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Barry Diller says Trump Media is 'a scam' and people buying shares are 'dopes'
DJT reports today that it expects to continue to lose money for the foreseeable future.
DJT is losing money, burning cash and revenue is declining. Where will the cash come from to attempt to “prop it up”?
HC Wainwright reiterates Buy price target $54 seems to be moving price up for now.
7:02 AM EST, November 28, 2023 (Benzinga Newswire)
HC Wainwright & Co. analyst Raghuram Selvaraju reiterates Anavex Life Sciences (NASDAQ:AVXL) with a Buy and maintains $54 price target.
Write to Benzinga at editorial@benzinga.com
I have no idea why the stock is moving up. My guess before the market opened was that the stock would continue downward. I certainly didn’t expect AVXL to make this move up today, but I am pleased to see it. I think Sab said yesterday that AVXL had more to move to the upside. I hope it closes up near its high of the day and continues to rally in coming days. But, what do I know?
That was likely Missling’s way of saying that the date we will have the data is the date of publication of the peer reviewed paper whenever that is. Does he know the date the paper will be published? I think not.
Excellent. Thank you for posting this.
Being a citizen of the United States and a believer in its constitution and the “Blessings of Liberty to ourselves and our Posterity”, I believe Investor has the right to freely express himself whether I/we always agree with him or not. Freedom of expression is not an absolute right in that it must not be used to harm others such as “shouting fire in a crowed theater”. Investor’s comments are not harmful but beneficial. And, yes, I believe his criticisms of Missling and Anavex are intended to hold the company and Missling accountable. Accountability is important, and it is a check on the power of leaders so that leaders like Missling as CEO will not do harm to others that may be subject to their/his actions, words and deeds such as shareholders. We should all be accountable for our actions and deeds that may harm others. Investor means no harm in his criticisms.
That is a rather obvious question, and I expect it will be asked or better volunteered.
Thinking about Monday and Missling's handling of past presentations and Q&A sessions does create some anxiety. On Monday, I would rather hear fewer adjectives and receive unambiguous, informative answers and information. Hopefully, he will be prepared and rise to the occasion.
At 8:30 am ET Monday.
Thank you, Abe.
A few articles discuss the effects of SR1 agonists on sleep. [One article published in the journal Sleep Science and Practice ](https://sleep.biomedcentral.com/articles/10.1186/s41606-018-0025-z)[1](https://sleep.biomedcentral.com/articles/10.1186/s41606-018-0025-z) suggests that medications that target the sleep-associated circadian neuroendocrine system, such as SR1 agonists, can be used to treat insomnia. [Another article published in the journal Neuroscience Bulletin ](https://sleep.biomedcentral.com/articles/10.1186/s41606-018-0025-z)[2](https://link.springer.com/article/10.1007/s43440-021-00339-8) suggests that serotonergic signaling, which is modulated by SR1 agonists, plays a role in sleep and memory. However, I could not find any direct evidence that SR1 agonists improve sleep.
I do see where Anavex reported this about sleep in connection with the PDD study: "Notably, blarcamesine did not impair sleep and had a positive effect on rapid eye movement (REM) sleep behavior disorder." However, no details were provided. See Blarcamesine Deemed Safe, Effective in Phase 2 Extension Study of Parkinson Disease Dementia. https://www.neurologylive.com/view/blarcamesine-deemed-safe-effective-phase-2-extension-study-parkinson-disease-dementia
As to anxiety, this was reported about fear and anxiety in connection with the Rett clinical trial: "Data from the phase 2 study was announced in 2021, with blarcamesine-treated patients showing significant increases in the expression of the SIGMAR1 mRNA biomarker, which correlated significantly with improvements in RSBQ (_P _= .035) and CGI-I (_P _= .029). Additionally, findings on the RSBQ demonstrated balanced improvements across all the instrument's subscales during the 7-week trial, including general mood, breathing, hand behavior, repetitive face movements, body rocking, night-time behavior, fear/anxiety, and walking/standing." Phase 2/3 Study of Blarcamesine in Pediatrics With Rett Syndrome Completes Enrollment, Jun 8, 2023
By [Marco Meglio](https://www.neurologylive.com/authors/marco-meglio). https://www.neurologylive.com/view/phase-2-3-study-blarcamesine-pediatrics-with-rett-syndrome-completes-enrollment. Again, no details were provided.
What information- data will we receive from Anavex in connection with the latest on Rett and AD studies, including possibly open label data? Anything meaningful regarding sleep-anxiety, among other things?
Thank you, that is helpful.
That’s helpful. Thank you.
Drug regulatory agencies weigh the risks and benefits of a drug in the approval process, but the scientific evidence must come from the clinical trials. I don't recall, but Anavex has mentioned the potential benefit of blarcamesine in treatment of insomnia although I am not sure about the evidence of that benefit from the clinical trials. Also, I don't recall what evidence from the trials, if any, Anavex may have relating to agitation and anxiety although I think I vaguely remember mention of anxiety and/or agitation in past reports on the progress of clinical trials. I think I may have partially answered my questions about using treatment for insomnia, anxiety and agitation as beneficial in the approval process in my research provided below, but I don't recall what proof we have from the clinical trials. If we have proof of those benefits from clinical trials, I think that will likely help to get Blarcamesine approval. However, what evidence do we have about these possible benefits?
The grant of a patent does not provide evidence of effectiveness for a particular use. It only provides the right to exclude others from making, using, offering for sale, or selling the invention.
Drug regulatory agencies such as the FDA in the United States, EMA in Europe, and NMPA in China, have a rigorous process for approving drugs. The process involves multiple phases, including pre-clinical research, clinical research, and post-marketing risk assessments 1 (https://www.drugs.com/fda-approval-process.html)2 (https://www.fda.gov/drugs/development-approval-process-drugs)3 (https://www.drugwatch.com/fda/approval-process/). The regulatory agencies evaluate the safety and efficacy of a drug based on the data submitted by the drug manufacturer. The benefits of a drug are considered along with its risks, and the regulatory agencies approve a drug only if its benefits outweigh its risks (https://www.drugs.com/fda-approval-process.html)2 (https://www.fda.gov/drugs/development-approval-process-drugs)3 (https://www.drugwatch.com/fda/approval-process/).
However, it is important to note that the regulatory agencies do not consider all benefits of a drug in their approval process. They only consider the benefits that are supported by scientific evidence and data from clinical trials 1 (https://www.drugs.com/fda-approval-process.html)2 (https://www.fda.gov/drugs/development-approval-process-drugs)3 (https://www.drugwatch.com/fda/approval-process/)
.
The regulatory agencies also consider the severity of the disease that the drug is intended to treat and the availability of alternative treatments 2 (https://www.fda.gov/drugs/development-approval-process-drugs).
In summary, drug regulatory agencies consider the benefits of a drug in their approval process, but only if they are supported by scientific evidence and data from clinical trials. They also consider the risks of the drug and the severity of the disease that the drug is intended to treat 1 (https://www.drugs.com/fda-approval-process.html)2 (https://www.fda.gov/drugs/development-approval-process-drugs)3 (https://www.drugwatch.com/fda/approval-process/).
Does Anavex have convincing evidence or data to show that Blarcamesine treats insomnia, anxiety and agitation? Will this provide some collateral benefit for EMA or other regulatory approval?
Agreed
Of course, the EMA process will take a while. However, depending on how the EMA views Blarcamesine as a potential treatment compared to alternative AD drugs, the potential is there for the EMA to move more quickly on promising Alzheimer’s drugs. Since 2018, the EMA has been targeting the development of Alzheimer’s drugs. The agency is keen on the qualification of biomarkers relative to Alzheimer’s drugs. “Dementia is a key public health priority for EMA. See below. Early approval in the EMA depends, among other things, on how the data demonstrates improvement in dementia symptoms, reduction of amyloid and a reduction of brain volume loss. Of course, the EMA also places emphasis on how healthcare costs for treating AD is impacted. Costs savings savings are potentially attractive for savings in the administration of Blarcamesine. What about savings for hospital care, caregiver time, community services and long-term care facility costs? The latter depends in part at least on how Blarcamesine may benefit patients on functioning and caring for themselves. What does the data demonstrate regarding the latter? Lastly, pricing of the drug is important. Seeking approval in the EMA I think means we will have to accept conservative pricing of Blarcamesine in the EU.
In any event see this:
Revised guideline on clinical studies for Alzheimer's disease medicines
News 28/02/2018
Guidance expected to facilitate development of medicines to prevent and treat condition
The European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a revised guideline on clinical studies for medicines that target Alzheimer's disease. This document aims to provide guidance for the development of medicines across all stages of Alzheimer's disease.
Alzheimer's disease, a condition that destroys brain cells and nerves, disrupting the transmitters which carry messages in the brain, is the most common cause of dementia in the elderly. According to the World Health Organization, 35.6 million people have dementia worldwide and this number is expected to double by 2030. It affects more than five million people in the European Union (EU).
Recent progress in understanding the pathophysiology of Alzheimer's disease suggests that the biological changes associated with the disease start to occur as early as 10 to 20 years before clinical symptoms start to appear. Many of the experimental medicines are therefore investigated in earlier disease stages as certain treatments may be more effective at that stage than later in the illness.
Currently available medicines for Alzheimer's disease only treat its symptoms. However, a number of therapies under development are targeting the biological mechanism of the condition to try and modify the course of the disease.
Dementia is a key public health priority for EMA. The Agency promoted several initiatives to encourage a broad range of stakeholders to share their experiences and challenges, which were reflected in the revision of the guideline.
Before revising the guideline, EMA organised a workshop for patients, academia, regulators, representatives from the pharmaceutical industry and independent experts to ensure that it was informed of the most up-to-date scientific developments in understanding and treating Alzheimer's disease.
This effort was complemented by a series of meetings between EMA and developers of medicines intended to slow down the disease progression, to discuss the issues encountered in their clinical trials.
The guideline also builds on scientific advice provided by the Agency to medicine developers on specific products and methodologies, such as the qualification of biomarkers for use in clinical trials and a longitudinal model describing changes in cognition in patients with mild or moderate Alzheimer's disease.
Agreed
I have long thought that seeking approval for Blarcamesine in Europe first is the best strategy for Anavex. The EMA is concerned about cost and has been leery of the side effects of Leqembi and its administration. However, Europe is in great need of a potentially treatment option for AD that may benefit the European healthcare system and potentially lower the cost for DD patients. The following language from today’s PR is key:
“…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.”
Thank you, Power.
Thank you.
In the Anavex 2b/3 Alzheimer's trial, were placebo patients typically allowed to continue taking their standard of care medication? I think I recall that in previous Anavex AD trials, placebo patients continued to take Donepezil(?). In the remdesivir clinical trial placebo patients received the stand of care and the odds ratio was used to compare remdesivir patients with standard of care placebo patients. Of course, that was the plan in remdesivir from the start of the trial and the trial participants numbered over 1,000. Therefore, the remdesivir trial may not be a valid comparison.
“ANAVEX®2-73 activates the Sigma-1 receptor (S1R) protein, which serves as a molecular chaperone and functional modulator involved in restoring homeostasis. S1R activation has demonstrated ability to reduce key pathophysiological signs of Alzheimer’s disease: beta amyloid, hyperphosphorylated tau, and increased inflammation.”
https://www.anavex.com/press-releases/first-patient-enrolled-in-anavex-life-sciences-phase-2b%2F3-clinical-trial-of-anavex%C2%AE2-73-for-the-treatment-of-early-alzheimer%E2%80%99s-disease
Thanks. Quote from Peter Marks article: ‘The agency can mitigate uncertainty by “using science to the fullest extent," according to Marks—be it available animal data or strong human biomarkers related to, for example, the expression of a particular protein.’
It’s High Time Anavex Moved From Operation Tortoise to Operation Warp Speed.
Anavex announced completion of the Excellence Phase 2/3 Rett clinical trial (92 pediatric patients with Rett syndrome ages ≥ 5 years to 17) on June 6, 2023. This week FDA's Peter Marks was interviewed by Endpoints wherein he called for the industry to embrace the accelerated approval pathway as the agency adapts an "Operation Warp Speed" line of attack in swiftly moving investigational rare disease drugs to market. Anavex has received Fast Track designation for Blarcamesine for the treatment of Rett. It seems to me that all of this puts the ball completely in Anavex's court. The FDA is waiving a flag encouraging Anavex to seek accelerated approval from the FDA for Blarcamesine to treat Rett, and Anavex has previously received Fast Track designation for Blarcamesine to treat Rett syndrome. The FDA has adapted an "Operation Warp Speed" mentality in moving investigational rare disease drugs to market. What more can Anavex ask for from the FDA? Nothing! Let's see if Anavex is up to meeting the challenge of matching the FDA's "Operation Warp Speed" line of attack in moving Blarcamesine to market to treat Rett.
# Completion of ANAVEX®2-73 (blarcamesine) EXCELLENCE Phase 2/3 Rett Syndrome Clinical Trial
## **NEW YORK -- June 6, 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 including Alzheimer's disease, Parkinson's disease, Rett syndrome and other central nervous system (CNS) disorders, today announced the completion of dosing of all participants of the placebo-controlled EXCELLENCE Phase 2/3 study ANAVEX®2-73-RS-003 in pediatric patients with Rett syndrome. The Company expects to announce topline results from this study in the second half of this year.
............
The completion of the randomized, placebo-controlled EXCELLENCE Phase 2/3 study ANAVEX®2-73-RS-003 for the treatment of 92 pediatric patients with Rett syndrome ages ≥ 5 years to 17 (inclusive) was preceded by the successful completion of both placebo-controlled Phase 2 U.S. (ANAVEX®2-73-RS-001) [2], and Phase 3 AVATAR (ANAVEX®2-73-RS-002)[3] studies in adult patients with Rett syndrome.
...........
ANAVEX®2-73 (blarcamesine) has Fast Track designation, Rare Pediatric Disease designation and Orphan Drug designation from the FDA for the treatment of Rett syndrome.
https://www.anavex.com/post/anavex-life-sciences-announces-completion-of-anavex-2-73-blarcamesine-excellence
### **FDA's Peter Marks on accelerated approvals**
This week, we (Endpoints) also spoke with **Peter Marks**, FDA biologics center director, who called for the industry to embrace the [accelerated approval pathway](https://e.endpointsnews.com/t/t-l-zkdzly-jdiihkkydu-p/) as the agency adapts an "Operation Warp Speed" line of attack in swiftly but thoughtfully moving investigational rare disease drugs to market.
In closing, let's remember that it has been well over a year since the Anavex AD 2b/3 trial was completed - past the one year mark (absent an extension) requirement for reporting clinical trial results. Peter Marks remarks indicate that the FDA is especially interested in accelerated approvals for promising treatments for CNS diseases. Anavex now has three former FDA employees. It is high time that Anavex change from what seems an "Operation Tortoise" mode to "Operation Warp Speed" to match the mentality of the FDA in moving Blarcamesine to market, if it can.
Yes, Anavex should have completed all the procedures and collected all the samples containing the relative to biomarkers. It should be done. The data should be available to report as required. Maybe Anavex was granted an extension beyond the 1 year requirement. However, the reason for the delay remains elusive.
Federal law has requirements for reporting clinical trial results, generally no later than one year after completion. However, an extension may be granted. Yet, it seems that an extension should be for good reason and would be limited to prevent indefinitely postponing a complete report.
Under the Food and Drug Administration Amendments Act of 2007, sponsors are required to submit certain results from clinical trials to ClinicalTrials.gov, generally no later than one year after completion of the trial. They can be granted an extension if they submit a request for a delay in posting the data, though the request must be submitted by a certain deadline.
The Food and Drug Administration Amendments Act of 2007 (also called FDAAA) was passed on September 27, 2007. The law now requires that the "Responsible Party" must register and report results for certain clinical trials of drugs, biologics, and devices that are subject to FDA regulation ([see Public Law 110-85, Title VIII](https://clinicaltrials.gov/ct2/manage-recs/fdaaa)). It also mandates that some previously optional data elements are now required. In general, the Responsible Party is defined as the sponsor of an applicable clinical trial. The law also allows the role of Responsible Party to be assigned to the Principal Investigator (PI) if the PI is responsible for conducting the trial, has access to and control over the data from the clinical trial, has the right to publish the results of the trial, and has the ability to meet all of FDAAA's requirements for the submission of clinical trial information. For investigator-initiated clinical trials, NIH is generally not the sponsor and, as such, NIH would not be the Responsible Party. **Under this law, the Responsible Party is accountable for compliance, including accuracy and completeness of the data.** Penalties for failure to register a trial with complete information may include civil monetary penalties and the withholding of federal grant funds.
https://www.niams.nih.gov/grants-funding/conducting-clinical-research/register-trials-gov#:~:text=The%20Food%20and%20Drug%20Administration%20Amendments%20Act%20of%202007%20(also,%2D85%2C%20Title%20VIII%20).
Investor: Agreed. Thank you.
Thank you. Yes, it is impossible to understand at this point.
In other words, this trial may be to show how the 325 patients respond after taking the drug for a year or more? The placebo patients enrolled in the OLE have not been on the drug long enough to satisfy regulators?
Could it be that the placebo patients from the phase 2b/3 AD trial are not included in this continuing EMA trial? However, former placebo patients may instead be enrolled in the OLE, but that group in the OLE may not constitute a clinical trial or be part of this trial? If we knew the number of placebo patients from the 2b/3 trial that chose to participate in the OLE, we might be able to figure this out? I’m just trying to understand the 325 figure?
Thank you, Sab.
Sab, TD sequential provided a 9 perfection for AVXL earlier in near the latter part of June and a solid 13 count this morning indicating selling is exhausted. Let’s see if we follow through to the upside into the coming week.
See this recent article about blarcamesine effectiveness in treating multiple CNS disorders.
[CNS Drugs.](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#) 2023; 37(5): 399--440.
Published online 2023 May 11. doi: [10.1007/s40263-023-01007-6](https://doi.org/10.1007%2Fs40263-023-01007-6)
PMCID: PMC10173947
PMID: [37166702](https://pubmed.ncbi.nlm.nih.gov/37166702)
# Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders
.....Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. ...
### ANAVEX2-73 (Blarcamesine)
Blarcamesine (ANAVEX2-73; Fig. [?Fig.2)2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/figure/Fig2/)) is a s1R receptor agonist with an affinity of 860 nM (IC50) [[222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR222)] developed for treating AD. Blarcamesine also has agonist activity at the muscarinic M1 receptor, and the NMDA receptor with affinities of 5 and 8 µM, respectively [[222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR222)].
#### Alzheimer's Disease
Pre-clinical studies have shown that blarcamesine can reverse scopolamine's long-term amnesic effects in mice [[222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR222)]. Furthermore, blarcamesine can reverse the effect of learning deficits in mice injected with Aß25--35 [[222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR222)--[224](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR224)]. Blarcamesine given to mice injected with Aß25--35 restored respiration rates in hippocampal mitochondria and reduced lipid peroxidation levels. Blarcamesine could also prevent tau-hyperphosphorylation and amyloid-ß (1--42) generation in mouse models of AD [[223](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR223)]. Furthermore, indicators of increased toxicity, including Bax/Bcl-2 ratio and cytochrome C release into the cytosol, were reduced [[224](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR224)]. Blarcamesine has protective effects in _Caenorhabditis elegans_ and cell culture models of AD by enhancing autophagic flux and increasing proteostasis [[65](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR65)].
A phase 1 clinical study in healthy male volunteers showed that doses up to 50 mg were well tolerated, with no serious adverse events reported in a poster at the CNS summit in 2014 [[225](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR225)]. At 60 mg, three out of four subjects presented dose-limiting CNS symptoms (dizziness and headache). The study concluded with pharmacokinetic analysis showing extensive biotransformation of blarcamesine to AV19-144 (the bioactive form of the drug) with assumed linear pharmacokinetics after single oral dosing of 1 to 60 mg blarcamesine [[225](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR225)].
A biomarker analysis, phase 2a study ([NCT02244541](https://clinicaltrials.gov/ct2/show/NCT02244541)), that include some exploratory study into the benefits of blarcamesine, where blarcamesine was administered over 57 weeks, showed a significant reduction in cognitive decline [[226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR226)]. When the study was extended to 265 weeks ([NCT02756858](https://clinicaltrials.gov/ct2/show/NCT02756858)), there was confirmation of this prevention of decline at 148 weeks with analysis of blood concentrations of blarcamesine and its metabolite AV19-144, showing that those with high concentrations of blarcamesine had improved therapeutic responses of 78% and 88% in adjusted MMSE and adjusted AD cooperative study--activities of daily living (ADCS--ADL), respectively, relative to the low/medium concentrations of blarcamesine.
Furthermore, genomic analysis also indicated the significant effects of biomarkers on clinical outcomes of blarcamesine. Two patients showed an exceptional therapeutic response at 148 weeks. Both subjects had s1R wild type and a high mean concentration of blarcamesine in plasma, with a baseline MMSE > 20 [[226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR226)].
The study of biomarkers that predict the potential therapeutic outcome of a drug is especially useful in a disease with such heterogeneity as AD [[226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR226)]. The ApoE e4 genotype alone lacks predictive power since only approximately 25% of people carry this genotype. The study discussed above identified that patients with a baseline MMSE greater than 20 who had the s1R wild type with a high mean blarcamesine serum concentration and _ApoE3_ alleles had significantly better outcomes in the ADCS--ADL. The _SIGMAR1_ Q2P variant, having a baseline MMSE score lower than 20 and a low mean serum concentration of blarcamesine were predictive of poor outcomes in the ADCS--ADL [[226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR226)].
Blarcamesine is undergoing further phase 2b/3 clinical trials (ongoing: [NCT04314934](https://clinicaltrials.gov/ct2/show/NCT04314934); completed with data yet to be published: [NCT03790709](https://clinicaltrials.gov/ct2/show/NCT03790709)). The results of these clinical trials will be interesting, given the promise blarcamesine has shown in the pre-clinical studies.
#### Multiple Sclerosis
Blarcamesine increased the proliferation of oligodendrocyte progenitor cells to myelin sheath-producing oligodendrocytes in a s1R-dependent manner and protected them from excitotoxic insults [[227](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR227)]. There are no currently listed clinical trials for blarcamesine in MS on [www.clinicaltrials.gov](http://www.clinicaltrials.gov/).
#### Rett Syndrome
Long-term administration of blarcamesine to mice deficient in MeCP2 restores physiological and neurological abnormalities that mimic the human Rett syndrome, including ameliorating motor and acoustic startle deficits and reversing expiratory apnoea [[228](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR228)]. Several s1R-related mechanisms could benefit the neurological and motor symptoms seen in this and other models of Rett syndrome. Enhancement of calcium homeostasis via s1R shuttling of calcium to the mitochondria leads to improved mitochondrial function and the activation of autophagy via s1R activation, resulting in a reduction of misfolded proteins and fewer damaged organelles or the restoring/upregulation of BDNF [[65](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR65), [228](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR228), [229](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR229)]. This leads to potential improvements in synaptic function in multiple brain regions.
Blarcamesine is currently in phase 2/3 clinical trials ([NCT03758924](https://clinicaltrials.gov/ct2/show/NCT03758924), [NCT03941444](https://clinicaltrials.gov/ct2/show/NCT03941444) and [NCT04304482](https://clinicaltrials.gov/ct2/show/NCT04304482)). Blarcamesine has shown positive results in a phase 2 clinical trial ([NCT03758924](https://clinicaltrials.gov/ct2/show/NCT03758924)) in female patients diagnosed with Rett syndrome (positive _MeCP2_ gene mutation), meeting both primary and secondary endpoints with no reported serious adverse events (press release) [[230](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR230)]. In another phase 3 ([NCT03941444](https://clinicaltrials.gov/ct2/show/NCT03941444)) clinical trial the primary and secondary endpoints were met with significant improvements versus placebo in the clinical global-impression of improvement scale (CGI-I); the anxiety, depression and mood scale (ADAMS); and drug exposure-dependent response of the Rett Syndrome Behaviour Questionnaire (RSBQ), all with a low incidence of adverse events (press release) [[230](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR230)]. It is important to note that the data available from these studies has not been peer reviewed and formally published. There are further ongoing phase 3 studies organized by Anavex Life Sciences ([NCT04304482](https://clinicaltrials.gov/ct2/show/NCT04304482)). However, while the data look promising, it will be important to see some independent studies with peer-reviewed results to fully assess the efficacy and safety of blarcamesine for Rett syndrome treatment.
### ANAVEX3-71
ANAVEX3-71 (AF710B) (Fig. [?(Fig.2)2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/figure/Fig2/)) is an agonist at the muscarinic M1 receptor and s1R, and the second drug developed by for AD treatment. ANAVEX3-71 has an affinity for the s1R of 1.3 nM and an affinity for the s2R of 10 µM [[62](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR62)]. The affinity for the M1 receptor is approximately 0.05 nM. ANAVEX3-71 also has affinities for the µ opioid receptor and serotonin receptor (approximately 10 µM for each) [[62](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR62)].
#### Alzheimer's Disease
Given the complex pathology of AD, it is of interest that a drug such as AF710B may interact with multiple target sites to have a beneficial effect in AD [[52](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR52)].
Pre-clinical studies have shown ANAVEX3-71 to be worthy of further study. AF710B has been shown to modify the disease-defining hallmarks of AD in transgenic (3×Tg-AD) mice, such as cognitive deficits, amyloid and tau pathologies, and beneficial effects on mitochondrial dysfunction and neuroinflammation [[62](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR62), [231](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR231)].
Phase 1 clinical trials ([NCT04442945](https://clinicaltrials.gov/ct2/show/NCT04442945)) in healthy individuals have been reported on Anavex Life Sciences' website, suggesting that in healthy volunteers, 5--200 mg daily had no serious adverse events. The pharmacokinetics of ANAVEX3-71 (serum concentration of AF710B) was also proportional to the dose for doses up to 160 mg. Furthermore, there were no clinically significant electrocardiogram (ECG) parameters throughout the study (press release) [[232](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR232)].
There are no further registered ([www.clinicaltrials.gov](http://www.clinicaltrials.gov/)) ongoing clinical trials with ANAVEX3-71. However, Anavex states on its website that they plan further phase 2 clinical trials. More independent studies are required. However, pre-clinical data on ANAVEX3-71 suggest it could be useful in treating dementia and AD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/
The number of job openings is unusual. It could be that Anavex is gearing up for a global phase 4 trial, which requires the collection of data and reporting to regulators. This, of course, is not definitive proof, but the openings like programming, global pharmacoviligence, etc., is consistent with plans for a phase 4 clinical trial.
Phase 4 trials look for side effects that were not seen in earlier trials and may also study how well a new treatment works over a long period of time.
Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold.
Postmarketing surveillance (PMS), also known as post-market surveillance, is the practice of monitoring the safety of a pharmaceutical drug or medical device after it has been released on the market and is an important part of the science of pharmacovigilance.
Post market surveillance is required by regulators such as the FDA.
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/postmarket-requirements-and-commitments#:~:text=The%20phrase%20postmarketing%20requirements%20and,%2C%20efficacy%2C%20or%20optimal%20use.
Good post. Yes, we have seen announcements that confirm that Blarcamesine does show improvement “day by day” and that stopping administration of Blarcamesine patients worsen only to begin improving again when treatment with Blarcamesine resumes.
We do have information that Missling says proves that continual dosing of Blarcamesine is important to response and that by halting intervention, patients worsen but can reverse for the better again by resuming treatment with Blarcamesine. So, it will be interesting to see if Anavex continues collecting data on patients in OLE and/or for compassionate use. It seems that Anavex is doing that. Some patients have been taking Blarcamesine for over two years. See below.
1. This is from Mayo's SOTC website. SOTC Update 5: 26 June 2023
Presentation at the H.C. Wainwright 4th Annual Neuropsychiatry Virtual Conference
- 11:15 min: Alzheimer's vs. Parkinson's
- - S1R does not discriminate based on pathology (initial cause of the disease). In Parkinson's genes, we found active arm (dosed patient) genes were up-regulated again. Functionality was improved on a molecular level. In the OLE, we proved that continual dosing is important to response and that by halting intervention, patients worsen but can reverse for the better again by resuming treatment -- beyond simple endpoint measures, this was also true at the gene level [new information]. We are now about to conduct the imaging (target engagement) study and Parkinson's disease pivotal trial which are both still being funded by MJFF.
2. Further, see ANAVEX®2-73 (Blarcamesine) Shows Clinical Benefit in Long-Term 48Week Phase 2 Extension Study in PDD - https://www.anavex.com/post/anavex-2-73-blarcamesine-shows-clinical-benefit-in-long-term-48week-phase-2-extension-study-in-pdd
Due to the COVID-19 pandemic, the start of the extension phase was delayed, on average, by approximately 41 weeks at the end of the preceding double-blind placebo-controlled study (DB). This led to a reduced enrollment rate for the extension phase. The period between the end of the double-blind phase to the start of the extension phase, where patients were not on ANAVEX®2-73 treatment, is known as a 'drug holiday'. The drug holiday period of treatment separation provided an opportunity to compare the trajectory of clinical scores between no ANAVEX®2-73 treatment (drug holiday) and ANAVEX®2-73 treatment in the extension phase.
All efficacy endpoints, which includes the MDS-UPDRS Part II + III and Clinical Global Impression -- Improvement (CGI-I) measured at the end of trial of the double-blind study (DB EOT), the OLE Baseline, OLE Week 24, and OLE Week 48, showed a worsening during the drug holiday. However, a consistent improvement was observed during the extension phase when patients resumed ANAVEX®2-73 treatment. These results are consistent with the pattern observed for all efficacy measures in the extension phase (see Chart and Table).[[6]](https://manage.wix.com/dashboard/e1cd7807-443e-425e-9433-41548681800c/blog/cb39a577-fa42-405a-a247-31bbefc78067/edit#_ftn3)
.....
"It is encouraging that the patients' clinical symptoms consistently improved longitudinally over time during the extension phase under active ANAVEX®2-73 treatment," said Christopher U Missling, PhD, President & CEO of Anavex. "This data suggests ANAVEX®2-73's potential capability to slow and potentially reverse the life altering symptoms of Parkinson's disease, an urgent unmet global need."
Moreover, at the request of the participants completing the 48-week open-label extension study, patient requested treatment with ANAVEX®2-73 is continuing beyond the open-label 48-weeks through the compassionate use Special Access Scheme. Currently, participants in the compassionate use program for ANAVEX®2-73 have been on average, for over 2 years and counting.
Yes, under the old outdated method of pharmaceutical companies hiring drug detail representatives and employees to market drugs, the information flow about new drugs was limited to representatives traveling to doctors offices and promoting big pharma drugs. Small companies could not afford to do this and do it effectively, but this new and innovative Partex approach changed all of that and can more efficiently and quickly disseminate information to more sources, including patients, care givers, advocacy groups, doctors, etc.
From AI chat:
“Partex NV has always been committed to innovation and making a positive impact on the industries it operates in. While Partex NV may not directly inform patients and caregivers about new innovative drugs, it can play a crucial role in facilitating the dissemination of information through its AI-powered drug asset management system.
Partex NV's AI platform can analyze vast amounts of data from clinical trials, research papers, and drug databases to identify potential breakthroughs and innovative drugs that are undergoing clinical trials or have recently entered the market. By leveraging machine learning algorithms and data analytics, Partex NV can rapidly identify emerging trends and advancements in drug development.
Once Partex NV's AI platform detects new drugs, the company can share this information with medical professionals, patient advocacy groups, and healthcare providers. By collaborating with these stakeholders, Partex NV can actively contribute to the flow of information to patients and caregivers, ensuring that they are informed about the availability of these innovative drugs.
To facilitate this knowledge transfer, Partex NV's AI system can generate reports, summaries, and insights on the latest drugs in clinical trials or on the market. These reports can provide details on efficacy, safety profiles, potential side effects, and access information for specific diseases. Partex NV can also work with healthcare providers and advocacy groups to host educational events, webinars, or conferences to disseminate information and enable dialogue between medical professionals, patients, and caregivers.
Furthermore, Partex NV can collaborate with pharmaceutical companies to support the development of patient-focused materials that explain the benefits, risks, and potential outcomes of new drugs. These materials may include patient information leaflets, brochures, websites, or digital applications that provide easy-to-understand information about the drugs and how they can be accessed.
Partex NV can also contribute to the development of online platforms or databases that aggregate information about innovative drugs, clinical trials, and ongoing research. These platforms can serve as comprehensive resources for patients and caregivers, empowering them to stay updated on emerging treatments and engage in informed discussions with their healthcare providers.
It is important to note that while Partex NV can support the dissemination of information, the responsibility lies with healthcare providers, patient advocacy groups, and medical professionals to communicate this information to patients and caregivers effectively. These entities play a critical role in empowering patients and caregivers, guiding them through treatment options, and ensuring that they have access to the necessary resources.
In conclusion, while Partex NV does not directly inform patients and caregivers about new innovative drugs, its AI-powered drug asset management system can contribute immensely to facilitating the flow of information. By analyzing data, generating reports, collaborating with stakeholders, and supporting the development of patient-focused materials, Partex NV aids in informing patients and caregivers about new drugs in clinical trials and on the market. Ultimately, the collaboration between Partex NV, healthcare providers, patient advocacy groups, and medical professionals can empower patients and caregivers, enabling them to make informed decisions and access new innovative treatments for better healthcare outcomes.”
Note: This Partex - Anavex partnership changes all of that and allows Anavex to market its drug platform without the traditional, old, expensive, and cumbersome drug marketing department system.