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Is amyloid good or bad? Currently, I do not understand the article that indicates that Sigma 1 Agonists may generate amyloid-b (article #1 below). However, I point out by siting the other articles below that amyloid "(functional amyloid") has many useful features. I speculate that it may also make a difference where and how amyloid appears or develops. One thing we do know for sure is that a lot of amyloid removal drugs have failed over many years of research and development. It should be obvious that the amyloid thesis is highly problematic, and I do not understand how useful, if at all, article #1 may be.
1. Axonal generation of amyloid-b from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes
https://www.cell.com/cell-reports/pdf/S2211-1247(21)00473-3.pdf
2. Good Amyloid, Bad Amyloid—What’s the Difference?
https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002362
3. Two Decades of Studying Functional Amyloids in Microorganisms
This year (2020) marks the 20th anniversary of the discovery that amyloids, typically associated with human diseases, can also play beneficial roles essential for normal cellular physiology.
Microbial functional amyloids are extremely diverse and are involved in structural scaffolding and biofilm formation, adhesion, surface-tension modulation, regulation of the cell cycle and gametogenesis, toxicity, host–pathogen interactions, and symbiosis.
Structural and regulatory polymorphism of microbial functional amyloid systems underlies their functional diversity.
A profound understanding of microbial functional amyloid systems could pave the way towards the development of bioinspired materials and anti-infective therapies.
The third decade of functional amyloid research begins with open questions regarding the canonical concept of these assemblies.
In the past two decades, amyloids, typically associated with human diseases, have been described to play various functional roles in nearly all life forms. The structural and functional diversity of microbial 'functional amyloids' has dramatically increased in recent years, expanding the canonical definition of these assembled molecules. Here, we provide a broad review of the current understanding of microbial functional amyloids and their diverse roles, putting the spotlight on recent discoveries in the field. We discuss their functions as structural scaffolds, surface-tension modulators, adhesion molecules, cell-cycle and gametogenesis regulators, toxins, and mediators of host–pathogen interactions. We outline how noncanonical amyloid morphologies and sophisticated regulatory mechanisms underlie their functional diversity and emphasize their therapeutic and biotechnological implications and applications.
https://www.cell.com/trends/microbiology/fulltext/S0966-842X(20)30239-0
4. Functional Amyloids
When protein/peptides aggregate, they usually form the amyloid state consisting of cross ß-sheet structure built by repetitively stacked ß-strands forming long fibrils. Amyloids are usually associated with disease including Alzheimer's. However, amyloid has many useful features. It efficiently transforms protein from the soluble to the insoluble state in an essentially two-state process, while its repetitive structure provides high stability and a robust prion-like replication mechanism. Accordingly, amyloid is used by nature in multifaceted and ingenious ways of life, ranging from bacteria and fungi to mammals. These include (1) Structure: Templating for small chemical molecules (Pmel17), biofilm formation in bacteria (curli), assisting aerial hyphae formation in streptomycetes (chaplins) or monolayer formation at a surface (hydrophobins). (2) Reservoirs: A storage state for peptide/proteins to protect them from their surroundings or vice versa (storage of peptide hormones in mammalian secretory granules or major basic protein in eosinophils). (3) Information carriers: The fungal immune system (HET-s prion in Podospora anserina, yeast prions) or long-term memory (e.g., mnemons in yeast, cytoplasmic polyadenylation element-binding protein in aplysia). Aggregation is also used to (4) "suppress" the function of the soluble protein (e.g., Cdc19 in yeast stress granules), or (5) "signaling" through formation of oligomers (e.g., HET-s prion, necroptosis-related proteins RIP1/RIP3). This review summarizes current knowledge on functional amyloids with a focus on the amyloid systems curli in bacteria, HET-s prion in P. anserina, and peptide hormone storage in mammals together with an attempt to highlight differences between functional and disease-associated amyloids.
https://pubmed.ncbi.nlm.nih.gov/31088827/
Gene therapy for Rett is good news, but gene therapy may not be a cure. The article you cite, for example, mentions Zolgensma, an approved gene therapy for spinal muscular atrophy. Zolgensma is not a cure for SMA (spinal muscular atrophy). In addition, it cannot reverse any damage already caused by SMA before treatment. Zolgensma, however, has been beneficial in improving certain conditions caused by SMA, and it may help stop the progression of the disease.
Gene therapy may also have some serious side effects.
There may also be a need for other drugs or therapy even if some form of gene therapy for Rett is eventually approved.
https://www.drugs.com/medical-answers/zolgensma-cure-sma-3559344/
Activation of Muscarinic M1 receptor may reduce Amyloid-ß. Anavex 2-73 is a mixed agonist. It appears to activate Sigma 1 and Muscarinic receptors M1-M4.
In my previous post on 10/20/21, I pointed out that Anavex 2-73 (Blarcamesine) is different from other drugs classified solely as Sigma 1 agonists. Anavex 2-73 is a multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions. Blarcamesine can activate both M1 and s1 receptors with high potency and selectivity. Activation of certain Muscarinic receptors may reduce Amyloid and Tau. Although it may be true that Pre-084, a Sigma 1 agonist, may for some reason increase Amyloid in animals at least, we cannot say that the administration of the mixed agonist Blarcamesine, causes the accumulation of Amyloid in animals or humans. Previously, it has been indicated that Blarcamesine may reduce Amyloid and Tau, but that too has not been clinically proven for humans. However, there is science out there that suggest that activation of certain Muscarinic receptors reduces Amylolid and Tau. In any event, the whole amyloid plaque hypothesis is debatable. I think it is good to discuss the pros and cons of sigma 1 agonists, etc., but we need to wait for the out come of the Anavex clinical trials and not get carried away drawing conclusions one way or another at this point.
1. Acute Effects of Muscarinic M1 Receptor Modulation on AßPP Metabolism and Amyloid-ß Levels in vivo: A Microdialysis Study
"Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-ß (Aß) production by shifting endoproteolytic amyloid-ß protein precursor (AßPP) processing toward non-amyloidogenic pathways."
https://pubmed.ncbi.nlm.nih.gov/25881909/
2. Muscarinic Agonists
The M1 muscarinic receptor is clinically significant in the central nervous system, and it influences neurologic functions. Muscarinic agonists play an important role in the treatment of Alzheimer disease(AD). Memory loss in Alzheimer disease patients is associated with a cholinergic deficit due to the reduced activity of choline acetyltransferase, which synthesizes acetylcholine. Another important feature of AD is the accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are aggregates of amyloid-beta derived from cleaving amyloid precursor protein. Muscarinic agonists appear to increase the activity of a protease enzyme that cleaves amyloid precursor protein in such a manner that there is no production of amyloid-beta. Through such mechanisms, muscarinic agonists treat memory deficit and amyloid deposition in AD.[17][18]
https://www.statpearls.com/ArticleLibrary/viewarticle/25378
3. Biological Activity for ANAVEX 2-73
s1 agonist (IC50 = 860 nM); also displays affinity for muscarinic M1-M4 receptors (Ki values < 500 nM), but not for s2 receptors. Exhibits neuroprotective effects, prevents tau hyperphosphorylation, and attenuates scopolamine- and (+)-MK 801-induced learning deficits in a mouse model of amyloid toxicity.
https://www.tocris.com/products/anavex-2-73_5058
The drug Anavex 2-73 (Blarcamesine) seems to be very different from other drugs classified as Sigma 1 agonist. Anavex 2-73 is multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions. It may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. Blarcamesine can activate both M1 and s1 receptors with high potency and selectivity. It may not only be active itself, but it may be active as a pro-drug. AVXL 2-73's metabolite is 19-144, which may protect against amyloid and oxidative stress. Reportedly, the metabolite, 19-144, may offer a longer duration of action. A theory is that cholinomimetic-only compounds may not have as much benefit as the mixed mechanism - a mixed ligand such as AVXL 2-73. See the three articles below.
1. Multi-Target Directed Ligands (MTDLs) Binding the s1 Receptor as Promising Therapeutics: State of the Art and Perspectives
The sigma-1 (s1) receptor is a ‘pluripotent chaperone’ protein mainly expressed at the mitochondria–endoplasmic reticulum membrane interfaces where it interacts with several client proteins. This feature renders the s1 receptor an ideal target for the development of multifunctional ligands, whose benefits are now recognized because several pathologies are multifactorial. Indeed, the current therapeutic regimens are based on the administration of different classes of drugs in order to counteract the diverse unbalanced physiological pathways associated with the pathology. Thus, the multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions, may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. This review aims to point out the progress in the development of MTDLs directed toward s1 receptors for the treatment of central nervous system (CNS) and cancer diseases, with a focus on the perspectives that are proper for this strategy. The evidence that some drugs in clinical use unintentionally bind the s1 protein (as off-target) provides a proof of concept of the potential of this strategy, and it strongly supports the promise that the s1 receptor holds as a target to be hit in the context of MTDLs for the therapy of multifactorial pathologies.
...The most exploited paradigm in medicinal chemistry is the “one-target, one-disease”, according to which ligands are developed to act toward a single target in order to exert a beneficial effect. This kind of approach, even if largely applied, may lead to unsuccessful results. Indeed, pathologies are mostly based on tangled mechanisms that involve different kinds of targets. Thus, a single target approach could be inappropriate because of its impossibility to produce an effect on the different pathways associated with the pathology.
On the basis of this idea, a multi-target strategy has been proposed in order to hit at the same time the diverse targets involved and modulate the diverse mechanisms that underlie the pathology......
The first step of this multi-target strategy has been the co-administration of more drugs all together, with the aim of obtaining a synergic effect.....
MTDLs Acting at s1 Receptor and Cholinergic System
Drug metabolism leads to metabolites that can be more potent or less potent than the parent drug. In the former case, the drug can be considered a sort of prodrug. Thus, the simultaneous presence of the two chemical entities may produce a synergistic powerful effect....
...Many pharmacological and genetic data have proven that activation of muscarinic M1 receptors (mAChRs) attenuates symptoms of neurodegenerative pathologies [78,79], as in the case of MTDLs able to bind both M1 and s1 receptors. The most investigated compound representative of this class is ANAVEX 2-73 (also known as Blarcamesine) (Figure 2). This compound is in advanced clinical phases for several CNS diseases such as AD, Parkinson’s disease (PD), Rett, and Fragile X Syndromes (anavex.com/#!/pipeline, accessed Apr 3, 2021). In addition to binding M1 and s1 receptors, Blarcamesine also binds M2–M4 receptors (with micromolar affinity), Na+ channel site 2, and NMDA receptor (NMDAR) [80,81]. In this context, Fisher and co-workers, who previously developed orthosteric M1 receptors agonists (e.g., AF102B, AF267B, and AF292), extended their approach in order to target also s1 receptors. With this aim, compound AF710B (also known as ANAVEX 3-71, Figure 2) that can activate both M1 and s1 receptors with high potency and selectivity was identified [66]. AF710B is a positive allosteric modulator (PAM) of M1 receptor, as it improves the efficacy of carbachol, and this activity, together with a comparable agonism at the s1 receptor can preserve synaptic elements in vitro. In vivo studies performed on trihexyphenidyl-treated rats and 3xTg-AD mice showed that AF710B can restore cognitive deficits and attenuate signs of AD phenotypes by the reduction of ß-secretase 1 (BACE1) levels, GSK3ß and CDK5/p25 activity (which contribute to the hyperphosphorylation of tau protein), neuroinflammation, soluble and insoluble Aß40 and Aß42 plaques, and tau pathology [82]. In fact, AF710B reduces the expression of the putative BACE1, so that proteolytic fragments produced by ß-secretase were considerably lower in 3xTg-AD treated than in untreated mice. Moreover, tau kinases GSK3ß and CDK5 take part in the mechanism of hyperphosphorylation of tau protein. In particular, in AD patients, CDK5 activator p35 is cleaved to produce the protein p25, which binds with high affinity and activates GSK3ß [83]. The activation of M1 receptors produces a reduction of GSK3ß expression, while the activation of s1 prevents the formation of CDK5/p25. Therefore, the inhibition of GSK3ß and CDK/p25 by AF710B, upon interaction with both M1 and s1 receptors, results as a promising approach in the treatment of tauopathies [82]....
...The effect of s1 receptors in inflammation through microglia modulation has been reported [54,86,87], and AF710B was shown to reduce reactive astrocytes and activated microglia in the animals, as detected by the low levels of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1). Notably, astrocytes and microglia are increased in number and size in AD patients.
Another study performed using AF710B on McGill-R-Thyl-APP transgenic (tg) rats revealed that this MTDL can reduce amyloid pathology and markers of neuroinflammation while increasing amyloid cerebrospinal fluid clearance and synaptic marker. The most important achievement is represented by the prolonged duration of these effects, which are maintained five weeks after the treatment is interrupted [88].
In addition to AF710B and ANAVEX 2-73, Anavex Life Sciences Corp portfolio comprehends an isomer of ANAVEX 2-73, named ANAVEX 1-41 (Figure 2) that next to the activity toward s1 and M1 receptors, also displays activity for a1, 5-HT2, and D3 receptors [81], with an indication for the treatment of depression, stroke, and neurodegenerative diseases (anavex.com/#!/pipeline)....
Conclusions and Perspectives
This review aims to point out the state of the art of MTDLs interacting with the s1 receptor. As a result of its pluripotent chaperone activity, the s1 receptor has the potential to interact and modulate several targets involved in a number of diseases and syndromes. The evidence that several compounds already in clinical use (e.g., Donepezil, HP, etc.) unintentionally bind the s1 receptor has shed light on the already exploited interaction with this protein as a successful strategy in treating illnesses or associated symptoms through a MTDLs approach. Donepezil, whose interaction with s1 receptors in vivo has been ascertained by receptor occupancy studies in the human brain [94,158], is co-administered together with Memantine through prescription medicines (i.e., Namzaric). On this basis, the rational development of MTDLs with a s1 intentional targeting profile may lead to more important therapeutic actions. The amount of herein listed proteins, which are the object of the MTLDs development in association with the s1 receptor, is not intended to be exhaustive. Other proteins may be taken into consideration in the MTDLs development, considering the wide range of s1 receptor direct and indirect interactors. Cannabinoid type-2 (CB2) receptors are an example, with recent support from computational methods that point out a partial overlap of the s1 and CB2 receptors’ pharmacophores [159]. These data strongly suggest the adoption of a merging approach for the development of dual s1/CB2 receptors ligands for a synergistic exploitation of the pathways activated by the two targets in oncology and neurodegenerative diseases. A number of s ligands, besides interacting at the two subtypes (see Section 3.7), are able to modulate the efflux pump P-glycoprotein (P-gp) [150,160]. This double action is worthy of being more intentionally addressed, as it may serve as a strategy to face drug-resistant tumors: the compound overcomes P-gp, which is overexpressed in many resistant tumors and exerts its cytotoxic activity (as a s1 antagonist). Importantly, this same double action may also have a role in the treatment of CNS diseases through the bypass of the P-gp at the BBB. The waving interest in s receptors research increased during the COVD-19 pandemic, when the proteins were found as important key host dependency factors for coronavirus infections. However, while the exploitability of the s1 receptor as a druggable target against coronavirus still needs to be fully investigated and validated, it appears clear that this protein is involved in a plethora of pathways hampered in multifactorial CNS and cancer diseases, rendering the s1 receptor a full-fledged target for the development of multifunctional therapeutics.
https://www.mdpi.com/1422-0067/22/12/6359/htm
2. See also: Anavex Life Sciences Corp. Presents Data on Neuroprotective Evidence for ANAVEX 2-73, Lead Compound for Alzheimer's Disease
...ANAVEX 2-73 is not only active in and of itself, but is also a pro-drug. Its only metabolite, ANAVEX 19-144, is also active (in animal models)....
...ANAVEX 19-144, when administered prior to amyloid 25-35, protects against amyloid 25-35-induced amnesia in mice.
- ANAVEX 19-144 protects against amyloid 25-35-induced oxidative stress, measured by lipid peroxidation in hippocampal cells.
“It is hypothesized that cholinomimetic-only compounds would not have as much benefit as the mixed mechanism of the aminotetrahydrofurans, which may be potentiating. Interestingly, the pro drug and active drug effect of ANAVEX 2-73, which has ANAVEX 19-144 ‘embedded’ in it, may offer a longer duration of action,” said Dr. Tangui Maurice, PhD.....
https://www.biospace.com/article/releases/anavex-life-sciences-corp-presents-data-on-neuroprotective-evidence-for-anavex-2-73-lead-compound-for-alzheimer-s-disease-405521/
3. Blarcamesine
It is a mixed ligand for sigma1/muscarinic receptors.
https://www.alzforum.org/therapeutics/blarcamesine
Ditto - Welcome back.
Investor: You raise good points. Yes, if Anavex proves in its placebo controlled AD trial that AVXL 2-73 reduces amyloid plaque alone, Anavex has likely hit a home run as far as AD is concerned. It is, however, more significant if Anavex proves 2-73 also reduces tau. In addition, the current Anavex AD trial is a good chance for advancement or progress in gaining the FDA's acceptance of other biomarkers involved in Anavex’s clinical trials. Acceptance by the FDA of other biomarkers may then be utilized in future trials for other CNS indications.
If Anavex can show a link between changes in biomarkers and a beneficial change in a patient’s cognitive abilities, it appears that the FDA will likely approve AVXL 2-73. It seems that some years ago Anavex realized this to be the case. The Biogen Aduhelm FDA precedent strengthens Anavex's chances for an accelerated approval of Blarcamesine if Anavex's clinical trials demonstrate a surrogate biomarker that is reasonably likely to predict clinical benefit such as a reduction in the rate of clinical decline. Biogen gained approval of Aduhelm by showing reduction of amyloid beta plaques and a very slight rate of clinical decline. Moreover, the FDA has recently raised the possibility that the agency could now be more willing to fast-tract treatments for many neurodegenerative diseases where there is an unmet need. The FDA has indicated that the oncology accelerated model may be replicated with neurodegenerative diseases. Anavex surmised this as early as 2018 by "borrowing from the cancer playbook to find treatment for Alzheimer's disease" as referenced in number 4 below, and is following through with the cancer model that the FDA spokesman cited in number 3 below says may be replicated with neurodegenerative diseases. I include 5 references below that, together with what we know about the science behind AVXL 2-73, suggest that Anavex has a reasonable chance of gaining fast-track approval for Blarcamesine for multiple neurodegenerative diseases.
1. FDA’s Decision to Approve New Treatment for Alzheimer’s Disease
"We ultimately decided to use the Accelerated Approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit. In determining that the application met the requirements for Accelerated Approval, the Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy."
https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease
2. ''The accelerated approval of ADUHELM has been granted based on data from clinical trials showing the effect of ADUHELM on reducing amyloid beta plaques, a surrogate biomarker that is reasonably likely to predict clinical benefit, in this case a reduction in the rate of clinical decline.''
https://investors.biogen.com/news-releases/news-release-details/open-letter-alzheimers-disease-community-our-head-research-and
3. Controversial Alzheimer’s drug approval could affect other diseases
"The recent controversial approval of the Alzheimer’s drug aducanumab by the US Food and Drug Administration (FDA) has raised the possibility that the agency could now be more willing to fast-track treatments for a swathe of neurodegenerative diseases — illnesses that have so far thwarted drug developers. ....
...Asked by Nature to elaborate on the implications for Parkinson’s disease, Huntington’s disease and ALS, an FDA spokesperson replied that “the FDA stands ready to work with research communities and drug developers to study more therapies for Alzheimer’s disease and other neurodegenerative disorders”.
Patrizia Cavazzoni, a high-ranking FDA official, has given a nod to aducanumab’s broader impact. “The accelerated approval pathway has been an incredibly useful tool in oncology,” she said in a press meeting. “We believe it serves as a model that we hope can be replicated with neurodegenerative diseases.”.....
https://www.nature.com/articles/d41586-021-01763-9
4. Borrowing from the cancer playbook to find treatment for Alzheimer’s disease - 2018
...Dr. Harald Hampel, a professor at Sorbonne University in Paris, explained that the experimental drug, Anavex 2-73, a precision medicine candidate from specialty pharmaceutical company Anavex Life Sciences Corp., activates the Sigma-1 receptor.
A worthy target for precision medicine, the Sigma-1 receptor “is involved in several important pathways related to Alzheimer’s disease,” Hampel said. It reduces beta amyloid (the signature plaque deposits seen in the brains of deceased Alzheimer’s patients) and hyperphosphorylated tau (the signature protein tangles also seen in patients’ brains), he said. It also lessens oxidative stress and inflammation in the brain, both of which have been linked to aging and age-related diseases.
The advantage of targeting the Sigma-1 receptor is that it “activates the body’s own defense mechanism to restore cellular balance,” Hampel said.
In their study presented at the Alzheimer’s conference, Hampel and his colleagues researched the drug’s effect in 32 mild-to-moderate Alzheimer’s disease patients. The study showed that “patients improved both cognition and activities of daily living” after taking the drug for 57 weeks.
blitzer alzheimers drug champions_00041904.jpg
Is Alzheimer's disease preventable?
“Some also experienced positive effects on insomnia, a common problem among Alzheimer patients, and improved sleep,” Hampel said.
Beneficial effects, however, varied among patients based on their individual genetic profiles.
“We were able to identify certain genetic variations for certain patients that explain their improved response,” Hampel said. Specific genetic features, shared by about 80% of the study participants, correlated with a strong, “clinically meaningful” response to the medicine, he said.
” ‘Clinically meaningful’ means that the improvements are noticeable for the patient and the people around the patient,” Hampel said. Participants with the conducive genetic profile also showed improved scores on gold-standard tests of cognition and activities of daily living, the study presentation indicated.
Though only 32 Alzheimer’s patients participated in the study, Hampel feels confident of the results.
“Genetic patient data is more precise, and therefore not many patients are required. Examples are genetic studies in oncology, where even smaller studies are performed,” he said. The next step, which has already begun, is a larger safety study of the drug in 450 participants with Alzheimer’s.
Ultimately, Hampel said, he and his co-authors follow the concept of precision medicine, which means “to treat the right patient with the right drug at the right time.”
Clearing an FDA hurdle
Overall, he said, there is some good news yet also “a host” of challenges to develop effective and safe drugs for the treatment of Alzheimer’s disease.
Alzheimer's Disease Fast Facts
First among the difficulties is getting a drug across the blood-brain barrier, the membrane that surrounds the intellectual organ with the purpose of stopping that from happening, he said. Another challenge is monitoring what’s happening inside the brain.
“Increasingly, there are imaging technologies that allow you to look at deposited amyloid plaque and even deposited tau in the brain,” Williamson said. These deposits of amyloid plaque and tau tangles are considered “biomarkers” of Alzheimer’s disease.
A past study as well as the new results for an experimental drug jointly produced by Eisai Co. Ltd. and Biogen Inc. have shown that certain treatments can reduce the buildup of plaque in the brain. But what has not been demonstrated to the satisfaction of the US Food and Drug Administration is an association between a reduction in the plaque biomarker (as seen on a scan) and positive changes in the mental functioning of patients, Williamson said.
The good news is that once a link has been established between changes in biomarkers and a beneficial change in a patient’s cognitive abilities, the FDA has indicated it will no longer require drug developers to prove that each potential new drug can modify Alzheimer’s disease, Williamson said.
Once a firm connection is established, drug developers will need only to show their candidate drugs affect the biomarkers.
“An analogy to this would be cholesterol-lowering drugs and heart disease,” Williamson said. Once the link between lowering cholesterol and heart disease was established, scientists no longer needed to conduct thousands of patient studies to show that a drug reduced heart disease. “You just needed to show you could reduce cholesterol.”
https://www.cnn.com/2018/07/30/health/alzheimers-treatment-precision-medicine-immunotherapy/index.html
5. ANAVEX®2-73-AD-004 STUDY
Name of the study
ANAVEX2-73 for Treatment of Early Alzheimer's Disease
During the study, participants will have to undergo brain scan (MRI) and CSF examination (spinal tap) to see if they have amyloid pathology in their brain.
Who cannot participate in the study?
Exclusion criteria include:
Contraindication to PET imaging, MRI procedures and lumbar puncture
https://www.alzheimer-europe.org/Research/Clinical-Trials-Watch/Phase-III-trials/ANAVEX-R-2-73-AD-004
(Note: What is not known is what other surrogate biomarkers may be acceptable to the FDA besides amyloid plaque, but the FDA’s language cited above leads one to believe that the FDA may accept other biomarkers together with beneficial changes in cognitive abilities of clinical trial participants.)
Conducting an Alzheimer’s Prevention Trial.
Possibly biomarkers may be used to conduct such an AD prevention trial.
Oxidized DNA, RNA, protein and lipid products may be used as possible disease progression markers.
1. Oxidative toxicity in diabetes and Alzheimer’s disease: mechanisms behind ROS/ RNS generation
Reactive oxidative species (ROS) toxicity remains an undisputed cause and link between Alzheimer’s disease (AD) and Type-2 Diabetes Mellitus (T2DM). Patients with both AD and T2DM have damaged, oxidized DNA, RNA, protein and lipid products that can be used as possible disease progression markers. Although the oxidative stress has been anticipated as a main cause in promoting both AD and T2DM, multiple pathways could be involved in ROS production. The focus of this review is to summarize the mechanisms involved in ROS production and their possible association with AD and T2DM pathogenesis and progression. We have also highlighted the role of current treatments that can be linked with reduced oxidative stress and damage in AD and T2DM.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606025/
2. Oxidative stress and the amyloid beta peptide in Alzheimer's disease
Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly.
.....The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aß peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aß peptide and surrounding molecules in terms of oxidative damage......
https://pubmed.ncbi.nlm.nih.gov/29080524/
3. Oxidative Stress, Amyloid-ß Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer’s Disease
...Oxidative stress is implicated in the pathogenesis and progression of Alzheimer’s disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-ß peptide, Aß1-42 oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in Aß1-42, but not in Aß1-42-poor regions, and was among the first to demonstrate Aß peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways in which these proteins normally play a role. ...
https://content.iospress.com/articles/journal-of-alzheimers-disease/jad170543
4. Future Therapeutic Perspectives into the Alzheimer’s Disease Targeting the Oxidative Stress Hypothesis
Alzheimer’s disease (AD) is a neurodegenerative disease that is usually accompanied by aging, increasingly being the most common cause of dementia in the elderly. This disorder is characterized by the accumulation of beta amyloid plaques (Aß) resulting from impaired amyloid precursor protein (APP) metabolism, together with the formation of neurofibrillary tangles and tau protein hyperphosphorylation. The exacerbated production of reactive oxygen species (ROS) triggers the process called oxidative stress, which increases neuronal cell abnormalities, most often followed by apoptosis, leading to cognitive dysfunction and dementia. In this context, the development of new therapies for the AD treatment is necessary.
https://mdpi-res.com/d_attachment/molecules/molecules-24-04410/article_deploy/molecules-24-04410.pdf
5. Clinical Relevance of Biomarkers of Oxidative Stress
See p. 1161 (P. 18) - Ox-LDL, MDA and 8oxoGuo biomarkers are highest evidence levels for Alzheimer's
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657513/pdf/ars.2015.6317.pdf
6. Inflammatory markers in matched plasma and cerebrospinal fluid from patients with Alzheimer's disease
Ox-LDL Biomarker
Our data extend previous reports regarding the inflammatory markers in the plasma and CSF of patients with AD and provide good evidence that levels of ACT, IL-6, MCP-1 and oxLDL in plasma and CSF might be candidates as biomarkers for monitoring the inflammatory process in AD.
https://pubmed.ncbi.nlm.nih.gov/12826739/
7. Blood markers of oxidative stress in Alzheimer's disease
MDA Biomarker
MDA arises largely from the peroxidation of PUFA. It exists either in a free form or in bound to proteins. Free MDA in vivo is rapidly metabolized in tissues. A number of studies document elevated levels of MDA in AD and MCI in the plasma/serum [34–42]. Increased concentrations of thiobarbituric reactive substances in the serum [43] or erythrocytes [44, 45] of patients with AD were also documented. In contrast, there are studies that did not find differences in the concentration of MDA between AD patients and controls [46–51].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823422/
8. The Significance of 8-oxoGsn in Aging-Related Diseases
8-oxoGsn Biomarker
Aging is a common risk factor for the occurrence and development of many diseases, such as Parkinson’s disease, Alzheimer’s disease, diabetes, hypertension, atherosclerosis and coronary heart disease, and cancer, among others, and is a key problem threatening the health and life expectancy of the elderly. Oxidative damage is an important mechanism involved in aging. The latest discovery pertaining to oxidative damage is that 8-oxoGsn (8-oxo-7,8-dihydroguanosine), an oxidative damage product of RNA, can represent the level of oxidative stress. The significance of RNA oxidative damage to aging has not been fully explained, but the relationship between the accumulation of 8-oxoGsn, a marker of RNA oxidative damage, and the occurrence of diseases has been confirmed in many aging-related diseases. Studying the aging mechanism, monitoring the aging level of the body and exploring the corresponding countermeasures are of great significance for achieving healthy aging and promoting public health and social development. This article reviews the progress of research on 8-oxoGsn in aging-related diseases.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505272/
Anavex 2-73 Prevention of Onset of Alzheimer’s Disease
ROS may be an underlying cause of neurodegeneration. Anavex 2-73 blocks oxidative stress and may prevent the onset of Alzheimer's. There is a strong association between the detection of increased ROS production and the increased oxidative damage observed in CNS disorders such as Parkinson's disease, Alzheimer's disease and ALS. Oxidative stress can also impair mitochondrial function, leading to a depletion of ATP and decreased antioxidant capacity. One of the most accepted hypotheses for AD onset implicates that mitochondrial dysfunction and oxidative stress are one of the primary events in the insurgence of the pathology.
1. Oxidative and nitrosative stress
Oxygen (O2) is critical to meet the energetic demands of biological tissues through the production of ATP by oxidative phosphorylation. However, aberrant O2 reduction produces radical species that can cause extensive damage to cellular components, cells, and tissues. This phenomenon of “oxidative stress” is de?ned by a broad range of phenotypes, including the accumulation of oxidized molecules and the disruption of normal cellular processes and viability. Oxidative stress is typically considered to be the state inwhich these phenotypes are measurable at higher levels than in a “normal” state. Neurons may be particularly vulnerable to oxidative stress due to their terminally differentiated state, complex morphology, and dependence on surrounding glia for metabolic substrates and glutathione (12). Reactive oxygen species (ROS) are generated by multiple conditions and sources, including sustained neurotransmission (e.g., of glutamate, dopamine, or serotonin), mitochondrial dysfunction, and production by glial cells. Depending on the species and location of the ROS, oxidative damage can affect nucleic acids, proteins and lipids. The best evidence that ROS may be an underlying cause of neurodegeneration is the strong association between the detection of increased ROS production and the increased oxidative damage observed in CNS disorders such as Parkinson's disease, Alzheimer's disease and ALS (12,13). Oxidative stress can also impair mitochondrial function, leading to a depletion of ATP and decreased antioxidant capacity (13). Along with ROS, reactive nitrogen species (RNS) can also be generated under pathological conditions in the CNS.
https://www.researchgate.net/profile/Linda-Nguyen-8/publication/271530073_Role_of_sigma-1_receptors_in_neurodegenerative_diseases/links/54cbf4500cf29ca810f4858f/Role-of-sigma-1-receptors-in-neurodegenerative-diseases.pdf?origin=publication_detail
2. ANAVEX 2-73 shown to block oxidative stress, preventing onset of Alzheimer's disease
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Anavex Life Sciences Corp.
Oct 18, 2012, 09:00 ET
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Data presented at Neuroscience 2012
VANCOUVER, Oct. 18, 2012 /PRNewswire/ - Anavex Life Sciences Corp. ("Anavex") (OTCQB: AVXL) today unveiled more promising new data regarding ANAVEX 2-73, the company's drug candidate for the treatment and modification of Alzheimer's disease currently in human clinical trials. The confidential status of the new ANAVEX 2-73 data has been lifted now that a formal presentation has been made at Neuroscience 2012 in New Orleans.
ANAVEX 2-73 demonstrated its ability to restore mitochondrial functionality, and prevent oxidative stress and apoptosis (cell death) in a scientific study at the University of Montpellier and INSERM, in France. Mitochondrial dysfunction caused by amyloid peptide toxicity has been consistently reported as an early event in Alzheimer's physiopathology and a telltale sign of the disease, appearing before amyloid-beta plaque deposits and memory deficits in patients.
"This new study emphasizes the effective mitochondrial neuroprotection provided by ANAVEX 2-73," said Tangui Maurice, PhD, CNRS Research Director, Head of Team 2 'Endogenous Neuroprotection in Neurodegenerative Diseases', at the University of Montpellier and INSERM. "The Anavex compound effectively restored mitochondrial respiration and integrity. This restorative effect decreases oxidative stress and disrupts Alzheimer's disease well before plaques can start to accumulate and memory loss begins."
A selective sigma-1 agonist reference drug showed similar results in the study, confirming the sigma-1 chaperone protein activation by ANAVEX 2-73.
This new data was presented at Neuroscience 2012, the premier venue for neuroscientists from around the world to debut cutting-edge research on the brain and nervous system, held this week in New Orleans. The presentation is titled, "Mitochondrial protection is induced by the novel tetrahydrofuran derivative ANAVEX 2-73 after ICV injection of oligomeric Aß25-35 peptide in mice, a nontransgenic Alzheimer's disease model."
The study was jointly conducted by Valentine Lahmy, PharmD, Romain Long, PhD, Didier Morin, PhD, team leader at INSERM, Institut Henri Modor, Créteil, Vanessa Villard, PhD, CEO of Amylgen, Alexandre Vamvakides, PhD, Chief Scientific Officer and Scientific Founder of Anavex, and Tangui Maurice, PhD. Full details of the study are described on Anavex's website at http://www.anavex.com/files/2012-10-17_ANAVEX_2-73_poster_Neuroscience_2012.pdf.
https://www.prnewswire.com/news-releases/anavex-2-73-shown-to-block-oxidative-stress-preventing-onset-of-alzheimers-disease-174759041.html
3. Mitochondrial Dysfunction: Different Routes to Alzheimer’s Disease Therapy
https://downloads.hindawi.com/journals/omcl/2014/780179.pdf
You are correct. However, nothing should be left to chance. You want to immediately maximize sales of the drug. You need to convince distributors, like wholesalers, to pre-order, obtain insurance coverage, and inform as many doctors as possible about the drug. You might be surprised that many doctors are not aware of clinical trials. For example, Alzheimer’s has not effective treatment also, but there are many doctors out there that have never heard of Anavex, etc. Drugs that sell well from the very start sell well from there out. Drugs that do not sell well from the start do not sell well form there on out.
There is more to the process than you may think. Briefly, Anavex has to apply for approval for Rett, establish that the drug can be produced in commercial quantities in accordance with good manufacturing practices, go through the approval and labeling process, build a commercial marketing team to have in place pre-launch, advertise, promote, launch/distribute the drug. And just because a drug is approved and distributed does not mean that physicians will immediately begin writing prescriptions and that insurance companies will be jumping all over themselves to provide coverage. Here's just a couple of articles you may read that touch on the subject.
https://www.convergencepointmedia.com/launching-a-drug-on-all-cylinders-winning-with-digital/
https://www.fda.gov/drugs/coronavirus-covid-19-drugs/developing-and-manufacturing-drugs-including-biologics
I agree. June 30, 2021 cash was 157.50 million per latest 10Q. Looking at the last year, the company burnt through US$25m, but Anavex seems to be ratcheting up spending. Even if we assume Anavex increased spending from over 2 million per month to 2.5 million in the last three months, Anavex should have $150 million cash on hand before this next raise. If Anavex raises $150 million within a month, it may have something around $297 - $298 cash on hand. If spending doubled from last year (from $25 million to $50 million), Anavex would have cash to last almost 6 years. I don't see Anavex spending $50 million per year on clinical trials. It is most likely for a Rett launch.
Chart 1 of Today’s Presentation: I noticed that this chart indicates that among Alzheimer’s phase 2a patients administered AVXL 2-73, the direction of ADAS-Cog improvement accelerated slightly between 57 weeks and 70 weeks. Apparently, Anavex is following and including patients involved in extensions? See the chart that shows Anavex 272-002 commencing at 57 weeks and Anavex 272-003 (Extension) commencing at 70 weeks??
It may not be much of a catalyst, but regarding Monday:
Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex, will present at the H.C. Wainwright 23rd Annual Global Investment Conference being held from September 13-15, 2021.
A webcast of the on-demand presentation will be available beginning Monday, September 13, 2021, at https://journey.ct.events/view/48684630-6af2-4c12-a206-f94233cde440 or on the Company's website at www.anavex.com. The on-demand presentation will open on September 13 at 7:00 A.M. (ET). A webcast replay will be accessible for 30 days following the event.
A couple of important past developments to keep in mind as we wait, patiently and impatiently, for updates on Anavex's clinical trials.
Parkinson’s Disease-related Scores (June 28, 2021 announcement):
ANAVEX®2-73 high dose demonstrated statistically significant improvements compared to placebo (ITT population) for MDS-UPDRS Total score (p = 0.034). From baseline to end of trial at 14 weeks, MDS-UPDRS Total score improved by -10.98 points in the ANAVEX®2-73 high dose group and worsened by 3.53 points in the placebo group, an adjusted mean difference of -14.51 points (p = 0.034). This corresponds to a relative improvement of 18.9 % over 14 weeks.
This far exceeds an empirically established cutoff score of -7.1 for detecting meaningful clinical change.[5] For reference, the observed worsening of MDS-UPDRS Total score in patients with Parkinson’s disease in the literature is estimated in the range of 3.99 to 7.45 points per year.[6]
Treatment with ANAVEX®2-73 not only slows the progression of motor and non-motor symptoms in moderately advanced patients with Parkinson’s. ANAVEX®2-73 also resulted in clinically meaningful improvements as measured by the global composite score of Parkinson’s disease symptom severity, MDS-UPDRS Total score on top of standard of care including dopaminergic therapy, levodopa and other anti-PD medications after 14 weeks of treatment, suggesting ANAVEX®2-73’s global capability of slowing and reversing symptoms that progress in Parkinson’s disease, an urgent unmet medical need.
Sleep was a tracked variable both subjectively and objectively including sleep continuity or incidence of sleep disorders symptoms. ANAVEX®2-73 does not impair sleep and has a positive effect on REM sleep behavior disorder.
.....
This is now the second independent placebo-controlled clinical ANAVEX®2-73 Phase 2 study to confirm the predictive biomarker of response established with SIGMAR1 mRNA expression. Both ANAVEX®2-73-PDD-001 Parkinson’s disease dementia study and the recently reported ANAVEX®2-73-RS-001 U.S. Rett syndrome study are persuasively consistent with the proposed mechanism for ANAVEX®2-73,” said Christopher U. Missling, PhD, President & Chief Executive Officer of Anavex. “We believe that the easily accessible predictive biomarker combined with the observed efficacy is a consistent explanation of the efficacy in this second largest CNS indication with unmet medical need. This data further strengthens the foundation of ANAVEX®2-73 as a cross-platform CNS drug.”
https://www.anavex.com/anavex-life-sciences-announces-anavex2-73-blarcamesine-improved-both-primary-cognitive-and-secondary-mds-updrs-efficacy-endpoints-with-significant-biomarker-correlation-in-placebo-controlled-p/
So, we have had two independent placebo-controlled clinical trials that confirm predictive biomarker response and show improvement in cognitive scores versus declines in cognitive scores in patients.
Plus, the Alzheimer's clinical trials that have been completed so far have indicated improvement in cognitive scores although these trials were small and not placebo-controlled. Some patients in these early trials responded better than others. As a result, we hired Ariana and we discovered that the majority (80%) of patients is expected to benefit from Anavex. See this.
• Patients with a wild-type SIGMAR1 gene were found to have an improved benefit from ANAVEX®2-73. Patients with a variant of the SIGMAR1 gene (rs1800866) were found to have a limited benefit from ANAVEX®2-73. Same for COMT variant (rs113895332/rs61143203)
• Including patients with milder disease stage (baseline MMSE ≥20) and the exclusion of AD patients carrying SIGMAR1 variants results in a score improvement of +1.7 MMSE and +3.9 ADCS-ADL, respectively at week 57. The additional exclusion of the COMT variant results in a score improvement of +2 MMSE and +4.9 ADCS-ADL, respectively for the same period. Both effects would be clinically meaningful
• The minority of the population (about 20%) has the variant SIGMAR1 gene, hence the majority of patients (about 80%) is expected to benefit from ANAVEX®2-73
https://www.anavex.com/wp-content/uploads/2019/03/AAIC_Anavex_Gene_poster_2018_Final.pdf
And, keep in mind authophagy and homeostasis:
See the book "Ageless'' by Andrew Steele
“The logical endpoint of the process will be to gradually retire the idea of treating “aging” and begin to see all human dysfunction and disease as a “loss of homeostasis.” Homeostasis is the collective term for the myriad processes which keep aspects of our physiology, from temperature and blood sugar to levels of proteins and numbers of a particular kind of cell, within the astonishingly narrow parameters needed to keep us alive. A 20- or 30-something human is in a state of very nearly perfect homeostasis, with odds of their system falling so far out of balance that they die less than one in 1,000 annually. If we could just return our physiological parameters to where they are in young adulthood, we’d be able to rely on our bodies’ existing homeostatic systems to keep us alive.
The processes we currently label aging are a very gradual loss of homeostasis ..... The best treatments for aging would gently nudge the network of processes causing us to gradually lose homeostasis back toward a stable state, keeping us safe and healthy for decades longer than we enjoy today. Intervening in clever ways to restore order to the whole system is surely the eventual future of medicine.” Excerpt From Ageless by Andrew Steele.
"Ageless" does not mention Anavex, but we know that Anavex is pursuing treatments to nudge the body back to a stable state of homeostasis. By way of only one of many announcements about this:
"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." Reference: Advances in Experimental Medicine and Biology Volume 964 (2017) Sigma Receptors: Their Role in Disease and as Therapeutic Targets. https://www.anavex.com/anavex-life-sciences-reports-new-publication-in-medical-journal-elucidating-the-mechanism-of-anavex2-73-blarcamesine-and-anavex3-71-af710b-related-to-the-treatment-of-alzheimers-dise/#_ftn17
The filer that filed the Citizen Petition to pause SAVA’s clinical trials is a N.Y. law firm.
https://www.labaton.com/ourpeople-attorneys
Download and take a look at these two documents filed with the FDA:
https://downloads.regulations.gov/FDA-2021-P-0930-0003/content.pdf
https://downloads.regulations.gov/FDA-2021-P-0930-0004/content.pdf
It’s a definite problem for SAVA. It will take quite some time to know the out come. No matter how one may try to sugar coat it, it is not good news.
Shareholders have had high hopes for simufilam’s quick development and approval. This Citizen Petition has cast a cloud over SAVA and how it has gone about developing and promoting simufilam.
SAVA’s negative news is affecting other biotechs that are in competition with SAVA, but the claims/allegations in this Petition have nothing to do with other biotechs that are developing Alzheimer’s drugs.
Yes, weigh the cost of dilution in comparison to what may be gained if approval is ultimately obtained for any of various CNS indications as well as any other indications for pain, cancer, disease prevention, anti-aging, or whatever. It’s not easy to do, weighing the various benefits, but I have learned that there is no easy route that is likely to pay large rewards. Bottom line, I am simply interested in focusing on what’s difficult - not easy. Easy is boring to me, and I have learned in life that nothing worthwhile has been easy for me as I approach my 80th year in a few months. I may fail to some extent, but I do not bet more than I can afford to lose although I made a large bet on Anavex, and it has already paid off.
I find satisfaction in constant research and due diligence that I hope guides me to what I should do without becoming overly infatuated with anything in particular. However, I am presently inclined to believe that Anavex has much more to gain given time. The company is certainly taking a very disciplined approach to every thing it is doing, including raising sufficient cash to fund its various endeavors. So, anyone criticize me or Anavex if you desire. I do not care. I keep moving forward, which is the only way I know to move. I continue to move forward with anything I do. I do not worry about dying tomorrow because I am too busy living today. I maintain a significant position in Anavex because I see no reason to do otherwise for the time being although I could change my mind in the future.
George Perry, PhD, Dean and Professor at the University of Texas at San Antonio and Editor-in Chief of the Journal of Alzheimer’s Disease, commented, “Although this is an open label study with 32 patients, I have never seen mild-to-moderate Alzheimer’s patients maintain near baseline cognitive and activities of daily living function and positive correlation with all other measures over a 41-week trial period in any prior study with an approved or experimental drug. It is quite plausible that complex CNS diseases like Alzheimer’s may require a comprehensive approach, including restoration of cellular homeostasis.”
https://www.globenewswire.com/fr/news-release/2016/11/22/891996/0/en/Anavex-Life-Sciences-Announces-Data-on-41-Week-Treatment-of-ANAVEX-2-73-for-Patients-with-Alzheimer-s-Disease-Investigational-Treatment-suggests-to-curb-Cognitive-and-Functional-De.html
Blarcamesine Slows Progression of Motor and Nonmotor Symptoms of Parkinson Disease Dementia
https://practicalneurology.com/news/blarcamesine-slows-progression-of-motor-and-nonmotor-symptoms-of-parkinson-disease-dementia?c4src=news-landing:feed
Yes, I agree. This is definitely something that may be cured. Receiving a CRL from the FDA is not good news, but the impact varies. In this case, the company may in the next few months produce the additional data from a study with multiple doses (as opposed to the single dose cited here) and a higher dose (as opposed to the lower dose also cited here). Lastly, the FDA in the … “CRL did not cite any clinical deficiencies related to the efficacy and safety data packages submitted to the BLA and confirmed the acceptability of the proposed proprietary name for teplizumab.”
“…. the FDA stated that a single, low-dose …. failed to show PK comparability.” What will multiple and/or higher doses show? “ The Company expects relevant additional PK/PD data being, or to be, collected from a substudy in patients receiving 12-days of therapy in the ongoing Phase 3 PROTECT trial in newly diagnosed T1D patients…”. The Seeking Alpha article indicated the company believes product quality has been addressed. Product quality should be easy to remedy. The only thing I am concerned about is what will the additional PK/PD data show? I will continue to hold for now. Biotech is volatile, and this is another example - look for anything that indicates that additional or higher doses may work?
It is often said that it is all about dosing. Designing the correct dosage regimen is important for achieving the desired therapeutic efficacy and avoiding undesired effects. Additionally, this is a biologic. Possibly the drug may work differently for different patients. The amount of dosing, dosing frequency, number of injections, and time to onset of effect, etc., are but a few factors involved in the administration of this biologic. Biologics, like many things, I think are complicated.
Don’t worry. Congress is very capable of dragging things out.
Bio - Great thinking. Anavex makes that suggested announcement at the perfect moment, and it slays the dragon! Thank you. Sokol
Possibly Biogen will be more desperate now with the LLY competition? So, what moves may Biogen make? My understanding is that LLY’s drug is safer. LLY’s drug is not surrounded by the controversy that Biogen faces. Biogen may be forced to go the acquisition route?
Biogen has big competition.
Eli Lilly (LLY) – The drugmaker’s shares surged 8.7% in the premarket after Lilly’s Alzheimer’s treatment received “breakthrough therapy” designation from the Food and Drug Administration. The designation means the treatment may show substantial improvement over existing therapies and qualifying it for expedited development and approval.
Thank you for the excellent post. As a long-term Anavex shareholder, I witnessed the short attacks to which you refer. I also remember reading your Seeking Alpha Article that you site at the end of the above post. Anavex endured brutal attacks every time it reported positive news from clinical trials. Additionally, several law firms filed securities class action lawsuits against Anavex wherein quotes from the false articles about Anavex were quoted supporting the litigation. Anavex was set back in conducting its clinical trials because it could not raise the money it needed due to its low share price. We are in a better position now. Clinical trials are well advanced, Anavex has raised capital and is in a place to raise more, articles about Anavex are positive, and shorts are subject to being burned again, as you point out. If and when we get good news from clinical trials, the share price should react differently and not get knocked down as in the past. Of course, we all know what happens if clinical trial results are not up to investor expectations, but that is legitimate - the short attacks of the past were not.
That is key!
Thank you for the sensational post, Bio. I have been on the sidelines, but I recall your many valuable contributions to this board over the years. You are correct—another way of looking at this Biogen approval is that most generally, whether they be investors, doctors, patients, caregivers, families of patients, or whoever tends to believe in big pharma. Everyone, including the media that caters to the public, likely ignore young biotechs. The belief is that bigger is better. It's another version of the Too Big to Fail Theory, although big pharma has done nothing but fail when it comes to developing a meaningful Alzheimer's drug. However, the FDA now, intentionally or not, set up this plaque mania hypothesis to die once and for all. The media is shifting its attention to the controversy surrounding the approval of this drug. Once that process begins, it tends to feed on itself. Biogen is rapidly getting bad press. Anavex and other biotech startups, on the other hand, are making headway on getting attention.
Before closing, I think that the FDA's decision to approve Adu will make it easier for Anavex to gain approval. The FDA based its Biogen decision solely on a biomarker, plaque, in concluding that this biomarker is "reasonably likely to predict a clinical benefit to patients." Anavex may demonstrate multiple biomarkers and produce additional evidence of AVXL 2-73's clinical benefit to patients.
Quite a few hoops to jump through to take this Biogen infusion drug with, in my opinion, no benefit. Infusions require the patient to go to a clinic to administer. AVXL 2-73 is a pill, capsule or liquid that you take at home - no visits for infusions -no expensive scans, etc. Scans are required with Biogen’s drug to find plaque in the first place and to check for brain swelling next. And too your head and brain does not swell with AVXL 2-73. Ouch! What a treatment. $56,000 per year just for the drug- how many visits for expensive and time consuming infusions- how many expensive brain scans - how much to treat a swollen brain - how much pain and suffering for a drug that does not treat the disease (only treats a symptom of the disease and that symptom may be a response to protect the brain but these jerks collect billions to remove what may be protective). No matter what, it does not effectively treat the disease- only a symptom of the disease. I feel sorry for the patients. However, if this dog can gain approval, drugs that have any benefit and are much safer should more easily gain approval.
Gbola Amusa, MD, CFA Partner, Head of Healthcare Research at Chardan Capital Markets said Friday that there are too many uncertainties for the FDA to approve Teplizumab on July 2, and the FDA will want to see more results from the ongoing phase 111 study into 2022; However, he maintained a buy rating on the stock. I believe the share price of Provention will be volatile going forward.
It is small biotech, and all biotechs are complicated. Moreover, all are risky - whether long or short. What's more, likely to be highly volatile, which can be very good or bad for long or short options depending.
FDA Advisory Committee Votes in Favor of the Benefits of Teplizumab Outweighing the Risks in Support of Approval to Delay Clinical Type 1 Diabetes (T1D)
So, what about this presentation this morning:
Galectin Therapeutics Inc. (NASDAQ:GALT), the leading developer of therapeutics that target galectin proteins, today announced that Pol F. Boudes, M.D., Chief Medical Officer, will present the belapectin program at the 4th Global NASH Congress taking place virtually on April 28 and 29, 2021.
On Thursday, April 29th, Dr. Boudes will review Galectin Therapeutics’ scientific and clinical activities in NASH cirrhosis, followed by a Q&A session. Only registered attendees are able to view the presentation. Additional details can be found below:
Title: An innovative clinical development program: belapectin for NASH cirrhosis
Date: Thursday, April 29, 2021
Time: 11:45 am, British Summer Time, 6:45 am Eastern
It may be worth going long near the end of the week or first of next week. Maybe buying some between 8.79 and 8.50?
Yes, I made a small profit off of a few shares. So, over all I have made some decent money the last few months. I have been distracted the last few days, and I have not had the time, but I will give it some study.
Digital health makes perfect sense for precision medicine, access that directs patients to practitioners that are familiar with the drug (whether a pill or biological), monitoring the patient while on the drug (especially important to track activity, movement, etc. for CNS diseases), etc. Digital medicine is disruptive. It may make it possible for a drug company to go it alone in launching a drug. Sales representatives, for example, are not necessary. It is economical, efficient, and potentially more effective. It is available 7/24 worldwide.
What is Digital Health?
https://www.fda.gov/medical-devices/digital-health-center-excellence/what-digital-health
May be a time to buy UNG again this morning.