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 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 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 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 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 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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Implications of Soon to Be Resealed 5 year Data on Extension of Blarcamesine Phase2a for Alzheimer’s in One Chart. $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 FYI

See this post first…. https://piotrpeterblog.com/2021/05/18/morbidity-and-disability-in-phase-2a-alzheimers-study-of-blarcamsine-vs-background-morbidity-in-similar-age-control-group-avxl/

Now to the Chart.

I will be on a 12 days vacations so might not post anything so I need a more beer money ….
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Who is Following Whose Success? $SAVA $ANVS $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 FYI

$SAVA Success Wave Lifting All Boats

The released $SAVA data brought about a wave of investment and renewed vigour to investing into smaller Alzheimer’s narratives. When most of the news is just shadowing the declines and any number above the initail score is reason for hope. A couple of things are transpiring among the companies searching for Alzheimer’s drugs. One, and the most impoortant is that most of them focused on MCI (Mild Cognitive Impairment) patients with MMSE scores 25 or ADAS-Cog11 15. This is a big departure from looking into average score of 21 MMSE points as it was done by $AVXL 5 years ago. It was learned the hard way that Mild to Moderate Alzheimer’s patient (16-25 MMSE) do not respond readily to experimental drugs as it was expected. For $AVXL drug Blarcamesine the cut-off MMSE score is 20. In the words of Dr Missling $AVXL “can rescue anybody over 20 MMSE”. That is now lowest the MMSE score that responds to an experimental drug. All late comers are treating those with average scores of MMSE scores 25 or ADAS-Cog11 15. As Alzheimer’s is neurodegenerative disease the relatively advanced disease can preclude a successful rescue of a patient or even possibility of stabilizing him. The other thing happening is massive outpouring of half-baked efficay data.

Here, we will strive to compare results from 3 companies $SAVA, $ANVS and $AVXL. Sometimes these are akin to oranges and sometimes apples and oranges.

The most fair comparision might be between $SAVA and $ANVS. Both treated MCI patients, the former up to 6 months the latter just 25 days. The narratives used by the companies differ but ultimatetly they are derived from the Amyloid plaque theory of AD. In my conviction both aim for limiting neuroinflammation notwithstanding their narratives. Though more widly touted, $SAVA presented less of improvement than the rapid results of $ANVS ANVS401. $SAVA over 6 months improved the patients cognition just by -1.6 ADAS-Cog11 points (negative values on this scale indicates improvement). Starting from similar conditions ANVS401 lowered the ADAS-Cog11 score by -3.3 in just 25 days (adjusted for placebo). In such short period of time the problem becomes the dispersion of the test data due to “statistical events” or chances of scoring higher even if the cognition objectively moves in any possible direction. The difference from initial condition was -4.4 ADAS-Cog11. The p-value went from p=.04 for initial scores to p=.13 indicating that some results could have been no different than the dispersion about placebo mean.

Let’s See How The Biomarkers Look for Both of Our Contenders

We can only directely compare A-beta42, Tau, p-Tau and YKL-40. If all those are undesirable then the winner hands down is $ANVS. ANVS401 pratically removes those from the brain. YKL-40 level indicates that neuroinflammation is practically gone. ANVS401 is supposed to lower the production of A-beta precursor APP by 60%. The mechanism of action has not been expained by $ANVS sufficiently well to come to definitive conclusions what the drug really does. Nevertheless is astoundingly effective in putting down neuroinflammation during the short span of time. I thought that all those drugs putting down inflammation will have middling results but ANVS401 does the real job on this front. This is compatible with the experiments conducted by one doctor who injected anti-inflammatory drug into neck portion of spine and the lowered the patients head down to have the drug migrate into the brain. The results were in just hours, with “fog lifting” as described by patients. Unfortunatelly, he was censured by FDA and videos were removed.

Looking into $AVXL and $ANVS as Synergistic Apples and Oranges

It is very hard to compare the above companies to $AVXL as it dosed the Middle and Moderate Alzheimer’s patients and not just MCI only. Nevertheless $AVXL scored great success with those who were on average MMSE = 23 or ADAS-Cog11 = 17. These aptients in just 5 weeks (35days) scored improvement of 1.2 MMSE or ADAS-Cogs11 -2.8, in 57 weeks this was 2 MMSE or ADAS-Cog11 -4.7 and finaly in 70 weeks 3 MMSE or ADAS-Cog11 -7.0.

ANVS401 shuts down neuroinflammation and Blarcamesine does on one hand the same but on the other hand it rejuvenates ( post [1] ) the neurons with possibly reversing the neurodegeneration described in post [2]. ANVS401 will probably have a quick action with a plateau whereas Blarcamesine will deliver consistent increases of cognition scores over longer period of time. These two drugs and will work in synergy.

$SAVA is no longer therapeutically relevant!

Bibliography

[1] SIGMAR1 Agonists – Therapeutic Swiss Army Knives $AVXL, Prilenia Therapeutics, $ATHA, $ALKS, $SAVA https://piotrpeterblog.com/2021/05/13/1372/

[2] https://piotrpeterblog.com/2021/03/05/novel-etiology-of-alzheimers-linked-to-neuronal-loss-of-function-due-to-changes-in-cellular-transcription-mechanism-and-dna-chromatin-complex-avxl-sava-atha-biib/

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The Alzheimer’s Etiology Wars! $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 FYI

A Battle in Etiology Wars!

The most prevalent hypothesis of the etiologies of Alzheimer’s disease is the A-Beta Amyloid deposits theory.  The theory has been evolving into few branches.  One of them states that there is production of A-beta in the axions of neurons in response to stress and the toxicity of A-beta works its way from axions to the whole neurons.  This evokes the problems of axonal transport with all its complexity, involving among others the A-beta deposits interference with the process of transport, autophagy and mitochondrial health.  Just to mention the most prominent ones, without talking in detail on the mechanism.  I refering here to paper titled

[1] Axonal generation of amyloid-b from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes link: https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00473-3


The precursor protein to production of A-beta is called APP. In the case of axion production of A-beta this compound gets palmitoylated that is another chain of a compound is attached to APP, since then it is referred as palAPP.  This is done to differentiate it from the A-beta produced from APP by the center body of the neuron, that is without being palmitoylated.  The researchers asks how they can control the production of A-beta by axions, as in their view that is what precedes axion swelling, indicating the onset of Alzheimer’s disease in vitro, and implied to be connected with axonal transport interference. Interrupting the production palAPP becomes in their eyes a therapeutic target. In a further explanation, palAPP is attached to the lipid rich outer cell membrane where the Mitochondria Associated Membrane (MAM) of Endoplasmic Reticulum comes into contact with the former.  As it can be seen in the illustration, the sheer number of MAM’s is connected with the increased occurrence of palAPP sticking from the cel membrane where the A-beta is cleaved off the palAPP chain by Beta-secretase to create the A-beta deposits in the extracellular  space.  These deposits of A-beta are blamed for toxicity which ultimately kills neurons starting with axions swelling. 

Literature provided few observations. First, that intra axonal A-beta is generated ahead of extracellular A-beta when axions are under stress. Would it mean that axions are the first under stress? The genetic degeneration which was described in the post (link: [2] https://piotrpeterblog.com/2021/03/05/novel-etiology-of-alzheimers-linked-to-neuronal-loss-of-function-due-to-changes-in-cellular-transcription-mechanism-and-dna-chromatin-complex-avxl-sava-atha-biib/ [2]) starts with the lack of trascription of the protein neccesary for the axions to function and atrophy of axions sets in. Nevertheless, the quantity of palAPP is just 20% of APP total created in the model of FAD (mutation) Human Neural Progenitor Cell. FAD stands here for familial AD. In healthy neurons ~40% of A-beta comes from axions so the 20% in FAD model of Alzheimer’s disease seems like changing the nature of the ratio. In grand picture of the disease this should not stand as the most importan source of A-beta. Should we think that the placement of pal APP in the axions matters? Again, the question of axonal trasport.

 If we connect this fact with turning on the cellular stress response mechanism and so increased transcription of the SIGMAR1 gene into the protein so that MAM’s population increases with the associated increase in palAPP on the cell walls then we have an explanation tying A-Beta etiology with function of SIGMAR1. I am only speculating here, all in the light of the information from the paper. In this scenario A-beta is part of the stress copying mechanism of axons and neurons.  Also another observation is that, Amyloid deposits decrease when A-beta generation moves from axions to body of the cell, and 70% of palAPP is concentrated in MAM’s. So if you fault the axions for production of palAPP and connected it with the occurrence in axions of MAM’s then if can you control the quantity of MAM’s you can lower the production of A-beta. This reasoning is only valid if you fault A-beta alone for the damage.  Here, enter our friend SIGMAR1 protein, which is associated with the creation of MAM’s on the surface of Endoplasmic Reticulum.  The researchers silenced the production of SIGMAR1 protein and after 48 hours halved the production of SIGMAR1 protein.  But what is more interesting for us, in 72 hours of  silencing SIGMAR1 production to the level of 10% remaining cells became none-responding to viability tests, they became zombies.   Further on, researchers used agonist/antagonist pair to double or halved the number of MAM’s with resulting production of palAPP.   SIGMAR1 is not yet here, a therapeutic target per se, but rather a tool to control palAPP through MAM population. Nevertheless, agonist to SIGMAR1 increased production of axonal A-beta40 vs. none made when antagonist where used, but that was in vitro so systemwide assessment is missing. How relevant this is?  We will give a tentaive answer at thee end of this post.

I want to quote here the paper.

The degree of dementia in AD is primarily correlated with loss of synapses. Synaptic dysfunction, preceded by reduced syn- aptic transmission and loss of dendritic spines, is largely driven by neurotoxic Ab42-oligomers (Cleary et al., 2005; Haass and Selkoe, 2007). Physiological levels of Ab42-oligomers have also been shown to suppress long-term potentiation (LTP) in hippocampal slices (Mango et al., 2019). In contrast, Ab in the picomolar range has also been shown to be required for LTP in- duction (Koppensteiner et al., 2016). 

I would like to stress here that the last sentence in this quotation bring the chickens to roost home.   Mostly in medicine, total removal of any compound can be detrimental so does the same applies to A-beta?  A-beta has its function in spite the fact that its currently blamed for the onset of the disease. It sure, is not toxic in small concentrations as the quote suggests. Well, your long term memory needs it. Besides the produced A-beta was A-beta40 not the most toxic A-beta42.  The other fact is that the interruption in axonal production of A-beta did not lower the total APP and A-Beta production in the 3D in-vitro model of Alzheimer’s disease. 

Scientific papers are not written in an objective manner.  From the onset they presuppose some approach that is tested in the papers.  In biology where the vastness of sheer number of connections overwhelms human cognition one has to go one step at a time.  There is number of competing views on Alzheimer’s and not all of them can be correct.  There, lies the root of the cause of 10 drugs out of 11 tried failing.  Papers can be convincing but the final word is with the clinical trials and the progress the patients make.  

Researchers face a dilemma, they can lower palAPP at the cost of silencing SIGMAR1 that ultimately makes cells not viable, in vitro.  If the cost of therapy is so defined as endangering the cells viability, they restore to hinting at “MAM deregulation” as a probable cause of axonal A-beta production leading to axon swelling. In the context of the paper I postulate that the as the axons become under stress they turn on their stress fighting mechanism and the increased transcription of SIGMAR1 gene leads to among others heightened production of palAPP as part of the copying mechanism.  Yet, few fold production of A-beta might interfere with axonal transport for example. This scenario makes sense in the face of few voices claiming that A-beta’s toxicity is part of infection fighting mechanism of the brain.  It  even turned out be toxic to brain tumors cells, but overproduced can be toxic to the whole brain.

From the years long results of dosing Blarcamesine, the stress fighting and neurotrophic factors released from MAM’s by the action of the agonist (see my previous post link: https://piotrpeterblog.com/2021/05/13/1372/   ) ultimately restore neuronal health. 

Search of Drugs to Lower palAPP Production

Though the researches make a point that SIGMAR1 antagonist could be used to control palAPP and axonal A-beta other target gets their attention, and I can directly quote them.


We and others have previously shown that the loss or inhibition of the MAM-resident enzyme acyl-co-enzyme A:ACAT reduces cell surface localization of APP and Ab genera- tion (Huttunen et al., 2009; Bhattacharyya and Kovacs, 2010; Murphy et al., 2013). More recently, we showed that inhibition of ACAT reduces palAPP in lipid-rafts by ~76%, in vitro (Bhatta- charyya et al., 2013). Palmitoylation inhibitors 2-bromopalmitate and cerulenin also reduced palAPP level and Ab generation in vitro (Bhattacharyya et al., 20 .  

The inhibitors for A:ACAT  already exist and are  being involved in treating atherosclerosis  due to their connection to cholesterol theory.  From short search I think that these drugs have been tested in animal models for  a decade, and as far as I searched it did not yield a drug which phase 3 onto market in both atherosclerosis and AD.  It seems to be a dead end. 

Possible Scenarios Implied by Paper [1]

  • In response to cellular stress SIGMAR1 gene is transcribed in larger amounts
  • The increased SIGMAR1 protein leads to more MAM microdomains
  • This leads to increased production palAPP in axions and larger amounts of A-beta is created
  • A-beta toxicity affects axonal transport affecting viability of neurons, and or lead to axonal swelling
  • Enter Blarcamesine: a SIGMAR1 agonists releases stored in MAM neurotrophic and cellular health compound
  • The consequenses of A-beta toxicity are reversed by these compounds
  • Patients score higher on congnition test and maintain their scores

Possible Scenarios Implied by Papers [1] and [2]

  • Epigenetic change deprives axions of the neccesery protein to build viable synapses and stresses them
  • SIGMAR1 transcription increases in stressed axons especially increasing production of palAPP
  • Overproduction of A-beta beccomes toxic to neurons in synergy with epigenetic degeneration
  • Enter Blarcamesine: a SIGMAR1 agonist releasing stored in MAM neurotropic and cellular health compounds
  • The consequenses of A-beta toxicity are reversed by these compounds
  • Patients score higher on congnition test and maintain their scores

Possible Synergy with ANNOVIS $ANVS Pophisen ANVS401?

Not much is known about the Mechanism of Action of the ANVS401. The only metric released was that 60% of production of APP total is taken out of the line, so to speak. The drug does not affect the RNA for synthesis but somewhere breaks the chain of events leading to the fully folded APP. The narrative touted by ANNOVIS is improved axonal transport. Alzheimer’s disease has number of scenarios where some aspect of cellular physiology can be visibly disrupted. Reseachers “marry” certain faults and spend years pursuing them in hopes of finding the underlying cause of the disease. Hat tip to their tedious and arduous work. Nevertheless, for investors what carrier the water is a good narrative limiting the scope of the disease to single fault being fixed with particular drug.

The link to the press release is here. https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=364451b1-06a7-4b96-a389-016f3ef3e6e3

The information on https://clinicaltrials.gov/ # NCT04524351

First let us consider the average MMSE and ADAS-Cog11 of the 14 early Alzheimer’s and Parkinson’s patients. 30% improvement with delta=-4.4 ADAS-Cog11 and 22% improvement with delta=-3.3 ADAS-Cog11 gives consistent reading of 15 ADAS-Cog11 points average starting score. On more familiar MMSE scale, that is equivalent of 25 points. All that is inspite the eligibility criteria of MMSE 18-28 points on clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT04524351?term=ANNOVIS&draw=2&rank=1

I have noticed that very consequently new trials in AD and PD sphere are enrolling subjects with earlier disease as it is easier to get a response from them. And no wonder, since hundreds of trials produced unremerkable results when the inclusion criteria are really MMSE 18-25. The down side of this trend will be visible in just few lines of text.

Patients improving -4.4 points on ADAS-Cog11 scale when compared to initial positions are achieving p-values p=.04. So measured against itself there is 4% chance that the data is result of statistical event and not workings of the drug in just 25 days. Isn’t p=.04 asking for some measure of randomness when measured against itself?

But when we compare these results to the placebo arm then this chance becomes 13%. The explanation of this discrepancy lies in the fact that dispersions about the average for the placebo and the dosed are a bit more indistinguishable. So versus placebo, there is the loss of the “statistically significant”.

Though the MMSE scores were collected, as well as ADAS-Cog11, by their nature they are less sensitive in this range and the company might be less prone to release them. Don’t get me wrong. Many companies recently have been releasing data from early phase2’s with just a handful of patients and after 30 days of dosing produces impressive numbers in some less known measure. I am being a bit facetious. ANVS401 is the first drug following A-beta deposit etiology and scoring high improvement rates in a short period of time.

I have been writing that the etiology of A-beta deposits is transitioning to inflammation narrative. The same etiology here lives under the narrative of axonal transportation. Would that be the more appropriate narrative for A-beta etiology?

I have also written that 30% patients diseased with Alzheimer’s diagnosis have no deposits of A-beta plaque (amyloid). Would Alzhimer’s be a syndrome, not a disease? We live in exiting times….

Writing is hard work, reward it with a beer…

Yet, for those who believe, could you just put a short parayer for me…….

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Morbidity and Disability in Phase 2a Alzheimer’s Study of Blarcamsine vs. Background Morbidity in Similar Age Control Group $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 FYI

I would like to add some additional information to the previously presented analysis on the dropout rate after 5 years. Though the number of remaing subjects in the Phase2a OLE and Humanitarian Extension is rather imprecise as Dr. Missling put it between 21 and 10, I used as reference paper titled

Variability in Annual Mini-Mental State Examination Score in Patients With Probable Alzheimer DiseaseA Clinical Perspective of Data From the Consortium to Establish a Registry for Alzheimer’s Disease

Christopher M. Clark, MDLianne Sheppard, PhDGerda G. Fillenbaum, PhDet alDouglas Galasko, MDJohn C. Morris, MDElizabeth Koss, PhDRichard Mohs, PhDAlbert Heyman, MD; and the CERAD Investigators

link: https://pubmed.ncbi.nlm.nih.gov/10404988/

Complex Picture of Age, Comorbidity, MMSE Test Sensitivity and Dispersion of Test Results

The paper contains an interesting graph as it represents the MMSE scores difference for patients at the end of the last year of given patient in the study. The line through the distribution of scores is the average decline per year.

What conclutions I draw from this graph?

First Year: The dispersion is the highest, most are scoring well below the initial scores and minority showing miraclously improvement. This was confirmed on the patients map for Phase2a as low to medium concentration cohorts followed this pattern of dispersion and the average rate of decline.

On subsequent years the dispersion tightens as well as the rate of average decline approaches with years = -3.4 +/-2.8. Also the frequency of miraculous test scores above initial scores falls precipitously. By year 5 there is nobody who scores above the initial score. There is also dying out of the patients as median age is 71 years old and average MMSE initial score was ~ 20. So the least healthy, both cognitevely and physically either die out or drop out. Age had a definitive influence on the average decline for given starting age. Quotation from the paper:

The MMSE score declined by an average of 3.41 points per year (P<.001) at age 71 years. Age had a statistically significant impact, with a 0.06-point-per-year (P<.001) additional decline for every year greater than 71 or a corresponding reduction in the rate of decline for every year less than 71. Sex had no significant effect (P=.43).

So on average if subject is 55 of age the anual decline is =-2.4, but at age 85 it is = -4.2. It seems as the older subjects die out the younger stay in the study.

I have been thinking how to measure the performance of Blarcamesine in this complex situation, where age, inital score, dropouts due to comorbidity and dropouts due to low MMSE scores can not be fully untangled or separated from the picture painted by the given data. Add to that a small sample size and you have gotten more than you can chew. I think that I found an alternative measure.

The paper had two cohorts. One was the people with probable Alzheimer’s diagnosis and the other was a control group of the same composition but cognitively healthy. Figure 1 shows the dwindling number of both groups over time.

Nothing is perfect in this picture, but it seems that by that measure Blarcamesine brings the morbidity very close to the background morbidity and disability experienced by the healthy controls. This is in some sense comparable as the study in the paper had recruited people from age 50 and up and average age being 71. Anavex recruited from ages 55 to 85, and used score from 14 to 24, if I am correct. The above study scored ranged from 10 to 24 MMSE.

Due to the advanced age of the subjects this comparison makes more sence than just looking at absolute numbers of survivors. In the study we can not separate death from disability due to very low MMSE scores, as both produced droping out of the study. I hope that similar situation was present in the Phase2a trial.

I do not know wwhether my analysis has any validity. The voices which want the dosing to be moved toward less progressed patients might indeed bring the morbidity of those who succumb to Alzheimer’s near those experienced by the cognitively healthy.

Now, give me a beer……

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Anavex Life Sciences Alzheimer’s Phase2a Dropout in Light of Info from Conference Call Q1 2021 Blarcamesine $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 FYI

On the 13th of May 2021, Dr Missling had conference call on the Q1 2021 results. The call was very brief but the questions from analysts were more detailed and aimed at elucidating future prospects of the company.

One was of interest to me over immediate promises. Namely, question about dropout rate in Phase2a Alzheimer’s study over the 5 years.

I have written about the dementia epdemiology and the dropout rate among Alzheimer’s patients in particular. link: https://piotrpeterblog.com/2021/04/11/the-ideal-dementia-drug-and-dementia-patients-population/ , link: https://piotrpeterblog.com/2021/03/20/can-blarcamesine-rescue-those-above-mmse-20-with-alzheimers-avxl-blarcamesine/ .

The Eligibility Criteria called for adults between 55 years and 85 years. This range covers Alzheimer’s of 85 years old patient to statistically last only 2 years to live to be cut short by comorbidity, and 55 years old otherwise healthy succumbing to Alzheimer’s dementia for the next 10 years till he dies of it. Sample with 32 patients is very sensitive to these varations so the data can be taken to be interpreted both ways. later we see that a suprising picture is emerging.

I have normalized the results of over 400 subjects study of natural run of the disease to 32 patient sample size. All this was done was to compare the amout of dropout in Phase2a Alzheimer’s and the reference link: https://pubmed.ncbi.nlm.nih.gov/10404988/ . I included the possible outcomes of 10, 15 and 21 patients left in the OLE and the Humanitarian Examption all counting on 5 years.

It is very hard to say anything specific here. We are not privy to the detailed data on all the patients. Dr. Missling has revealed that the drug works best on people who have not deteriorated below 20 MMSE points. 6 patients intially responded strongly to the drug. Later 4 responded strongly with 2 deteriorating much slower. Most of the death with dementia are due to comorbidity. Statistically, raw dropout rate give us an indication that Blarcamesine is doing better than “natural” progression of the disease but the situation is so complex that nothig can be said with any certainty. But then again, let’s look at the first year (57 weeks data for MMSE scores) results.

I made the calculations for three separate groups of patients. What is initialy visible is that;

  1. 4 patients with average MMSE score = 23 increased score by 3.5 points with narrow SD +/-0.7
  2. 4 patients with possible average MMSE score = 19 deteriorate -4.1 MMSE points/y the rate of 184% of ADNI model and wide SD of +/-3.2
  3. 15 patients detriorated even faster -5.3 +/-2.4 MMSE points/y 240% of ADNI rate -2.2 MMSE points/y. Yet the dispersion is smaller than in case of patients in point 2.

Let’s put in equaly importan piece of information. The APOE e4 gene distribution.

What puzzles me is that most of the patients are deteriorating double the rate ADNI synthetic placebo. If this continues then soon may be that many of these patients will die with very low MMSE scores. Either the large portion of Phase2a subjects were very old or deteriorated rapidly double the rate of ADNI synthetic placebo. In period of 5 years this can make a big difference. Taking into consideration APOE e4 distribution, and the double rate even the low number of 10 patients remaining after 5 years is Big Big Number.

There has been other statement from Dr. Missling who said that over time even those who do not initially respond to Blarcamesine start responding over longer time frame. The first year brings very high number of dropouts as if the population would be “very sick” then next 2 years the dropouts beat the normalized curve on slope first than on absolute number of patients still in program. This result holds for the next 2 years to total of 5 years.

My take on the Conference Call. People are concenrned about the data, but not the data itself but the timely data release. The data release might be done allright, but the research organization might drag its feet. Dr. Missling might have been very optimistic and enthusiastic over the data but the research organization might be not be keeping its inintial deadline.

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