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Regarding the Korsinskynlawsuit, in my view, the presence of Marwan Sabbagh, Walter Kaufman and Kun Jin at Anavex does not support a thesis of deception.
It is interesting that Anthony Caggiano, M.D., Ph. D, the CMO and head of R&D at Cognition Therapeutics, a company investigating S2 receptor agonists for the treatment of neurodegenerative diseases, stated on Oct. 16, 2023, “The approval of monoclonal antibody therapies against amyloid beta protofibrils represents an important milestone in Alzheimer’s drug development, but industry experts agree that combination treatments will likely be required to achieve greater impact on the disease.” Dr. Timo Grimmer, an expert in neurodegenerative diseases and a member of Anavex’s SAB, has stated, “We all agree that combination therapy will be needed in the end.” One could argue that Anavex 2-73 is in itself a combination therapy, in light of the multitude of positive effects that it, or S1R agonists in general, have been shown to exert on the cell. This is not to say that it won’t be used in combination with other medications being developed by other companies. I believe it will.
In brief, these are some of the positive effects:
—it increases Nrf2, considered the master regulator of the cell’s antioxidant response
—it increases the expression of AMPK, considered a master cellular energy and re-dox sensing protein
—directly regulates amyloid beta production, an upstream effect
—regulates tau phosphorylation, another upstream effect
—improves neuron morphology by increasing dendrite spine formation, promoting growth cone formation, and potentiating
Nerve growth factor induced neurite sprouting and axon formation
—increases BDNF (brain derived neurotrophic factor), which promotes synaptic plasticity and neuronal survival
—promotes Ca ion exchange from the ER to the mitochondria(M) which increases ATP production from the electron transport chain
(neurons in AD are know to have deficient energy levels)
—by its antioxidant response, it decreases ROS production induced by A beta (ROS are known to damage many cellular elements such as 1) proteins, many of which are enzymes, causing misfolded or unfolded proteins, which causes ER and cellular stress; 2) nuclear DNA, causing toxic RNA, causing toxic proteins/enzymes, causing cellular and ER stress; 3) mitochondrial DNA, resulting in Mitochondrial dysfunction; 4) membranes, resulting in leaky membranes; 5) microglia, causing neuroinflammation by increasing cytokine production
—enhances MAM function, which plays an essential role in autophagy by promoting autophagosome-lysosome fusion and promoting TFEB nuclear translocation which causes transcription of the autophagy-related gene and lysosome biogenesis.
Anavex 2-73 specifically has been shown to increase autophagic flux by three-fold. The S1R is a surrogate biomarker of mitochondrial function. Note that S1R has been found classically at the MAM, but has also been found in mitochondria
Themselves as well as at the nuclear membrane, where it stabilizes nucleoporins , participating in transport of molecules between
The cytosol and the nucleus, such as TFEB mentioned above, many of which are chromatin remodeling components.
—S1R has been found to be able to bind with toxic RNA and clear it from the cytosol
—S1R affects the calcium concentration in the microglia, and inhibits microglia inflammatory response
—S1R is critical for the supportive function of astrocytes on neurons (it is the astrocytes that nourish the neurons)
—S1R is necessary for the formation of proper myelin sheaths and for the maturation of oligodendrocytes
—S1R increases glia-derived neurotrophic factor (GDNF) which enhances the integrity of the blood brain barrier
I think this is what Missling is referring to when he talks about the “complete housekeeping function” of Anavex 2-73.
In the adult Rett trial, the seizure risk decreased by 50%. That P3 trial was successful. In the pediatric Rett trial, we have anecdotal evidence of a Rett girl whose seizure frequency went from multiple daily to one every 3 weeks. It would be very hard to convince that family that the trial “failed” and that this medicine won’t be available to them. Seizure frequency is an endpoint that is much easier to “measure” than other endpoints, and to me is a strong indication of Anavex 2-73’s overall neurological efficacy. I hope the EMA and FDA see it this way.
Thank you for this article about an experimental method to increase the expression of Nrf2, a transcription factor that activates the ARE (antioxidant response element) in the nucleus, which “drives the expression of detoxifying and antioxidant genes.” It’s useful to remember that S1R agonism (such as with (+)-pentazocine) also increases the expression of Nrf2. I would think Anavex 2-73 would also have such an effect, as it is a potent S1R agonist. Refer to ‘Targeting S1R: A Promising Strategy in the treatment of Parkinson’s Disease’, Neurochem Res 2023, May 31: 1-11.
An interesting tidbit from my notes on this subject: “When Nrf2 is activated, it enters the nucleus and turns on several hundred genes, known collectively as “survival genes.” This, in turn, initiates the production of several of your body’s own enzymes that fight free radicles. These include catalase, glutathione, and superoxide dismutase. These are much more effective than exogenous antioxidants at getting rid of free radicles. Nrf2 is known as the “master regulator” of our body’s antioxidant response.
George has provided more references than anyone else to relevant scientific articles regarding the S1 receptor and a plethora of other issues regarding neurodegenerative diseases. He is to be thanked for that. I read all his posts.
Another reason Rett should be approved first is that rare disease drugs are priced much higher than those for non-rare diseases. It’s much easier to drop the price for an AD indication than to raise it for a rare disease indication.
Wow, Sokol! Thanks!
It’s interesting that this paper comes out of the National Institute of Health
Excellent article. Thanks! Wow!
Terrific article! Thank you.
I agree with your thinking. Combination therapy will likely be necessary for a complex disease like Alzheimer’s. Stem cells may also be a part of the “answer,” but these will have to be injected into the ventricles of the brain through a burr hole in the skull which will require general anesthesia but fortunately is only a 20 or 30 minute procedure. My view, though, is that not even stem cells will be a “magic bullet” for Alzheimer’s. I believe that there are no “holy grails” for Alzheimer’s and that combination therapy will be needed. I think Anavex 2-73 will be a part of this.
I enjoyed that article, George. Please keep it up. We know that the S1R translocates to the plasma membrane and affects ion channels, kinases, G protein coupled receptors, and integrins as well as affecting store operated calcium entry. Over 90% of the cell’s ATP is used to control calcium levels/fluxes in the cell. Now we also know of S1R’s ability to fine tune potassium channels, for which there are no current pharmacological strategies. This increases our knowledge of the wide ranging homeostatic effects of Anavex 2-73. I appreciate these articles.
Thank you for posting that wonderful article.
It’s hard to make predictions with our history of missed timelines. However it seems to me that the FDA is “motivated” when it comes to Alzheimer’s, as evidenced by its approval of two MABs that had less than stellar results, one of which did not even get approval from their advisory board, and all of this in the setting of dire need for an Alzheimer’s remedy.
I own shares and am happy that I bought them in 2015. I didn’t think the progress of the trials would be this slow, but I’m not sorry to be an investor here. The pandemic and a more precision trial approach are part of it. For me, slow and methodical is good. In the meantime, I have learned a lot along the way and I find that fascinating. Reminds me of the old joke: what does the snail say while riding the turtles back?*
* Wheeeeeeeeeeee!!
I’m very busy, not much time, but still interested in Anavex and continue to follow the board, as I appreciate those who generously post scientific articles relevant to neurodegenerative diseases. And you have to admit, it’s rather entertaining at times. Enough to make Jesse Livermore proud.
I have a couple of thoughts/observations to relate. This represents my own thoughts/opinions and is not intended as investment advice.
In the Avatar Rett trial, “seizure frequency via seizure diary” was one of the “other outcome measures.” The results showed that there was a 50% decrease in seizure risk.” From my reading, epilepsy has been reported in 60-80% of patients with Rett syndrome. Epilepsy continues to be a major concern in adults with Rett syndrome. 2/3 of women above thirty years of age remained with active epilepsy and 50% of them had seizures at least weekly.
To contextualize this, note that the preclinical anti-seizure efficacy of Anavex 2-73 was strongly positive. Anavex 2-73 was compared to three generations of epilepsy drugs in multiple standard seizure-inducing animal models. It was tested both alone and in combination with these three drugs, all of which are still in use. The data demonstrated significant improvement in the reduction of seizures by Anavex 2-73 relative to these three generations of epilepsy drugs, as well as significant synergy with each of them.
Regarding this, Missling stated, “Efficacy is important in an anticonvulsant drug candidate. The key, however, to the next generation of epilepsy therapies is safety since most currently used epilepsy drugs require therapeutic drug monitoring given their significant differences in individual’s therapeutic dosages. Adding Anavex 2-73 to a current epilepsy drug regimen has the potential to increase safety by means of a dose reduction, while at the same time significantly improving anti-seizure efficacy. This data also suggests that Anavex 2-73 has the potential to become a platform drug for additional indications beyond Alzheimer’s disease.”
Missling went on to say, “Another important implication is a recent finding that Alzheimer’s disease and seizures together seem to accelerate the worsening of symptoms, suggesting that the seizure disorder adds to the degenerative Alzheimer’s disease pathology to exacerbate the cognitive decline. We are encouraged to explore this additional indication.”
Alzheimer’s patients are estimated to have anywhere from a two- to six-fold increase in the risk of seizures compared to the general population. 10-26% of Alzheimer’s patients will experience seizures over the course of the disease. Having two or more seizures is classified as epilepsy.
Dr. Jacqueline French, professor of neurology at NYU, past president of the American Epilepsy Society, Chief Medical Officer of the Epilepsy Foundation, who lectures internationally on clinical trials and the use of anti epileptic drugs, and who is a member of the Anavex SAB, had this to say about Anavex 2-73: “I am extremely impressed with the positive preclinical epilepsy data for Anavex 2-73…Additionally, Anavex 2-73 was shown to be safe in a phase 1 human trial, which is critical to next generation epilepsy therapies…I look forward to collaborating with Anavex and it’s impressive team of scientific advisers as we work to further develop Anavex 2-73.”
It is known that patients with epilepsy are at significant risk for cognitive impairment and behavioral abnormalities. Also, adverse effects of anti epileptic drugs are considered by patients to be at least as important as repetitive seizures in terms of quality of life. To my knowledge, no anti-seizure medication has been shown to promote improvement in cognition. However, Anavex 2-73 has shown evidence of cognitive enhancement in three different neurodegenerative diseases, including Rett, PD, and AD. As noted above, Anavex 2-73 has been associated with a 50% decrease in seizure risk in the Avatar Rett trial. This is not a formal epilepsy trial. But it does increase my optimism about Anavex 2-73 not only as a Rett treatment but also as a platform drug for other neurodegenerative diseases. I am happy with my investment in Anavex on the basis of its two completed Rett trials alone. Additionally, with multiple other potential indications for this drug, as well as its other pipeline drugs, Anavex has multiple shots on goal.
As has been discussed on this board before, neurodegenerative diseases such as Alzheimer’s are considered complex diseases. Complex diseases, such as hypertension, usually require multiple medications that work in different ways and thereby complement each other. Hypertensive patients frequently require two, three or even four medications for adequate control. In regard to Alzheimer’s, Timo Grimmer, an investigator in the Anavex 2-73 P2/3 Alzheimer’s trial and head of the Centre for Cognitive Disorders at the University of Munich School of Medicine, and the newest member of the Anavex SAB, stated in his CTAD comments in the Roche podcast, “…we all agree that we will probably need combination therapy in the end.” I suspect the FDA realizes this as well. This is why I am (somewhat reluctantly) OK with the FDA’s approval of Lecanemab and Auhelm (I am not a Biogen investor) because anti-Alzheimer’s drugs need to be available to be used in combination. Perhaps lecanemab and Anavex 2-73 (or other AD drugs in development by other companies) will had additive or even Supra-additive effects. So, downstream drugs are now available. My view is that upstream drugs are now needed, and that Anavex 2-73 fits the bill. It has a good safety profile, is orally administered, does not cause brain swelling/bleeding, does not require.MRI follow up, and has shown impressive efficacy in multiple neurodegenerative and neurodevelopmental diseases.
Unfortunately, the wheels of science turn slowly (and by saying this I do not mean to say Missling is “off the hook” for missed timelines). My concern is that the cost of Alzheimer’s is projected to bankrupt Medicare in the not-too-distant future so there’s no time to waste. And this applies to Missling and to the FDA. Meanwhile, millions are dying or losing their memories and personalities
Agree with Sokol’s information/assessment. Also. Missling said years ago that Anavex 2-73 causes transient headaches and dizziness #wgich you want to see in a CNS drug.”
Additionally, Timo Grimmer, in his interview on the recent Roche CTAD podcast, said about Anavex A2-73 that “it is largely well tolerated, causes a bit of tiredness, maybe confusion, but not to a large extent, definitely no brain swelling. That means you don’t need MRI monitoring.”
Any news, rumors, rumors of news, news of rumors?
Also (correct me if I am wrong) it is my understanding that no more than 5% of Alzheimer's cases are related to the APOE gene.
No problem It would be nice to have MRI's on these patients to assess hippocampal volume because we know from Maurice's studies that A2-73 increases proliferation of neurons in the hippocampus.
Thanks. Do you think "brain scan" means CT scan or might it mean EEG?
Where did you get the information that the patients in our trial had their brains scanned? I have no recollection of this.
I might add that, as we all know, he has been invited to Washington, D.C. multiple times to participate in government sponsored roundtables regarding Alzheimer's disease. He graduated summa cum laude from the Ludwig Maximilian's University in Munich which, in case anyone wants to know, is ranked the best University in Germany. (Google "Best Universities in Germany). In my opinion, he is "the real deal."
I agree with you. Thanks for your comments.
Wow!!! Thanks for this post!
vTv failed. A2-73 has not.
I agree with you in that some of the poor efficacy of anti-amyloid compounds may relate to patients that were in a stage of the disease too far advanced to benefit. Some of these compounds may still be found useful, but I believe it will be in the context of a multimodality approach. I don't know of any complex diseases which are treated with a single medication. I don't anticipate a "magic bullet" for Alzheimer's or any other complex disease. However I continue to believe that A2-73 will play a central role in the armamentarium of medications that will be used for this and other neurodegenerative diseases. Positive results in the Rett trial will be widely noticed.
Yes they are smart--they were all interested in amyloid and downstream and got slaughtered.
everything is a guess.
It'll be too late then don't bother.
Seizure meds are sedating. A2-73 is not. Seizures promote cognitive decline. A2-73 promotes cognitive enhancement.
Interesting to remember that the A2-73 clinical trial began in Jan., 2015. It was designed to fail early but did not. On Sept. 21, 2015 Anavex announced the appointment of Harald Hampel to the SAB and made a publicized announcement of the appointment. So Hampel has been with Anavex for almost 2 1/2 years. As has been discussed, Hampel is particularly interested in improving early detection of AD at the silent stage before there are any clinical signs or symptoms. This includes genetic analysis, or so-called pharmacogenetics. Here are some of Missling's comments about Hampel at that time: "We believe Harald's vast knowledge of Alzheimer's, his experience and interest in drug development, and focus on early detection, diagnosis and intervention complement our therapeutic approach and offer significant value as we advance Anavex 2-73 through the clinic."
In regard to the genetic analysis re Alzheimer's that has been discussed on the board today and yesterday, we know that Anavex has a relationship with Illumina for the gene sequencing data that has been collected on the patients in our clinical trial. Illumina has various commercial agreements with Thermofisher regarding complementary expertise which is used in the gene sequencing. Thermofisher bought out Affymetrix a couple of years ago. Affymetrix is also involved in genetic analysis. In 2015, Affymetrix put out the following news release: "Cytox and Affymetrix form strategic partnership to develop and commercialize blood-based genetic assay for Alzheimer's disease risk assessment." Cytox is a British company described as "an innovative developer of assays for risk assessment and prediction of dementia." The CEO of Cytox commented, "Our early research studies...suggest that by using a customized genetic variation panel, it may be possible to better assess the risk of an individual developing AD or MCI. The Axiom genotyping platform from Affymetrix...is ideally suited for use in a blood- based test for researchers interested in AD and MCI risk stratification and longer term diagnostic and prognostic use...Cytox will provide new genetic content using our comprehensive AD and dementia expertise which, when combined with Affymetrix's technology, know-how and marketing support makes an ideal partnership."
And how about their muscarinic effects?
And they likely don't have muscarinic effects.
According to MacFarlane, P300 studies are what got Aricept approved by the FDA.
Biomarkers like A2-73's EEG effects and BDNF enhancement.
What else is new?
Certainly also true re anti-seizure effects of A2-73, as it has been shown to be very synergistic in multiple preclinical studies with all of the major epilepsy drugs on the market today. Those drugs are sedating and have no affect on the cognitive decline that accompanies epilepsy.
Thank you. I appreciate your responses and input. One other aspect of this company I wonder about is the idea that the very large amounts of data that can be generated by its software could be "monetized" and sold to health insurance companies, government agencies, etc. How significant do you think that could be in terms of revenue generation?