Parkinson’s Drug Delivered, Not Just Parkinson’s Disease Dementia Drug! $AVXL

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor! And I am long $AVXL $ANVS $CRTX FYI

Etiology Battle Won

The first paragraph says it all.

ANAVEX®2-73 treatment resulted in significant increase in the expression of the SIGMAR1 mRNA biomarker that significantly correlated with improvements in the primary and secondary clinical efficacy endpoints CoA (p = 0.029) and MDS-UPDRS Part III (p = 0.024) and MDS-UPDRS Total (p = 0.038)

Wherever Blarcamesine has been treating patients increased SIGMAR1 messengerRNA has been detected, this direcetly connects the drug with the biomarkers and the therapeutic effect. Clear and known Mechanism of Action has been established. Blarcamesine is a pathblazer for other SIGMAR1 drugs making iself the first of a new class of drugs. This warms considerably the icecold feet of FDA.

Parkinson’s Disease Dementia Addressed

.……which correlated with clinical efficacy as measured by primary cognitive efficacy endpoints, CDR system Continuity of Attention (CoA) (p = 0.029) and CDR system Power of Attention (PoA) (p = 0.015),….

Broad and statistically significant improvements in CDR system Cognitive Domain of Attention assessed by Choice Reaction Time (p = 0.039) and Digital Vigilance (p = 0.008) and CDR system Episodic Memory (p = 0.047), representing complex cognitive tasks with impact on quality of life such as making a choice between similar objects and remembering daily personal experiences, which are mostly impaired in both PD and AD.[15] 
Statistically significant dose-dependent (p = 0.003) improvement of Episodic Memory, which has been shown to be highly correlated (70%) with the Alzheimer’s Disease Assessment Scale–Cognitive score (ADAS-Cog; r = 0.7).

See my previous post on Episodic Memory as was reported initially. link: https://piotrpeterblog.com/2020/12/04/after-conference-of-3rd-of-december-2020-on-alzheimers/ . I have calculated the Effect Size for Episodic Memory which in my reckoning was supposed to be about 1.40. We don’t have and other data than what is given in the quotation. Firstly, CDR is composed from few subtests like Continuity of Attention, Episodic Memory, Choise Reaction Time, Digital Vigilance and Power of Attention. Those subtests measure errors and speed of response. The only metric given here is the p-vales of each subtest. P-values refer to the probability of the results being part of the characteristic dispersion of data among the placebo cohort. The lower the number the better results, or data points are better separated from placebo. They are both statistically significant, with Power of Attention being the best. Nothing more can be said at this moment. This calls for deeper research than done by me at this time, and a separate post.

Did Blarcamesine Put Parkinson’s in Its Bag of Tricks?

I shall not engage in speculation right now. (Just for a moment) Let me quote from the PR.

….and secondary Parkinson’s efficacy endpoints Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)[4], MDS-UPDRS Part III (p = 0.024) and MDS-UPDRS Total (p = 0.038).

Let’s us analyze the MDS-UPDRS test. It consists from 4 parts. I read through the questionnaire and tried to evaluate the maximum score obtainable which equates with scoring the worst on all measures. I can approximate the number of points to be about 230-240. The average Parkinson’s patient in the Phase2 PDD trial scores about ~77 points (1/.189*14.51= 76.8)(at the end of 14 weeks). Quick search revealed this to be about right.

Let us engage in pure speculation. We have the two mean values at 14 weeks and one of the standard deviations. We could explore the possible values for the dosed cohort standard deviation in order to calculate Effect Size for the Blarcamesine as Parkinson’s disease drug.

  • The placebo score is 77+/-32.8
  • Dosed score is 62.5+/-30 (assumed sdandard deviation of +/-30)

The Effect Size @ 14 weeks is 0.45. This is almost enough to approve the drug (minimum) but we would expect this to increase witht the duration of the trial as Blarcamesine Effect Size in progressive neurodegenerative diseases increases with the duration of the dosing. We have to remember that Donezepil was approved with Effect Size of 0.28 after six months of dosing (24 weeks).

Not without a reason, Dr Missling singled out the Part III (p-value of .024) from the MDS-UPDRS Total (p=.038). Part III is the motor examination which loss of is characteristic for the disease. Here, the implication is that patients on Part III score “better” than on measures of dementia and daily living, and the drug is engaging the core etiology of the disease.

Additionally, Blarcamesine improvement has been twice the empirically established cutoff score for spurious improvement of -7.1 points of MDS-UPDRS. We have remember that all this is happening at 14 weeks of dosing. As I previously pointed out, Parkinson’s is a progressing condition so even staying in place makes for larger Effect Size with time. A relatively small Effect Size is due to large size dispersion around a mean. The same reason might be behind the empirical cut-off of -7.1 points as such small difference in between the two mean is not sufficient to separate the two dispersions for any meaningful effect. After pluging the numbers into the formula for Effect Size we arrive with the number of 0.22, which qualitatively is below small. I guess many trials produced somewhere below -7 points only ultimately to disappoint. One might compare it to gravitation and Blarcamesine breaking away from it to leave its pull permanetly.

The Phase2 PDD has given us enough of data to claim that Blarcamesine is not only able to treat Parkinson’s dementia but also Parkinson’s disease itself. The experience with the extension of Phase 2a Alzheimer’s give us confidence that the effect of the drug will not wane with time but might reverse the ravages of the disease.

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Intense Politics of Biogen’s Aduhelm and Companies like Anavex Life Sciences and Annovis. $BIIB $AVXL $ANVS

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor! And I am long $AVXL $ANVS $CRTX FYI

“Phase 4” and Aduhelm

Biogen’s Aduhelm has been approved along the line of pratice in cancer drugs field where barely promissing drugs are allowe to go on with the caveat of phase 4 – post approval verification that the efficay is there when patient numbers are large enough. No wonder that Big Pharma loves this cancer treatment paradigm, test and approve drugs with ever increasing efficay but a long way from cure and be always under patent protection. All with sufficiently high price tag for people who face the stark choice between certain death and possible cure. The Aduhelm label did not limit the drug to carriers of APOEe4e4. It opened the gates for virtual everybody witht the diagnosis. Biogen claims that it needs a decade in order to confirm that the drug works against Alzheimer’s as it claimes. In 3 years there should be undeniable proof that the drug does not work, or works as $BIIB maintains. Due to the dispersion of testing data and outcomes after 3 years there should be sufficient data to determine the efficacy of any Alzheimer’s drug. You can find this information in a paper link: https://pubmed.ncbi.nlm.nih.gov/10404988/. This is a brazen raid on Medicare and by extension the federal budget. The politics around this will become intense. On one side we have Biogen, FDA reputation and lots of free money (see new allies sharing the spoils), on the other side almost dead politics of limited resources as represented by some in the Congress, honest scientists and doctors, perhaps rank and file FDA bureaucrats, may be even federal bureaucracy, and companies like $AVXL and $ANVS. Depending on the pull of one or the other side in this contest of clout the approval of other Alzheimer’s drugs can be either accelerated or delayed, and it is hard to say who will prevail here. I do think that Dr Misslings emphasis on Autism Spectrum Disorders might be a way of advancing Blacamesine forward without relying too much on the Alzheimer’s market alone to creat value as Alzheimer’s Phase 2b/3 slowly comes to its reading of top data.

Rett Syndrome Phase 2 (RS-001) Which was Really Phase 1 Which Turned Almost into Phase 3 $AVXL

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor! And I am long $AVXL $ANVS $CRTX FYI

To start talking about the 15 person dosed cohort in RS-001 Phase 2 one has to get on the subject of the dose right away. At 5mg/daily, it seems that $AVXL thought it was dispencing poison to the girls, when the maximum dose is 50mg/daily. By all accounts, that is only 1/10 of the maximum dose. I am of the impression is that we were really dealing with phase 1 trial turning into phase 2 which might then turn out to be phase 2b/3. Was this by Dr. Missling design or by FDA’s? Nevertheless, we have three trials cascading. Of course, there was a bit of a specious reasoning in what I said. Nevertheless it illustrates the astounding results and the relationship between dose and the results.

The companies PR on the results reads like a scienfific paper on the merits of SIGMAR1 platform not just regular PR with few data points dispersed words of “statistically significant” and “clinically significant”. The earlier analysis of the 6 pharmacokinetics patients seemed to imply slightly higher scores to the RS-001 but they were lacking depth. Link to Post: https://piotrpeterblog.com/2020/12/07/rett-syndrome-data-already-out-anybody-pays-attention/. The extremely low p-values suggest that the probability of these results being just part of dispersion of placebo is very low, if none. Moreover, almost all measures point to improvement over placebo.

Quoting from the PR:

The RSBQ demonstrated balanced improvements across all the instrument’s subscales during the trial period of 7 weeks, including general mood, breathing, hand behavior, repetitive face movements, body rocking, night-time behavior, fear/anxiety, walking/standing.

This is unidirectional change leaving no possibility to some statistical event, or rather what we call a fluke. The most important is the night time behavior. The sufferes of Rett Syndrome often wake up in the night and scream or moan. Sleep belongs to the most underappreciated CNS functions, unless you don’t sleep deeply for two or three nights. Depriving somebody of sleep is a form of torture and can even lead to death. On YouTube one can find the horrific results of Soviet experiment with sleep need-stopping gas. The whole thing reads like a horror story, not a scientific experiment. This anecdote conveys the importance of sleep like no other. Through all the trials of Blarcamesine the thread of sleep quality weaves from one trial to another but never becomes the main story. In RS-001 it becomes salient, for care-givers it is very disruptive of the their lives and the lives of the girls. It testifies to the ability to assuage the suffering of the girls.

I wanted to point to a type in the data and one important point. Let’s see the slide.

in the data for CBI-I those for the dosed with Anavex2-73 the none responders should be marked 15.3% not 60%. Just a remainder but an essential one.

These scales are very subjective. You can see that when you compare CGI-I and RSBQ scales and the resultant numbers of none reponders. CGI-I is completed by medical practitioners. RSBQ consistes with responses from care-givers. The practitioners saw only 2 cases with no improvement whereas the care-givers saw just 5. This discrepancy spreads to the evaluation of those on the placebo arm, practitioners seem more improvements than care-takers. No wonder, paractitioners must rely heavily on memory for assesment, but on the other hand, care-givers will not notice subtle changes as they are easly habituated to them.

Comparing results on RSBQ scale with the pharmacokinetics cohort we see that we have the same fraction of the non-responders as in the previous release of data. we don’t have the initial RSBQ or CBI-I scales to give any percent improvement vs. the initial score. On average, the RSBQ score of a patient with Rett Syndrome is about 45 points. Phamacokinetics cohort specified this at 50 points on RSBQ scale. So we have 29% improvement in just 7 weeks on miniscue dose of 5mg/kg daily.

Though, the number of reponders on ADAMS scale is just 60% of the 15 patients vs. 66% on RSBQ scale the same pattern of unidirectional improvement follows.

ADAMS is 84 point scale, improvement of 12.9 points makes 15.4% of the scale. Usually, the average patients is somewhere on the scale so that improvement starts from there. If it is comparable to RSBQ we couldd have about 27% improvement from the average initial score. Larger Cohen’s d (1.31 vs RSBQ 1.11) suggests even greater improvement from the initial score or lower initial score on severity of Anxiety, Depresion and Mood Scale.

What is important, is that Cohen’s d Effect Size is 1.31 for ADAMS and 1.11 for RSBQ scales. In the land of drug development these are very good number meaning very large and large respectively Effect Sizes. Effect Size ~.50 is considered large enough to warrant an approval.

That is all folks, on a trial named Phase 2 but being more of a phase 1 and turning into phase 3 by Effect Size alone.

SIGMAR1 is a platform, not a drug. Blarcamasine is the first drug interacting with SIGMAR1 receptor. The sigma 1 receptor from an obscure begining has evolved to position of providing explanation to incidence of CNS degenerative diseases as solely connected with its expression and action. That makes sigma 1 receptor to be another player in the etiology wars for AD. The response in AD and PDD happens only with the maximum dose but in Rett Syndrome it appears at just 1/10 of that. If indeed the SIGMAR1 platform drugs are ubiquitous in their actions against CNS diseases, as it can be seen in their abilities to improve patients in AD, PDD and Rett, we might soon be addressing the need for the disease under the umbrella of Autism Disorder Spectrum diseases. Autism Disorder Spectrum might be an concoction, and the underlying etiology might be different for similar phenotypes. I am not stating that this is the case but it is the worst case for disease as it might see diversity of yet not fully known or unknown etiologies. But there is possibility that SIGMAR1 platform drugs can address them.

The arena of AD and PDD is crowded. It is my perception that the ADS field is not that full of competition as AD’s. The numbers of patients and the need might be even larger than AD. The results in Rett Syndrome and soon Fragile X might have ushered the need to raise additionally money as opportunities in ADS field need to be explored.

Moar Beer Money!

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Aduhelm (Aducanumab) Value vs. Its Truly Restricted Market, and The Same for Blarcamesine $BIIB $AVXL

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor! And I am long $AVXL $ANVS $CRTX FYI

Biogen surge of $15bln in market capitalization due to Aduhelm approval does match the restricted market the drug faces. I am taking off where Lane Simonian left without giving any numbers in its latest SeekingAlpha article, link: https://seekingalpha.com/article/4435705-post-biogen-post-amyloid-world-for-alzheimers-disease .

Following Bazilian study looked at the incidence of all allels of the APOE gene in Late-Onset Alzheimer’s Disease (LOAD). Link: https://pubmed.ncbi.nlm.nih.gov/22068907/. This is the table with the distribution of APOE e4 gene in the LOAD population.

The control group lists something like the number of APOE e4e4 people in the general population. It is indeed a miniscule number, but due to its high odds to develop Alzheimer’s the poplution of LOAD sufferes with both e4 alleles is at 13% of all cases. You can expect that discrepancy in the light of odds almoet 14 times larger to develop LOAD than general population.

Annually, about 500,000 new cases of Alzheimer’s are diagnosed. I would add that Aduhelm should not be prescribed to those who a advanced into the disease more than that. This gives 56,000 patients to be dosed at $56,000 a year. Is this any numerlogical coincidence? The revenue from the drug might reach ~$3.16bln. Looking at cool 1/3 going towards the bottom line ~$1.05bln, with 20 P/E ration gives $21bln market capitalization. Indeed prized like an orphane disease.

If the inital success of Blarcamesine in Phase 2a High Concentration Cohort will be replicated and even improved in Phase 2b/3, what can we expect? Let’s make some assumptions; average length of dosing 5 years but we only will consider 1 year, 50% of those diagnosed (50% of 500,000=250,000) on the drug as the drug works on 80% population at the least, annual cost $20,000 (a off the patent generic CNS medication cost about that $8,000/y ) and half the revenue goes to bottom line. $AVXL Market capitalization could reach ~$50bln initially.

This analysis does not involve the idea of all the 50’s old people taking small doese to gaurd against senescence. I have pointed out that there are the three Alzheimer’s epidmics. Those with healthy bodies getting early disease and after 5-10 years dying of Alzheimer’s, those slowly deteriorating due to senescence and those who start deterirating rapidly from low cognition level already (due to age) and dying due to other comorbidity. The incoming evidence in basic research points that SIGMAR1 receptors agonist could tackle the three populations of dementia patients making dementia a rare occurance in later life. You can look at the previous posts on this blog which document the outpouring of possible etiologies of Alzheimer’s, all connected to the SIGMAR1 receptor mecanism of action. If the numbers of patients taking Blarcamesine can be extended to general population the calcuation of the $AVXL bottom line become too spectatula and speculative to ponder even if Congress will put restrictions on drug price .

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Post On “Multi-Targeted Ligands (MTDLs) Binding the SIGMAR1 Receptor as Promising Therapeutics” $AVXL Blarcamesine Anavex3-71

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor! And I am long $AVXL $ANVS $CRTX FYI

The paper of the same title, link here https://www.mdpi.com/1422-0067/22/12/6359 , described number of compounds and their chemistry, among them it mentioned ANAVEX 2-73 and 3-71 as examples of the most studied drugs in the class of MTDLs drugs. It also listed number of other drugs and their targets besides SIGMAR1, touching here on the logic of pain-relief and fighthing cancers which might be connected with the functioning of the Brain Blood Barrier.

There are two types MTDL drugs. Hybrid Drugs which are synthesized from two drugs with “weak bonds” between them to be easly metabolized by the liver producing two metabolites acting on two different receptors. The other type is Chimeric Drugs which are combination of two or more acting domains with strong bonds, acting on two or more receptors. They have better pharmcokinetics and better interaction with the targets.

The paper describes trials at synthesis of such drugs, all working on SIGMAR1 and on other receptors. What is very interesting is that in Mitochondria Associated Membranes where SIGMAR1 protein most likely resides the protein itself occures in oligomer structure. This has very interesting consequences as agonist and antagonist are not clearly defined by binary like action. Agonists tend to lower the number of copies of the protein in these structures more than the antagonists, in very gradual manner from drug to drug. This creates a situation where different agonist and antagonist can have varying therapeutics effect based on the minutia of their chemistry. The therapeutic effect can be dependent on the chemical structure of the drug and be very specific to the drug itself. Quote:

…..the different oligo‐ meric structures could be responsible for the many activities performed by these versatile receptors, with agonists and antagonists differently influencing the association among protomers: agonists produce lower oligomeric structures such as monomers and dimers, while antagonists produce higher ones [29].

There is plethora of very specific to chemistry information, of SIGMAR1 and drug design in this paper.

I want to quote the paper on the location of the SIGMAR1 receptor in human body. This is very interesting as number of organs might be ultimately under the beneficial influence of the SIGMAR1 drugs. Yet, I have to add that these can be either beneficial or harmful.

σ1 Receptors have been found in the central nervous system (CNS), particularly in the granular layer of the olfactory bulb, in many cortical layers, and in the dentate gyrus [6], where they exert their most important activities. A slightly lower expression has been also found in some pyramidal layers of the hippocampus, various hypothalamic nuclei, the septum, the central gray, the motor nuclei of the hindbrain, and the dorsal horn of the spinal cord [6]. At the cellular level, σ1 receptors have been found in ependymocytes, which border the ventricular compartments, and in neurons located within the CNS parenchyma [6].

In peripheral organs, σ1 receptors have been found in the gastrointestinal tract [7], vas deferens [8], in liver and kidney [9], heart [10], adrenal medulla, pituitary, testis, and ovaries [11].

The olfactory bulb referece to the sense of smell. Haven’t we all heard about the peanut butter smell test for Alzheimer’s?

Another quote from the paper.

The neuroprotective action of σ1 receptor agonists is well established, and it has been proved that this activity is exerted through different mechanisms such as intracellular Ca2+ regulation, the prevention of oxidative stress, and anti‐apoptotic effects. The σ1 subtype contributes to protein homeostasis: it can stimulate neurotrophin receptor signaling and reduce protein aggregation responsible for neurodegenerative disease, and it can also ac‐ tivate autophagy as a protective mechanism against damage arisen by misfolded proteins. Recently, many studies proved the ability of σ1 receptors to directly or indirectly interact with receptors or enzymes with key roles in neurodegeneration, particularly in Alz‐ heimer’s disease (AD). Importantly, in patients with AD, a reduction of σ1 receptor density [20] has been demonstrated. Some studies attributed such reduction to the E4 variant of the apolipoprotein E gene (APOE 4) [21], although some controversies still exist [22]. All these mechanisms can promote cell survival and consolidate the role of the σ1 receptor as a target for therapies against neurodegeneration [23].

The key piece of information is that Alzheimer’s patients display reduction in SIGMAR1 incidence in CNS cells. Agonist such as Blarcamesine could stimulate release of the beneficial proteins from the MAM domains to compensate for the lower incidence on SIGMAR1 protein. The other piece of infomation is tentatively connecting this with the APOE e4 gene variant. I have “committed” a post where I stated that APOE e4 carriers were helped by Blarcamesine but I assumed that those 3 which I dentified were drop outs, but they were actually helped and stayed in the trial. We have anecdotal evidence from later data on the 3 year performance of the High Concentration Cohort, keeping 8 out of 9 in the cohort over 3 years time, and Dr. Missling saying that (praphrase) even those with bad genetics can be helped if dosed long enough.

In this particular study in late-onset Alzheimer’s (LOAD) , about 56% are APOE e4 carriers. Those with two copies of e4 are almost 14 times more likely to get AD than the general population. Those with one copy, like e3e4, are 2.33 times more likely. Compare this with 75% carriers in the High Concentration Cohort.

If I am not wrong APOE e4 is the only clear link in genetics to Late-Onset Alzheimer’s Disease. If this connection between APOE e4 and SIGMAR1 is indeed true then there is a clear connection between SIGMAR1 lower incidence and Alzheimer’s. Since the SIGMAR1 covers broad spectrum of physiology, this could be overwhelming evidence that SIGMAR1 agonist and among them Blarcamesine and Anavex3-71 are the Alzheimer’s go to drugs, and not only Alzheimer’s. Most other drugs usually interact with one or few of the compounds SIGMAR1 agonists release.

One of interesting facts, yet of little value for us, is that one of the endogenous ligands to SIGMAR1 is DMT which is a hallucinogen. YouTube is rife with stories of trips taken under the drug. One more quote on the various effects ligands to SIGMAR1 might cause:

Molecular dynamic simulations at the σ1 receptor binding pocket have shown how the diverse chemical structures to which high‐affinity σ1 receptor ligands belong may easily be accommodated producing different associations among pro‐ tomers that lead to the different activities observed.

The therapeutic search for various SIGMAR1 drugs has just started. Number of drugs which had been previously treating other disease have now been connected with SIGMAR1 interactions. A new wave of drugs are synthesized to have the ability to interact with SIGMAR1 and other receptors. Not all of them are going into the clinic but the capabilities of SIGMAR1 are now more than ever recognized as primary therapeutic target.

Both Blarcamesine and ANVEX3-71 are examples of MTDLs as they interact with SIRMAR1 and muscarinic receptors. ANAVEX3-71 has also been known to reduce beta-secretase 1 levels. This might be helpful in treating Lewy Bodies Dementia. Let me again quoote from the paper:

The effect of σ1 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.

In addition to AF710B and ANAVEX 2‐73, Anavex Life Sciences Corp portfolio com‐ prehends an isomer of ANAVEX 2‐73, named ANAVEX 1‐41 (Figure 2) that next to the activity toward σ1 and M1 receptors, also displays activity for α1, 5‐HT2, and D3 receptors [81], with an indication for the treatment of depression, stroke, and neurodegenerative diseases (anavex.com/#!/pipeline).

I have presented here information mostly pertaining to Alzheimer’s and neurodegenerative diseases. SIGMAR1 is also through the method of MTDLs implicated in creation of new drugs fighting pain and drug resistant cancer cells. Next post will be drawing on that theme from the same paper.

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Two Measures of Efficacy in Alzheimer’s Trials. Blarcamesine $AVXL $SAVA $ANVS

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor! And I am long $AVXL $ANVS $CRTX FYI

There are two measures by which go trials of Alzheimer’s/dementia. The most popular and the most expeditious is the average increase/decrease in MMSE or ADAS-Cog points of the dosed cohort vs. the placebo. The other is taking much more time and is probably more telling of the drugs potential. It is the number of dropouts or remaing patients in the dose cohort over time vs. the placebo. Why do I make a statement like this? It is because the average change is scores can be much easier a statistical event (fluke) during the 18 months long trial than the dropout rate during few years of study. Again, I use the information in the reference https://pubmed.ncbi.nlm.nih.gov/10404988/ to make the point. In this study 372 subjects were followed over the natural progresion of the disease from diagnosis to droping out. The event of disappearing from the study rolls was connected with severe disease or natural death, almost exclusively. There was a plot of the changes in MMSE scores in consecutive one year periods. If indeed, the change in a patient was in given year over 10 points then we can reasonably believe that he might become soon a dropout due to severe AD and find himself institutionalized. This rate of those declining 10 or more points MMSE is almost steady during the 6 years of the study. The picture of the disease I see in this graph is that of a disease which accelarates rapidly during the final year in the study leading to removal from the study. Notable is that the first year results do not confirm this phenomenon and as such are the event which confirms the phenomenon taking place later in the study, as the initail scores are still not in the domain of severe Alzheimer’s/dementia leading to dropping out. The average decline in MMSE scores for this study was -3.8 SD +/-4.3. This is visible as the line under the zero MMSE line. The average rate is almost constant. Also remember that a dot stands for score not a patinets and can represent few patients.

The overwhelming efficacy of the drug can be seen in the ability to stop or at least control this phenomenon of rapid and accelerated decline and in effect lowering drop out rate.

In this plot I normalized the 372 subject trial to 32 patients in Phase 2a of Blarcamesine. At 5 years the number of normalized 32 patients dwindle to 5.

During the latest Conference Call Q1 2021, Dr. Missling said that the number of remaing patinets in Open Label Extesion after 5 years is between 10 and 21. Parsing it a bit, any number in between is technicly true now so we were not given an answer but a clever way of confounding us. 10 patients left and we still are much better than placebo from the study. 21 patients might be equally true and we are shining. See my last few post on the possible meaning and interpretation of that data. I shall refrain from further interpratation of the Conference Call statment by Dr. Missling. Hat tip to Tom Bishop from BI Research for asking this question. Does anybody know what BI Research wrote about $AVXL if ever?

Currently not company can boast data that deep and rich as $AVXL. I am waiting for data from $SAVA and $ANVS.

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Is There More than Just Alzheimer’s, Parkinson’s and Rett Syndrome in Blarcamesine Bag of Tricks? $AVXL

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor! And I am long $AVXL $ANVS $CRTX FYI

See press release from Anavex Life Sciences. https://www.anavex.com/anavex-life-sciences-announces-notice-of-allowance-for-u-s-patent-application-anavex2-73-blarcamesine-for-the-treatment-of-cardiac-dysfunctions/

Heart has its own little nervous system which in part is independent from the brain. Blarcamsine as SIGMAR1 agonist does its work as far as we know primarily in the nervous cells. Yet, the SIGMAR1 receptors are expressed in different organs too. I was trying to provide a detailed list but unfortunately it is much harder task than a quick search. Leaving this aside, is there general health advantage to Blarcamsine besides CNS health? We can speculate on this due to the nature of Blarcamesine action on SIGMAR1 receptors as detailed in this post https://piotrpeterblog.com/2021/05/13/1372/ .

To just shortly explain, agonists of SIGMAR1 cause the release of large number of health improving signaling molecures. Is there already evidence that Blarcamesine can alter the general health of those receiving it? I looked at certain data from reference study https://pubmed.ncbi.nlm.nih.gov/10404988/.

I created an illustration and published it two weeks ago without extensive explanation. I am attempting to provide some logic under which I constructed the graph. Let’s see the graph.

  • There are two lines. One (dashed) is for probable Alzheimer’s patients numbers remaing in the reference study over a period of 7 years. The other is the controlled group consiting in 50% of healthy spouses or volunteers reporting every year for check up.
  • Both groups are very similar in make up, the only difference being the probable Alzheimer’s diagnosis. For the Alzheimer’s cohort the reason for no showing up can be deterioratiom due to demantia, death, or general health deterioration. For the controls cohort it can be the same, save the dementia.
  • The number of no-shows is expresed in percent of starting cohort group population still reporting. 32 patients in Phase 2a study is consitent with the minimal sample of a general population. The reference study used about 300-400 participants to arrive at these plots.
  • The first year Phase 2a loses more patients than the reference study so arrow is red and pointing down.
  • The second year, the phase 2a numbers are comparing favorably with the precentages of participants staying with Alzheimer’s staying in the study so arrow points up and is green.
  • By third year the patients from the phase 2a study are in the Open Label Extension for two years. The procentage of popluation of Phase2a OLE still within the study seems to emulate the population of the healthy cohort in the reference study. Can we state that the morbidity due to Alzheimer’s has been removed from the Phase 2a participants?
  • We do not have data for the 4th year of the study.
  • We now reach the 5th year of the study. In the statement by Dr. Missling the number of patients within the study has been set between 10 and 21. With 10 patients we “remove morbidity due to Alzheimer’s”, but with more than 10 patients left with the study the implication is that the general health of the patients improved over the level of those participating in the healthy controls cohort of the reference study.
  • Caveat: The Phase 2a study has not been designed to answer this question. Neither, we know for sure the doses received by the patinets in the OLE extension.
  • A word of caution, this is a very creative way at looking at the data but the word “creative” has as on its other side the meaning of something unbecoming. This is just an excersize in free style data analysis. I could be close to the truth or can be way off, so please take it with grain of salt.

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