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Here's an interesting post on clearance of waste from the brain. While they don't mention Anavex, it appears to be shifting the discussion to mechanisms which are right in Anavex's wheelhouse. I'd love for Anavex's AD paper to come out in Nature. ToeMind
"About 170 billion cells are in the brain, and as they go about their regular tasks, they produce waste — a lot of it. To stay healthy, the brain needs to wash away all that debris. But how exactly it does this has remained a mystery.
Now, two teams of scientists have published three papers that offer a detailed description of the brain's waste-removal system. Their insights could help researchers better understand, treat and perhaps prevent a broad range of brain disorders.
The papers, all published in the journal Nature, suggest that during sleep, slow electrical waves push the fluid around cells from deep in the brain to its surface. There, a sophisticated interface allows the waste products in that fluid to be absorbed into the bloodstream, which takes them to the liver and kidneys to be removed from the body."
"There's growing evidence that in Alzheimer's disease, the brain's waste-removal system is impaired, says Jeffrey Iliff, who studies neurodegenerative diseases at the University of Washington but was not a part of the new studies.
The new findings should help researchers understand precisely where the problem is and perhaps fix it, Iliff says."
Those of us long AVXL watch closely for any details regarding sigma-1 cellular mechanisms, including on mitochondria functions.
In light of that, I found this wonderful podcast, done by the BBC, on the mitochondria, including some discussions of disease processes (about half-way through the episode). Perhaps other's here will find it interesting. https://www.bbc.co.uk/programmes/m001md34 ToeMind
Regarding the schizophrenia trial from clinicaltrials.gov: Looks like the formal end of study is May 15th, 2025. Who knows what the specifics will be within that time frame. ToeMind
"Detailed Description: ANAVEX3-71-SZ-001 is a two-part study. The first part is Part A: Multiple Ascending Dose, PK, safety, and dose selection. The second part is Part B: Double Blind, Placebo Controlled for exploratory efficacy and continued repeat-dose safety. This study will investigate the effects of ANAVEX3-71 in patients with Schizophrenia for the first time. This is an in-patient study. In both parts, participants will undergo either 10 or 28 days of dosing (Part A and Part B, respectively). Standard clinical outcome measures used in the clinic and novel fluid and electrophysiological biomarkers will also be assessed. Study Design Go to
Study Type : Interventional (Clinical Trial) Estimated Enrollment : 40 participants Allocation: Randomized Intervention Model: Parallel Assignment Intervention Model Description: Parallel Assignment in Part A and Part B. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) Primary Purpose: Treatment Official Title: A Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics, and Electrophysiology of ANAVEX3-71 in Adult Patients With Schizophrenia in a Multiple Ascending Dose Study (Part A), Followed by a Double-Blind, Randomized, Placebo-Controlled Study (Part B) Actual Study Start Date : March 15, 2024 Estimated Primary Completion Date : May 15, 2025 Estimated Study Completion Date : May 15, 2025"
F.D.A. Delays Action on Closely Watched Alzheimer’s Drug Eli Lilly’s donanemab was expected to be approved this month, but the agency has decided to convene a panel of independent experts to evaluate the drug’s safety and efficacy.
I have a general question about these patents that I realize I am not clear on. Towards the end of the patent application, there is usually a list of examples briefly describing human administrations. This may seem like a silly question, but are these actual patients who have been dosed with the A2-73, or hypothetical cases? they seem like actual cases, but wanted to confirm that nature of these entries on the patent application. Thanks, ToeMind
Copied from the patent application: "Example 1 Breathing Variability Reduction [00561 A 6 vear old female presenting with Rett syndrome si administered oral doses of A2-73 at 4 mg daily for 10 davs. On presentation. her breathing is abnormal. Her mean breaths per minute i scalculated to assess breathing variabil- ity. After 10 days of A2-73, administration the 0 (breaths/ minute) was significantlv reduced ( i m p l i n g less variability).
Example 2 Cardiac Pulse Rate [0057] A10 year old female presents with Rett syndrome. Her real time cardiac pulse rate is monitored. Prior to commencing therapy, her heart rate is 49 beats per minute with substantial variability. Following treatment with oral doses of A2-73 at 20 mg daily for 5 days, the variability is reduced while the average rate is increased to 75 beats per minutes.
Example 3 Seizure Reduction [00581 An 18 month old female presents with Rett syn- drome. She experiences 6 to 10 seizures per day prior to commencing therapy. She begins treatment with oral doses ofA2-73 at 2mg daily. After 5 days of treatment, the number of daily seizures is reduced to 3 or fewer.
Example 4 Eatingand Choking [0059] A 20 year-old f e m a l epresents with Rett syndrome. She experiences feeding difliculties exhibiting as choking and poor food intake prior to commencing therapy. She begins treatment with oral doses of A2-73 at 40 mg every other day. After 60 days of treatment. the instances of choking are reduced and she exhibits a 10% weight gain
Example 5 Angelman Sleep and Seizures [0060] A 25 year-old male presents with Angelman syn- drome. He experiences disturbed sleep and frequent seizures prior to commencing therapy. He begins treatment with oral doses of A2-73 at 30 mg/day. After 15 days of treatment, his sleep is markedly less disturbed and his instances of seizure are reduced by 50%.
Example 6 Williams Syndrome Weight Gain [0061] A 2 year-old male presents with Williams syn- drome. He exhibits a failure to thrive with low weight gain. He begins treatment with i.v. doses of A2-73 at 5 mg every other day. After 60 days of treatment. he exhibits a 10% weight gain.
Example 7 Smith-Magenis Syndrome Sleep [0062] A 5 year-old male presents with Smith Magenis syndrome. He experiences disturbed sleep. He begins treat- ment with oral doses of A2-73 at 10 mg/day. After 15 days of treatment, his sleep is markedly less disturbed.
Example 8 Multiple Sclerosis [0063] A 17 year-old male presents with multiple sclero- sis. He begins treatment with oral doses of A2-73 at 40 mg every fifth day. The total number of gadolinium-enhanced lesions on MRI at weeks 12, 16, 20 and 24 is substantially reduced as compared to his 12 week pretreatment MRI."
Given Dr. Grimmer is presenting on March 9th in Europe and Dr. Missling is presenting on March 4th in Boston, does that suggest in any way that the peer-reviewed paper will be released soon (I.e., prior to the talks)?
Anavex Initiates Regulatory Submission of Oral Blarcamesine for Alzheimer’s Disease to the European Medicines Agency (EMC)
NEW YORK – November 20, 2023
Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders announced today that representatives of Anavex met with team members of the European Medicines Agency (EMA).
These meetings discussed the debilitating pathology of Alzheimer’s disease and Anavex’s blarcamesine (ANAVEX®2-73) Alzheimer’s disease clinical program results, including data obtained in the ANAVEX®2-73-AD-004 study.
Pursuant to the discussion at the meetings, Anavex initiated the process for submitting a Marketing Authorisation application to the EMA with the submission of the Centralised Procedure request with the goal of the Authorisation allowing direct access to the market of the European Union for oral blarcamesine for the treatment of Alzheimer’s disease.
Anavex’s goal is to take care of patients in a patient-centric way with the preference for convenient oral treatment options for Alzheimer’s disease not requiring complex logistics resources and added personnel for drug administration and monitoring for brain edema and brain bleeds.
Severe symptoms in relation to Amyloid-Related Imaging Abnormalities (ARIA) is a known risk factor for Alzheimer’s patients taking the class of drugs called monoclonal antibodies, and requires constant and repeated MRI examination, for which not all regions in Europe are currently sufficiently prepared and equipped for in addition to the requirement to address affordability and inequalities in patient access within European Union countries. [1],[2]
“We look forward to working together with the team from EMA,” said David Goldberger, RPh, MLS, Senior Vice President of Regulatory Affairs at Anavex. “We continue to work towards fulfilling our purpose of improving patients' lives with oral blarcamesine not requiring any complex additional procedures for the treatment of people with Alzheimer’s disease.”
There are an estimated 7 million people in Europe with Alzheimer’s disease, a number expected to double by 2030, according to the European Brain Council. [3]
The World Health Organization (WHO) estimated the cost in Europe of caring for people with dementia, including Alzheimer's disease, at $439 billion, or $31,144 per person in 2019. That includes hospital care, medicines, diagnostics, informal caregiver time, community services, and long-term care facility costs. [4],[5]
“There remains an urgent need for convenient once-daily oral treatment options for Alzheimer’s disease, and Anavex is moving forward to potentially addressing the preference for simple patient-centered administrations and shared decision-making,” said Christopher U Missling, PhD, President and Chief Executive Officer at Anavex.
In addition to significant improvement in dementia symptoms, blarcamesine demonstrated a reduction of pathological aggregation of amyloid in early Alzheimer’s disease as well as a reduction of brain volume loss, a well-known marker of neurodegeneration.
Data from the blarcamesine in Alzheimer’s disease Phase 2b/3 randomized clinical trial will be published in an upcoming peer-reviewed journal.
) just published an article in JAMA focusing on "establish a systematic neurodegenerative disease framework for information collection and communication to standardize language usage for research, clinical, and public health purposes".
Progress in the field is moving forward on many fronts. ToeMind
"Abstract: Importance Nomenclature in the field of neurodegenerative diseases presents a challenging problem. Inconsistent use of terms such as Alzheimer disease and dementia has compromised progress in clinical care, research, and development of therapeutics. Dementia-associated stigma further contributes to inconsistent and imprecise language. The result is a lack of clarity that produces confusion with patients and the general public and presents communication challenges among researchers. Therefore, the Advisory Council on Research, Care, and Services of the National Plan to Address Alzheimer’s Disease authorized a committee to make recommendations for improvement.
Objective: To establish a systematic neurodegenerative disease framework for information collection and communication to standardize language usage for research, clinical, and public health purposes.
Evidence Review: The Dementia Nomenclature Initiative organized into 3 major stakeholder working groups: clinicians, researchers, and the public (including individuals living with dementia and family caregivers). To inform the work, the initiative completed a narrative literature review of dementia nomenclature evolution over the last century across the PubMed, CINAHL, PsycInfo, and Scopus databases (January 1, 2000, through July 31, 2020). Initiative working groups used the results as a foundation for understanding current challenges with dementia nomenclature and implications for research, clinical practice, and public understanding. The initiative obtained additional input via focus groups with individuals living with dementia and caregivers, with separate groups for race and ethnicity (American Indian or Alaska Native, Asian or Pacific Islander, Black or African American, Hispanic or Latino, and White) as an initial assessment of the meaning of dementia-related terms to these groups.
Findings: From working group deliberations, the literature review, and focus group input, the initiative developed a framework clearly separating the clinical syndromic presentation experienced by affected individuals from possible underlying pathophysiologies. In the framework, domains of clinical impairment, such as cognitive, behavioral, motor, and other neurologic features, are graded by level of impairment between none and severe. Next, biomarker information describes underlying disease processes, explains the syndrome, and identifies possible disease labels: Alzheimer disease, frontotemporal degeneration, dementia with Lewy bodies, or vascular cognitive impairment dementia.
Conclusions and Relevance: The Dementia Nomenclature Initiative established a framework to guide communication about cognitive impairment among older adults. Wider testing and refinement of the framework will subsequently improve the information used in communicating about cognitive impairment and the way in which the information is used in clinical, research, and public settings."
Hoskuld, I like your list. Might you add onto that list a full peer reviewed article in JAMA, NEJM, Nature or other top sited journal, laying out the S1 platform program along with specific data from several indications (Rett, AD, Parkinsons,....). Thanks, ToeMind
Thanks Baltimorebullet for the fascinating article on another role of the mitochondria. Might Blarcamesine positively influence these process of the mitochondria also? Developmental growth & aging? The S1 programmatic platform Anavex is developing continues to look to have far-reaching potential. ToeMind
Quote: " “Pretty much everything we looked at so far is scaling,” Pourquié said, “which means that there is a global command for all these processes.” The Tick-Tock of Metabolism
What could this upstream control system be? Pourquié and Diaz Cuadros pondered which system could potentially affect a variety of cellular processes — and they landed on metabolism, driven by mitochondria. Mitochondria produce ATP, the energy currency of the cell, as well as a host of metabolites essential for building proteins and DNA, regulating the genome, and performing other critical processes.
Somewhere in their genome, there has to be a sequence difference between mouse and human that is encoding that difference in developmental rate.
Margarete Diaz Cuadros, Massachusetts General Hospital To test that idea, they devised genetic and pharmacological methods to speed up and then slow down the metabolic rates of their stem cells. If mitochondria were indeed setting the cellular tempo, they expected to see their experiments alter the rhythm of the segmentation clock.
When they slowed metabolism in human cells, the segmentation clock slowed too: Its period stretched from five to seven hours, and the rate of protein synthesis slowed as well. And when they sped metabolism up, the clock’s oscillations accelerated, too.
It was as if they had discovered the tuning knob of the cell’s internal metronome, which let them accelerate or decelerate the tempo of embryonic development. “It’s not differences in the gene regulatory architecture that explains these differences in timing,” Pourquié said. The findings were published in Nature earlier this year.
This metabolic tuning knob wasn’t limited to the developing embryo. Iwata and Vanderhaeghen, meanwhile, figured out how to use drugs and genetics to toy with the metabolic tempo of maturing neurons — a process that, unlike that of the segmentation clock, which runs for only a couple of days, takes many weeks or months. When mouse neurons were compelled to generate energy more slowly, the neurons matured more slowly, too. Conversely, by pharmacologically shifting human neurons toward a faster pathway, the researchers could accelerate their maturation. The findings were published in Science in January.
To Vanderhaeghen, the conclusion of their experiments is clear: “Metabolic rate is driving developmental timing.”
Looking for a reference: Does anyone have good references (or discussions) for the percent of AD patients who have elevated Tau or Amyloid versus those without such elevations: and, the percentage of individuals with elevated Tau or Amyloid who do not show any cognitive decline or other AD symptoms? Thanks in advance, ToeMind
This article on the mechanism of S1R modulation via two monomers is way beyond my biologic pay grade, but strikes me as excellent information for further explaining the underlying putative utility of Blarcasamine.
"In conclusion, we propose that transitions between the DM spectrum of conformations and the AM conformation of S1R forms the basis for its biological function in cells. While in AM form, S1R is able to form large-scale oligomers via H1-H1 and BIND-BIND intramolecular interactions (Figure 6A). Conditions that stabilize AM conformation, such as a high local concentration of cholesterol or the presence of S1R antagonists, are expected to facilitate the formation of large-scale oligomers of S1R. In contrast, conditions that destabilize AM conformation and shift the equilibrium towards the DM spectrum of conformations, such as E102Q pathogenic mutation or the presence of S1R agonists, are expected to prevent the formation or lead to the disassembly of large-scale oligomers of S1R. S1R is a therapeutic target for treatment for a variety of neurodegenerative disorders, and the proposed model (Figure 5 and Figure 6) may help to explain the neuroprotective effects of a variety of S1R ligands and modulators which appear to be directly linked to their ability to modulate S1R and cholesterol clustering in the ER membrane [16]." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10455549/
Potentially new method of identifying Parkinson's Disease (PD) early. I wonder whether this may be useful when Blarcamesine is further tested and/or hopefully approved for use in PD?
Parkinson’s disease is a progressive neurodegenerative movement disorder with a long latent phase and currently no disease-modifying treatments. Reliable predictive biomarkers that could transform efforts to develop neuroprotective treatments remain to be identified. Using UK Biobank, we investigated the predictive value of accelerometry in identifying prodromal Parkinson’s disease in the general population and compared this digital biomarker with models based on genetics, lifestyle, blood biochemistry or prodromal symptoms data. Machine learning models trained using accelerometry data achieved better test performance in distinguishing both clinically diagnosed Parkinson’s disease (n?=?153) (area under precision recall curve (AUPRC) 0.14?±?0.04) and prodromal Parkinson’s disease (n?=?113) up to 7?years pre-diagnosis (AUPRC 0.07?±?0.03) from the general population (n?=?33,009) compared with all other modalities tested (genetics: AUPRC?=?0.01?±?0.00, P?=?2.2?×?10-3; lifestyle: AUPRC?=?0.03?±?0.04, P?=?2.5?×?10-3; blood biochemistry: AUPRC?=?0.01?±?0.00, P?=?4.1?×?10-3; prodromal signs: AUPRC?=?0.01?±?0.00, P?=?3.6?×?10-3). Accelerometry is a potentially important, low-cost screening tool for determining people at risk of developing Parkinson’s disease and identifying participants for clinical trials of neuroprotective treatments.
Very interesting and extremely encouraging blog by Piotr. This is nicely summarized in his last paragraph. Toemind
"Did Blarcamesine Failed? Of course not, it hit the limit of cognitive improvement but avoided the Donepezil Trap. The other thing is that the various measures of cognition are not comparable to each other, each is in its own domain. That is why Dr. Missling works hard behind the scenes to approve the drug before he has to release the data which would scare the retail investors into selling. Dr. Grimmer expressed optimism for Blarcamesine best when he said that he is very excited by the fact that Blarcamesine showed efficacy in the three CNS conditions currently tested. Indeed, Blarcamesine has avoided the Donepezil Trap, and rest assured it is the winner. "
"Patients assigned first to ANAVEX®2-73 (blarcamesine) in the double-blind part of the study and who continued on ANAVEX®2-73 (blarcamesine) during the open-label extension (OLE) study had a statistically significant (p = 0.01147) reduction in disease severity when compared with patients assigned first to placebo in the double-blind part of the study and then received ANAVEX®2-73 (blarcamesine) during the open-label extension (OLE) part of the study – a criterion for classification as a disease modifying agent.
Continued improvement from the drug as measured with RSBQ total score was observed from the start of the double-blind study to the end of the open-label extension part for patients continuing on ANAVEX®2-73 (blarcamesine). Patients previously on placebo, who switched to ANAVEX®2-73 (blarcamesine) in the OLE part of the study experimented with improvement during the OLE part.
Additionally, disease progression, which is defined as a change in Rett syndrome disease severity with time, was also reduced by long-term treatment with ANAVEX®2-73 (blarcamesine).
Patients assigned first to ANAVEX®2-73 (blarcamesine) in the double-blind part of the study and who continued on ANAVEX®2-73 (blarcamesine) during the open-label extension (OLE) study had a statistically significant (p = 0.01752) reduction in disease progression when compared with patients assigned first to placebo in the double-blind part of the study and then received ANAVEX®2-73 (blarcamesine) during the open-label extension (OLE) part of the study – a criterion for classifying a drug as a disease modifying agent."
Interesting study on the possible role of gut microbiome in the development of Alzheimer's and the central role of inflammation. Is Anavex including gut microbiome assessments in any of its studies?
Regarding the new hypertension patent, how much empirical data is needed to be filed with a patent application in order to be granted a patent of this sort? Is data collected as part of other studies sufficient, or do specific trials have to be run in order to successfully apply for a patent? Can anyone with experience in patent applications cast light on this? Thanks in advance, ToeMind
My hope for the next public event is the peer reviewed paper on the AD data in either New England Journal of Medicine, JAMA, Science, or Nature. That would provide the visibility and subsequent high citation index score that it appears this breakthrough data will warrant. ToeMind
It looks like the Alzheimer's Association is going to bat for Biogen & Eisai.
"The Alzheimer's Association has filed a formal request with the Centers for Medicare & Medicaid Services (CMS) that it provide full and unrestricted coverage for Alzheimer's disease (AD) treatments approved by the US Food and Drug Administration (FDA). In a letter addressed to CMS administrator Chiquita Brooks-LaSure, MPP, the association has asked the agency to remove the requirements for "coverage with evidence development" in its national coverage determination for FDA-approved anti-amyloid monoclonal antibodies."
We’ll said Mycroft. Anavex is spearheading a major paradigm shift that will take a while to move towards full recognition. Reminds me of penicillin….. ToeMind
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