimes have difficulity appreciating the progress Anavex has made under his leadership. Anavex’s progress, financially and clinically, has been gradual. However, I suspect we will see things pick up from here on now that Anavex has established sources of funding for completing existing trials and to add future trials. We will have four clinical trials in play in 2020, and I think more to come.
Additionally, below I cite findings that drug targets with genetic support are more likely to be approved. Here is the article:
Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval.
Emily A. King1*, J. Wade Davis1 & Jacob F. Degner1 1AbbVie Genomics Research Center, North Chicago, IL. January 7, 2019
"Analyzing historical pipeline data, Nelson et al. 2015 (Nat. Genet.) concluded pipeline drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. Taking advantage of recent clinical development advances and rapid growth in GWAS datasets, we extend the original work using updated data, test whether genetic evidence predicts future successes and introduce statistical models adjusting for target and indication-level properties. Our work confirms drugs with genetically supported targets were more likely to be successful in Phases II and III. When causal genes are clear (Mendelian traits and GWAS associations linked to coding variants), we find the use of human genetic evidence increases approval from Phase I by greater than two-fold, and, for Mendelian associations, the positive association holds prospectively. Our findings suggest investments into genomics and genetics are likely to be beneficial to companies deploying this strategy"
https://www.biorxiv.org/content/biorxiv/early/2019/01/08/513945.full.pdf
Going forward, I believe we will see more and faster developments. Using a quote from someone: “There are decades when nothing happens, and weeks when decades happen,”
Thank you.
From the transcript - encouraging:
.... there are moments where you cannot buy anymore because you know certain things. So I would not bring this to the forefront. I would just leave it like that we are very excited about all our programs.
The Alzheimer's study, it's very exciting that we are moving forward and we're rolling very nicely actually in Australia, the Parkinson's disease study because it's really around the corner and it's going to be a data announced very soon and two Rett studies and the third Rett study starting soon as well. We're very excited about all our programs and also not to mention that the ANAVEX 3-71study, which we had announced that we plan also for moving into Phase 1. This is also something we are looking forward to this year.
Tom Bishop
Okay. And one last question on the financial side. I saw something about, well, I know you have a deal with Lincoln Park and kind of ATM and then this Cantor Fitzgerald and now I see Leerink. And I'm a little confused if those are two different programs? Or is it basically all programs that you’re using to stay funded?
Christopher Missling
So the major contribution for funding was in the past. The Lincoln Park, we call it a purchase agreement where we are able from time to time if we like the stock price levels and our burn rate is not so big and our volume is very easily able to absorb that to just able to keep the cash position relatively constant over quarter-over-quarter as you can see. The ATM was Cantor Fitzgerald.
We're very excited that we were able to add now to this agreement Leerink. And that is basically just an amendment of the existing program with Cantor to add Leerink. It's not a different program. It's exactly the same. We’re just adding Leerink to this -- to this program, to this ATM program, which we have not used yet. And we got this program as a safety net if we are not able to find alternatives to fund, but we have not used this program.
Anavex maintains that it is excited about its clinical trials and has sufficient capital in the bank and that it can access. Missling intimates that he knows certain information that we do not know, of course, and he is excited. Additionally, he is clearly financially confident and comfortable. A few observations. First, ability of a young biotech to fund its drug development is usually worrisome, but Missling has solved this problem. Second, we know we have one drug that is safe. Third, three clinical trials are advancing well with one, PDD, to report results soon. Fourth, an additional clinical trial with another drug is to commence very soon. Fifth, we are not hurting for sources to fund any of these clinical trials. Sixth, the company has no debt. Seventh, both drugs in four clinical trials this year have scientific support.
I could go on, but you get the point. Anavex is feeling no pressure, it has the ability to fund its trials/studies, and it possesses promising drugs one of which is far along in development.
If you want to make real money, invest in biotech, but do your DD first. I have researched Anavex and its drugs for going on something like 6 years now. During that time, it has endured when many thought it would rapidly fail because of various reasons such as it was a scam, it did not have sufficient capital, its drug AVXL 2-73 was not safe, it had too few employees to carry on, etc., etc. Again, I could go on and on. However, Anavex is more in the game than ever before, and it has the foundation to continue.