Measures of Dementia in Alzheimer’s and Their Distortion of Trial Results $AVXL $LLY Blarcamesine Donanemab

I have been asked about different measures of dementia and their impact on the trials. There are two basic aspects of these measures and dementia.

  • There is the innate to human cognition nature of deterioration resulting in greater or lesser progress to an observer.
  • There is the sensitivity of type and mix of measures build into a test tasks, or selected to create the composite score expressing the amount of deterioration

Mini-Mental State Examination on average has such plot for Alzheimer’s sufferes. In the pursuit of ideal measure DSRS has been created as it strives to produce straight line from MMSE 20 to 7. [3]

That is prospective decline from MMSE 17 points initial position to zero for an average patient.

Another illustration presents the respective scales relationship between 30 and 19 MMSE. [1]

Notice that MMSE scale is very insensitive at the almost healthy 30 points scale having a ceiling effect, that is early demantia, but is doing much better at 19 MMES vs. ADAS-Cog and CDR-SOB at this interval. The best to sense changes in early stages of dementia is ADAS-Cog and it is reasonable at 19 MMSE. The illustration of the relationship of these scales is in itself suspect of bias as the x-axis “Cognitive dysfunction” calls for its own criteria which is doubtful to be just entirely objective.

Some measures are questinnaires to be filled by care givers or doctors like CDR-SOB other are tests like ADAS-Cog or MMSE. At different points in patient deterioration they will have varing difficulties with relating the progress of the disease as the cognition is heterogeneous and each individual might follow a slightly differnt pattern. There are even problems with repeatibility as results taken few days apart might not be the same.

Depending on the movement of patients on these scales different values of Effect Size will be calculated. Effect Size Cohen’s d calculations need only the means and standard deviations. So it looks how the means are separated from each other and whether the distributions don’t overlap each other.

The p value in statistical parlance means that if you run the sample size experiment you have to get a p*100% chance to get it wrong, that is at least in the layman terms. Once this is below 5% chance of getting the difference between the drug and placebo as nonexistant due to random effects it is called statistically significant. The calculations take into consideration the distribution of data points and sample size.

Anavex posted the results for the 148 week OLE extension of the phase 2a trial. Assuming that the bars are standard deviations I calculated following Effect Sizes from the data.

Can these disparities between Effect Sizes be placed squarely on the shoulders of scale sensitivities? I do not know. One is certain that these things are real hard to assess as there is no completely objective measure of cognitive deterioration of people with Alzheimer’s or dementia. The large Effect Sizes are a bit concerning to me as to their authenticity but they follow the assumption of the bars being SD (standard deviations). I guess I must be doing somethig wrong or this is just insane efficacy. LOL

The trials are run against placebo. But if the sensitivity is varying along the path of progress or deterioration the picture is somewhat distorted. A solution could be to select few measures which complement each other. This can run foul of the accepted till now standards or the limited resourse a small biotech can expand on the trial. another solution could be to run all drugs on standard set of measures so that distortions are equivalent from trial to trial. But even this has it down side as different trials with cover varing parts of the scales. An example is trial by Anavex where MMSE hits ceiling effect with patients actually recovering and $LLY Donanemab trial where patients are deteriorating so close to placebo that the theory that one’s runs against placebo makes this to be the case where the distortions are equal in both arms is close to valid.

When Anavex run the phase 2 trial of PDD (Parkinson’s Disease Dementia) it used the CDR-CA (computerized assesment). As I said we have for most no objective measure of dererioration and all we can do is to compare between them and design ever better ones more inclusive but then they become extensive. Here are some results of comparison of MMSE, ADAS-Cog and components of CDR-CA. [2]

Ss you can see for the scores of MMSE 27-30 that the ADAS-Cog can actualy show improvement which is just another way of saying that it can detect improvement where MMSE can not find any. CDR-CA is correlated to AD but mostly used for PD as it measures also time delay in psychomotor skills and memory. The shortcomings of this measure vs. MMSE is exclusion of certain languge skills. One can see that it is most sensitive between 26 to 21 MMSE points. So follows ADAS-Cog. Both ADAS-Cog and CDR-CD lose their sensitivity below MMSE 20 points. I am speaking here of sensitivity but I am not able to distinguish it from the acceleration and deceleration in deterioration as percieved by humans. Nevertheless this graph confirms the information contained in the second plot in this post.

Here is a graph representing detrioration over some period of time in group of patients dosed with different SOC Alzheimer’s drugs which in general have a similar performance. The components of CDR-CA are enclosed in a box. They probably are going to be weighted to give a final score. In a sense all these measures are very close. Nevertheless ADAS-Cog is just 70% of MMSE score on the same deterioration but if the dosed arm does not move to different regime on the scale the distortion is minimal but the point is to have the drug to do precisely this thing. In case of Anavex2-73 phase 2a trial this was introducing uncertainty as MMSE scores lacked the sensitivity to pick up changes from the 4 patients who in general seemed to beat the odds and recovered from the disease.

Bibliography

[1] link https://www.tandfonline.com/doi/abs/10.1080/13854046.2015.1119312?journalCode=ntcn20

[2] link https://europepmc.org/article/MED/20047570

[3] link https://pubmed.ncbi.nlm.nih.gov/19812470/

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Cortexyme and The Brave New Ideas in Alzheimer’s Drugs. $CRTX $SAVA $ATHA $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.

In the list of the banes of our brains neuroinflammation has its lion’s share. Indeed, only the Amyloid plaque can compete with it on cenceptual level in medicine nowadays. This ancient way of defending multicellular organisms from harm and infection can easly turn into the damage itself. Similarly, the probable etiology of Alzheimer’s can be traced to the infection of brains by the ubiquitous Porphyromonas gingivalis, this is the position of some researchers and $CRTX. I said “ubiquitous” since 65 million Americans are affected by P. gingivalis. The story gets even more twisted as many other bacteria are involved in gingivitis. From the statistical point of view the occurance of gingivitis is not a done deal for Alzheimer’s since 5 million of Alzheimer’s patients give ratio 1:13 to gingivitis sufferes, but this you can blame on the immensely intricate relationship between the host and the bacterium just like with the gut bacteria. And this can be two way street from bacterium to the disease and from Alzheimer’s innate neuroinflammaton to bacterium infection. Researchers looking into the causes of Alzheimer’s make this statistical connection and look only at this as a one way street. But I wonder, whether anybody looked for the bacteria in brains of people not affected by dementia?

Cortexyme has as its therapeutic target the Porphyromonas gingivalis secreted Gingipain (protease virulence factor) which the company in its presentation does not explained what its function to the bacterium is. Nevertheless this substance Cortexyme claimes is linked to Amyloid plaque/Tau deposits in the brain of mice introduced to the bacterium.

Since, some time ago an epidemiological link has been established between ginvivatis and Alzheimer’s the number of papers around this subject has grown giving Cortexyme reasonable confidence in the pursuit of physiology of Porphyromonas gingivalis as therapeutic target. They presented it in very compelling slide on their March 2021 Corprate Presentation.

Let us turn our attention to mouse models (murine). There is indeed strong evidence in the murine models. Playing here a devil’s advocate I can point out that as the cancer scientists quip, “we have cured the cancer in mice long time ago”. All these model are a bit artificial as in the case of gingivitis the bacterial load can be overwhelming to the mouse system just like anthrax can be to human beings. Humans rarely get infected with anthrax but if enough anthrax spors get into our lungs we might die from anthrax infection.

What is interesting is that 22 weeks corresponds to 5 months, which is a similar amount of time into the life of the 3xTg mouse model when first signs of cognitive deterioration appear. The other argument which I can make that there might be more to it than just gingivitis leading into Alzheimer’s is that only 90% of Alzheimer’s patients have the bacterium in the brain. On one hand all it could be that EOFAD (early onset familial AD) don’t and the sporadic form LOAD (late onset AD) is the 90%, on the other the 10% exception might mean that it is a secondary infection, just like the 30% of Alzheimer’s diagnosis do not carry into having Amyloid plaque post mortem. Dementia in general might be much more complex than we can imagine it yet.

Having cast so much doubt in the Cortexyme therapetic target it is now time to turn to the expaloratory phase 1b trial results of Cortexyme Atuzagistat COR388.

Just 9 patients divided into 6 dosed cohort with 3 placebo. The placebo cohort of 3 is kind of riduculous but the p value lower than .05 on the languge measure is astounding. The MMSE is irrelevent with that few participants in that time span, so is CANTAB. The Winterlight Lab is sepcializing in software which picks up the differences in languge usage of elderly people in order to determine whether they succumb to dementia. The entire description given to the results is “Winterlight Assesment Prepositions & Conjuctions”. From my own experience I realize that use of such is indeed connected with the incidence of dementia but on the other hand this is just a part of the whole cognitive landscape. The Effect Size of 3.6 given to this measure outcome might much more be dependent on the scale itself as the placebo stays on the same level during this ultra short period of 30 days of dosing. Much needed comparison with other standard measures is lacking. This astounding result in languge analysis might be the mouse that roared or the real McCoy. Simialr testimonials to sudden recovery from Alzheimer’s related drugs can be seen on YouTube. One involved a doctor making injection into neck’s spinal cord of anti-inflammatory drug and then tilting the patients so that the drug would flow into their brains. The effect was immediate and patients testimonial were drawing an image of mental fog receding. He was sactioned by FDA as the proceedure was deemed unsafe, and the video was removed. Another one involved the drug Anavex2-73 (Blarcamesine) and was made by Australian television. Link: https://youtu.be/hZEVSxLQbbk . Recoveries in just days are not uncommon in Alzheimer’s Bold New Ideas drugs trials ($AVXL (5 weeks), $ATHA (8 days), and $SAVA (28 days)) the real problem is will the recoveries hold for years, and the other is that all those four, including $CRTX (28 days), have different measures to jump start their respective therapeutic promises for the afflicted and the investors. The closest to revealing its full potential is $AVXl with Blarcamesine (Anavex2-73). The phase 2a has been extended to 148 weeks with following results.

If we align all these Companies along the line of distancing them from the pure Amyloid removal therapetic target of let’s say $LLY $BIIB we get: $SAVA, $CRTX, $ATHA and $AVXL. They start from trying to return health Amyloid accumulation and inflammation indirectly $SAVA, work on inflamation and Amyloid plaque direcetly (hypothesis of Amyloid being a defense mechanism) $CRTX, indirectly on inflammation and direcetly on cell health $ATHA, and all of these above, indirectly, through improvement in protein misfolding mechanism, and into cell trascription mechanism (the latter is just well supported hypothesis) $AVXL. All these are promissing new drugs for the dementia/Alzheimer’s field. Some overlap but do this in different ways.

The company $CRTX is selling its stock to investors based on the hopes of helping the sick with dementia and Alzheimer’s and investors selling their stock once it reaches its fair value upon company profit. Their argument is on one hand is very strong but on the other there are doubts about the duration of the effect and of the measure itself. It is only after the phase 2/3 that clearer picture to its efficacy can emerge. All these theories of the disease can not be true as the one and only exclusive cause, although they can supplement each other.

$CRTX recently released news regarding the futility interim data. The release can be found here: Link https://www.cortexyme.com/cortexymes-phase-2-3-gain-trial-of-atuzaginstat-cor388-in-patients-with-alzheimers-disease-successfully-advances-past-interim-analysis/ .

The p-value of .005 is below the threshold of .05 so results can be called statically significant, which in statistical parlance means that there is difference in performance between the dosed cohort and the placebo cohort. In other word also that there is 0.5% probability that on repeat of test the results will turn false on random events. The smaller the number the better, the greater the number of participants in the study the easier to achieve lower p value number. But on the other hand $CRTX management is a bit disingenuous claiming “overwhelming efficacy” already. The data points in this direction but it is not a clear indication of it. If indeed p=.005 for then we can expect some efficacy and this can be easly measured with Effect Size Cohen’s d, which I tried to use in this post on preeliminary results from $CRTX and $AVXL. The latter has 3 years of dosing 8 patients and measuring this in the above given cognition tests which are the industry standards with p=.00001 as the number diminished with time due to increased efficacy but itself it is not a measure of one directly. $CRTX started right now to do the same. Only with these results we can comapre all these comapnies. If I am not wrong $CRTX will release data in December 2021 and $AVXL in June 2022. Nevertheless, the true performance shall be seen in a long distance run against the disease.

Two thirds of all dementia and Alzheimer’s sufferes die because of other comorbidities, only one third dies because of severity of the disease. The largerst cost of the disease lies in the length of time a given person needs to be institutionalized or cared by the family. If you can make then to retain their cognitive skills you can cut these costs signifinatly and collect the prize.

If you feed your dog or cat wouldn’t you feed me and drop me a fiver so that I can buy my wife a french pastry? Thank for reading and come again.

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Cassava Sciences Drug Simufilam in The Pecking Order of New Breed of Alzheimer’s Drugs. $SAVA $AVXL $BIIB $LLY

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.

I have a sleepless night so……

The 3xTg (Tg for transgenic) murine model of Alzheimer’s disease uses the same gene, PSEN1 (actually, a trasngenic version of the mutation prevalent in familial AD) and two others are connected to amyloid plaque and Tau deposits. The same mutation was used in the experiments described in paper linked in this post: 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/

Having made this connection let us turn to this slide from SavaDx presentation by Cassava Sciences $SAVA:

An explanation first, PTI-125 is an old moniker for ATH-1017 called now Simufilam. I have been touting in my blog that the 3xTg mouse model at about 4 month old develops mental disability, 2 months before first signs of Amyloid plaque appear. Here, at 4 months alpha7nAChR/FLNA linking apear to rise at 4 months in the model mice but not in the Wild Type mice. 8 months old WT mice do have elevated level of the complex but in the 3xTg mice it is even higher. In 8 months 3xTg mice one would expect Amyloid plaque to be present. Just to give insight into the timeline 4 months of mice life is about 35 in human terms, 8 months is 70 years, and 6 months is about 50. In the paper referred in the post I presented link to, the degenerating neurons set off a cascade of chemicals calling on the immune systen to removed them. Inflammation is then intrinsically linked to ever increasing degeneraton of neurons under conditions described in the experiment.

What the linkage of alpha7nAChR/FLNA mean in context of Alzheimer’s. Again a slide from $SAVA presentation:

Altered FLNA binds to alpha7nAChR and Toll-like Receptor TLR4. Sumifilam reverses that action. $SAVA claims that is reducing neurodegenration and neuroinflamation. Here, you have to make a leap in conceptual thinking with me. There are papers which make the point that AlphaBeta42 act as kind of “antibiotic” fighting baterial infections and one particular paper stated that it is toxic to neuroblastoma cells. There is a growing evidence linking Amyloid plaque to defence mechanism in case of brain wide inflamation. link: https://stm.sciencemag.org/content/scitransmed/8/340/340ra72.full.pdf It seems that Amyloid plaque which comes in different peptides chain lengths and molecular weights is kind of part of inflammatory responce from the CNS, and might be only indirectly connected to the degeneration of neurons.
  • 3xTg Murine model of AD mimics familial Alzheimer’s
  • By the same mechanism by 4 months of age mice develope mild inflammation leading to mental decline all due to increasing degeneration of neurons.
  • The occurance of inflammation during this time is in line with the novel etilogy of the disease described in my previously published post (link above). Degeneration of neurons leads to inflammation.
  • Simufilam addresses just one mechanism out of many affecting the brain under this new etiology: a misfolded protein FLNA.
  • With age the brain is assaulted by inflammation but in 3xTg model it appears way sooner and is much greater in magnitude.
  • In responce to prolonged inflammation Amyloid plaque is produced as the deep brain defence mechanism.
  • Simufilam regulates the mechanism of Amyloid plaque production but does nothing to stop neurodegeneration as described in the novel ethiology paper. It acts downstream from neuronal degeneration and misfolded protein.
  • Neuroinflammation is so essential to the destructive power of AD that simufilam can improve cognition but in very limited way.
  • Simufilam can be used to rescue the Amyloid Plaque Theory of AD but for all the wrong reasons. It has to do more with inflammation than anything else!
  • Simufilam beats drugs like Donanemab and Aducanumab which just remove the Amyloid plaque but do not address inflammation.
  • Yet Simufilam is inferior to Blarcamesine ($AVXL), drug which might be affecting the degeneration of neurons and the inflammation source.
  • The evidence supporting the last point can be seen in the latest communique from Anavex Life Sciences. See the link below for my recent post.

This sums up my train of thoughts on Cassava Sciences ($SAVA). The performance of Blarcamesine can be seen in my recent post, link : https://piotrpeterblog.com/2021/03/20/can-blarcamesine-rescue-those-above-mmse-20-with-alzheimers-avxl-blarcamesine/

Indeed, there has never been a better time to be an investor in Alzheimer’s drug, or in general CNS neurodevelopmental and neurodegenrative drugs, as with the advent of genetics and the stem cell field of research, the focus now statrs to be clearly on the root causes of those diseases, leading to therapetics targets with real good prospects of success.

This blog is more energy efficient than Bitcoin mining but will mint many millionairs so please drop a coin.

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Can Blarcamesine Rescue Those Above MMSE 20 With Alzheimer’s? $AVXL Blarcamesine

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.

Please, read the latest news from $AVXL (3-16-2021), first. There is a link here: https://www.anavex.com/anavex-life-sciences-reports-anavex2-73-blarcamesine-featured-as-a-disease-modifying-small-molecule-in-phase-3-clinical-trials-in-a-new-publication-in-medical-journal-titled-future-av/

My take on this is that we are being given early insight into the result of the phase2b/3 (Alzheimer’s). The company has never kept the same group of patients to present the data or rather it kept changing many metrics as the knowledge of the benefits of the drugs has been deepening or became broader. From the wording of the newspiece my conclusion is that it references to the Super Responders as the ones who are SIGMAR1 wild type and are above 20 MMSE baseline, therefore respond readily to Blarcamesine.

There has been a change in Dr. Missling’s tight lip policy, before we had to deal with just the bland official information from the company communiques. But now Dr Missling gives to this data a lot of color with statements like this (paraphrase here) “If we give Blarcamesine, even to those who do not readily respond, for long enough time we can also rescue them” (acctually combining of mine of two statements into one). And another green shoot of hope: “We can rescue those who are above 20 MMSE points”.

Where the first statemet comes from? Maybe from this plot:

Please, read this old post link: https://piotrpeterblog.com/2018/08/18/something-about-dropout-rate-avxl/ But think about it the extension still keeps everybody on their initial dosing so it includes those on 10mg and 30 mg. Yet, I have heard voices that the dose was adjusted in the extension so the avove paraphrased sentenses from Dr. Missling might hitting the nail on the head.

And the second statement from this slide from CTAD 2017 presentation:



The comunique states that the initial average score was 22.3 for those patients (71.1 ADCS-ADL) and that they improved @57 weeks +2 MMSE and +3 MMSE @ 70 weeks. I have long ago determined that standar deviation for that group of patients was +/-2.6 and assumed that it was +/-1.2 for placebo or Donezepil. Combining these into the formula for Cohen’s d Effect Size we get 2.2 @ 57 weeks and 3.4 @70 weeks.

Just as a remainder:

It seems that with ever additional month the Cohen’s d for Blarcamesine is going to increase. The name of the game becomes to hold your patients at least steady as the placebo cohort deteriorates, which means that these people ultimately need be taken care of or institutionalized. The added bonus is that in reality Blarcamesine can raise the MMSE scores of those above 20 MMSE baseline. From all the information released I teased out the picture of a drug which can rrescue the majority with only minority still declining in slow motion respective to placebo.

Right now, the cost of Alzheimer’s drugs is higher than cancer drugs, and the later is about $65,000 per death (USA). There is 600,000 deaths due to cancer and only 120,000 deaths due to Alzheimer’s, but one fact explains this disparity best. Only 1/3 of all those afflicted by dementia, mostly Alzheimer’s, die due to its severity. 2/3 dies of other comorbidites. Maybe in next post I tackle this.

Thank for visiting my blog.

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Eli Lilly’s Donanemab And The Lack of Little Ideas Among The Big Pharma Giants $LLY Donanemab $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.

I have listen to the webinar from Elli Lilly $LLY on 15th of March, 2021 about the phase 2 Donanemab results. The biotech business is fraught with failure, and spinning the results so that investors won’t lose hope and leave. In just couple of years, we have witnessed triple failures of monoclonal antybodies aimed at the amyloid and tau plaque. I have to confess, I was unable to concentrate the whole time so I would rather go over the presentation slides.

The most interesting slide in the presentation, we saw at the very beginning of the show. I shall call the slide number 4 the Illumination on the Reasons for the Reluctance to Let Go of the Amyloid/Tau plaque.

Words in purple – Cure By The Other Name …..

The other name are the biomarkers named the Amyloid and Tau. This is the case of mistaken identity. The obstinacy is amazing. The Giants complain that FDA or rather all of us pay too much attention to symptoms. Haven’t they cured the disease already by removing the plaque? This indeed is the case of making the results for the drug not the drug for the sick.

Words in blue – The Statiscally Insignificant Blues

In a trial you have two populations, placebo and dosed. Each of these are defined by the mean and most of all by the distribution around the mean. The phrase “statistically significant” references to the possibility that distribution of those dosed can’t be part of the placebo cohort distribution, when the two overlap too much hypothesis that the drug has efficacy is in question. This might be the case when the efficacy is low and patients are widly scatered.

So $LLY decided to select its own patients, ITT (Intent To Treat (population)) became large enough to justify the drug financially but lowered the dispersion of the population. However $LLY selected intermediate tau deposits patient, and it threw out all those who decline rapidly. This significantly lowers the dispersion in the subjects. Hey, they almost made it! See those p-values! Hypothesis is not null! FDA did not let $AVXL to select patients based on biomarkers. There is tendency to set the bar even lower, since researchers have realized that there is a threshold at which a patients can not be turned back or helped. The example is $AVXL Blarcamesine phase 2b/3 trial with patients between 20-28 points on MMSE scale and with proven amyloid plaque deposits, but that is because many patients above 20 points can be actually rescued form the disease by the drug. Following this thinking $LLY went for average 23.6 ppoint MMSE.

The placebo performance can affect the statistical significance but it can not make the drug perform better. I wonder how far they got with negotaiting this with FDA on Trailblazer-ALZ 2 study. Let’s see!

Seems like FDA wants those rapidly declinning in, to add to the mix. $LLY got the traditional for plaque trials thousands. Oh! Things might not be going well! Whenever I see thousands I think watch out below.

Words in green – Green Light for Profit

Let’s start with the green stuff first. In 2018 the global market for oncology drugs has been about $77 billion, half of it is the US. Since 1970’s we made some progress against cancer but very significant only in few cases, the worst ones. So 5 years survival rate for liver and interahepatic bile duct cancer is now 19% which is 6 times more than it was in 1970’s. Similarly with pancreatic cancer, the worst offender, it is now 9% or 3 times what it was in 1970’s. Most kinds of cancer the improvement has been between 1.8 and 1.3 times. The best survival is with prostate cancer 99%, used to be 66%.

The cost per death is quite high, $65,000. There is about 600,000 deaths per year due to cancer in the US. But this is not the real toll of cancer. Some doctors once having cancer decide to forgo the slash and burn therapies which destroys the quality of life of people desperately fighting for few more years of life. We, the public, only hear the stories of the happy survivors, not those who were afflicted and lost threasure, life and final quality of life in the struggle.

This is a dream scenario for drug companies, drugs for terminal diseases with efficacy slowly rising so that higher prices can be justified, but also not quickly enough to lower the deaths significantly. This summarizes the oncology analogy.

FDA is a part of government bureaucracy and is relactant to open another pandor box of tens of billions of dollars to be paid out by Medicare in new field reminiscent of oncology, but even worse, since Donanemab can only make the disease more costly and still keep it not survivable. The rest of the words are just window dressing.

In the final calculation, would Donanemab hold its own with the placebo it would only delay the disease by theoretical 6 months, but at what cost? Few thousands a month, $30,000 a year? That would double the cost of Alzheimer’s care with almost no benefit. Is this accidental lack of ideas or something programed?

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Athira Pharma Revisited. Future Cure for Alzheimer’s or A Dud. $ATHA $AVXL ATH-1017 Blarcamesine

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.

The advancements in the genetics and the growing body of knowledge of embryonic development have altered the search for the cause of Alzheimer’s disease, and many neurodegenerative diseases. The new paradigm fixes the primary cause to lie within the cellular gene transcription mechanism of the neurons leading to their degeneration into a kind of dysfunctional and devolved Franken cells.  The amyloid and tau plaques are relegated to secondary effects. Due to the large amount of capital poured into the research and careers, the plaque theory might still try to linger a bit, but the writing is already on the wall and the frustration shall soon set in as trials are failures or at least are presenting the industry with results incommensurable with drugs cost as most of them are monoclonal antibodies. 

About one-third of the drugs in the development, targeting the plaque, are now seem to be defunct.  Most drugs targeting the neurotransmitters might find some limited synergy with new breed of drugs, but that to be seen though.  The future belongs now to those who pursuit the new targets.

See link to reference https://advances.sciencemag.org/content/6/46/eaba5933

These new targets are likely to be neurotrophic growth factors and some drugs directly or indirectly affecting the cellular transcription mechanism, like Sigma 1 receptors agonists.  CRISPR therapies seem not to be ready yet to tackle Alzheimer’s, if at all, can only be limited to familial AD which accounts for just 5% of cases. The field might be also open to RNA interference drugs but this has be proven yet, if ever. 

Athira Pharma ($ATHA) sports the ATH-1017 small molecule HGF/c-Met modulator as a drug against Alzheimer’s disease.  Some things need to be explained first about HGF/c-Met complex.  HGF stands for Hepatocyte Growth Factor.  As the names has it was probably first identified in and connected with liver as the name says. Liver is a very peculiar organ in human body because it is the only one able to regenerate.  You can remove half the organ from a patient and then see that liver will regrow soon to its previous size.  

From what can be read on Wikipedia page about HGF, the most conspicuous facts about the compound are the ability to generate healing and the involvement of the HGF/c-Met complex in oncogenesis that is the process of growth and development of tumors. 

In more detail, the interactions of HGF and its receptor c-Met are connected with embryonic growth and wound healing, that at least on the more desired part.  These two phenomena require divisions of cells, differentiation into their respective cell fates, and mobility of cells, called motility, in order to allow them to move around and settle into the cell matrix for specific structures for organ or tissue functions to emerge.

We are best familiar with small wound healing. This is possible as autologous stem cells residing in the both edges of cut skin are coxed into dividing, differentiating into proper cell type and migrating into new cell matrix specific to skin, slowly closing the wound. Similarly the rejuvenating effort in the brain would have to rely on autologous stem cells present in the brain. There is a theoretical limit of usefulness of such compounds like ATH-1017 as the research had revealed that the population of those cells in brain dwindles with age and the capability of self regeneration of the brain diminishes, unless ATH-1017 can “rejuvenate” the Franken neurons, either directly or through neurotrophic action from the galia cells. But would that be enough to turn them back from the brink of the total dysfunction? (see first reference) These are my doubts about ATH-1017.

Wound healing is much more complex phenomena as it involves also the immune system, and inflammation.  As it has been revealed run away inflammation does immense amount of damage to those suffering from Alzheimer’s.  An example later on will be provided. 

The word modulator means that the small molecule drug acts as some kind of “amplifier” to the original amount of HGF acting on local c-Met receptor present on the cells in given tissue. HGF is not endocrine compound, that it is not systemwide.  Since its presence is localized to a particular tissue the action is local. Such compounds are called paracrine. 

The premiss on which the ATH-1017 should help the patients sick with Alzheimers is that the low expression of HGF/c-Met complex existing in Alzheimer’s patients should be helped by modulating it higher. This should cause the fall of inflammation, increase in neuron health as HGF enhances the cell survival, neurogenesis by enhanced cell division, and last but not least the growth of dendrites and creation of new synapses. The list is taken from company presentations, I gather that these were observed in vitro or in murine model. These effect seem mostly to refer to changes induced in existing neurons. These are necessary for ATH-1017 success.

HGF/c-Met modulates the function of NMDA receptor in neurons. NMDA receptor among others regulates the flow of positive ions into the cell. Synaptic health relies on proper flow of ions for its status. Here is an interesting take on the effort to target neurotransmitters and their respective receptors. NMDAs are glutamate receptors and are connected with excitatory system in the brain. Like many features in cell biology there is a dark side to NMDA receptors. Since the receptors are present not only at the synapses, they have another role to play outside of the synapses. Extrasynaptic NMDA receptors form a death signaling complex with TRPM4. There has been years long pursuit of compounds like ATH-1017 and the company claims that the drug increases the expression of NMDA receptors in the synapses vs. the extra synaptic ones without causing any harm to neurons or astrocytes feeding the neurons.

The fear of using modulator for a complex HGF/c-Met which is involved also in oncogenesis is that safety of the drug can be suspected of being in synergy with cells on their way to turn cancerous. Athira Pharma claims that the drug went through complete GLP (Good Laboratory Practice) toxicology testing regiment, and was approved for Phase 1b.  I think due to above reasons and others, those seen in animal models, the dosing has been limited to 8 days but lest we forget that this is just phase 1b and not phase 2, we should dismiss any misgivings. 

It might be that oncogenesis requires a number of mutations before it can snowballing into fully formed tumors, and even more so to reach the stage ready for metastases.  On the other hand, octogenarians’s bodies might have accumulated more mutations so they might be more susceptible to oncogenesis than semi-centennials (50 years old).  In general I would accept the verdict of safety. 

The 8 day dosing period is too short a period to allow for meaningful measurement of the cognitive abilities so Athira Pharma has selected the more susceptible to change in such short period of time measure that is the latency in P300 response to audible stimuli. 

The test set up relies on detecting oddball sound in steady stream on noise and requires the subject to press a button upon hearing it so it calls for the engagement of attention and memory. Standard setup of electrodes is placed on the scalp of patients. For more information I suggest viewing the presentation on Athira Pharma investors page. I will use slides from this presentation in the post.

https://investors.athira.com/events/event-details/athira-pharma-webinar-predictive-nature-p300-determine-clinical-benefit

The slide presents the comparison between the waveform of healthy age adjusted individual and Alzheimer’s afflicted patients.  There are two most conspicuous differences between those two:  The Latency which varies from 250ms to 450 ms in healthy subjects and Amplitude. Though these two are semi-independent  in general the difference in early and moderate Alzheimer’s is better viewed through the difference in the square of the area under both curves (age-adjusted).  The debate of latency vs amplitude rages on and is best presented in abstract to this paper.  https://content.iospress.com/articles/journal-of-alzheimers-disease/jad0061 

Alzheimer P300

The amplitude of the event-related potential P300 component is sensitive to aging and Alzheimer’s disease (AD). Using a standard 20-electrode configuration, the P300 was measured during an “oddball” task in 14 young normal individuals (YN: 21-41 years), 11 elderly normal individuals (EN: 61-80 years), and 23 probable AD patients (AD: 63-93 years; NINCDS-ADRDA criteria). P300 latencies and amplitudes were measured at PZ. Additionally, algorithmic calculations were made from spline plots across the 11 central electrodes for P300 peak voltage latency and total field energy. The measured versus calculated latencies were in general agreement. Furthermore, the measured P300 voltage amplitude was closely related to the calculated total field energy. P300 voltage latency was significantly prolonged in the elderly, but not more so in AD patients (average latency [ms ± SD]; YN, 315 ± 21; EN, 364 ± 48 and AD, 361 ± 56). P300 amplitude showed the expected pattern of change from young to elderly to AD (average voltage [uV ± SD]; YN, 13 ± 5.1; EN, 8.3 ± 2.8; and AD, 4.9 ± 3.3). Summing the squares of each wave (an indication of power: P = V2 R) showed the expected change with age more strongly than the P300 amplitude (average ± SD; YN, 44,397 ± 32,386; EN, 9,996 ± 7,018; and AD, 3,347 ± 2,971). Mini-Mental State Exam scores showed no relationship to P300 latency and minimal relationship to amplitude. Results suggest that the P300 is not obliterated in early AD, but is barely discernable in late AD. The approaches to calculating the P300 described here are potentially useful for measuring specific neural systems affected by aging and AD.

The most important information contained in this quotation is that “Mini-Mental State Exam scores showed no relationship to P300 latency and minimal relationship to amplitude.”  

Another source I have checked comes to similar conclusions about sensitivity of latency testing vs. changes in cognitive measures like Mini-Mental State Exam.  Though Athira Pharma posts it on its page, it rather supports my point.

Link. https://www.athira.com/wp-content/uploads/2020/08/Olichney-et-al_2011-ERP-and-synaptic-dysfunction-in-AD.pdf 

The latency data is provided on new slide. 

I plotted this information and tried to fill-in the hypothetical daily dosing.

The X-axis is the duration of trial in hours, the y-axis is the diminishing latency.   Black line is the data taken from the slide.  Red line is data filled in based one the former behavior. 

From what I see is that in 3 hours there is a rapid fall in latency then followed by slow return to almost previous level. Though I don’t want to discredit the steady average drop in latency over the 8 days, the immediate action depends heavily on concentration of drug soon after injection. In my opinion this form of response is connected to rapid fall of inflammation in the brain due to injection of ATH-1017.

I had seen a video where a medical doctor would inject people with anti-inflammatory drug directly into the space between spine and peridural membrane, in the neck region. Then he would tilt the table on which was the Alzheimer’s patient to allow the CSF flow in the brain and in just an hour the patient would talk of mental fog lifting. I guess every investor in Alzheimer’s stock would get severe case of FUD upon seeing such simple remedy. The video was taken off Youtube and the practitioner was sectioned by regulators as his approach was deemed too unsafe and experimental.

Another reason for sudden change in latency can be placed at the doorsteps of affecting NMDA receptors in positive way. The ATH-1017 showed an extraordinary efficacy in lowering the latency. Now, comes the question to what can this can be attributed. Boosting NMDA function, lowering inflammation or “rejuvenating” neurons? To fully answer this in positive or negative we need cognitive improvement data as planed in ACT-AD phase 2 trial (ADAS-Cog11) which is the gold standard here. The latency or amplitude data is just auxiliary information.

Similar data exists for Anavex Life Sciences Blarcamesine which is more advanced in dosing and results than ATH-1017.  This data can be used to speculatively evaluate future prospects of Athira Pharma drug. 

From 2017 Presentation on Phase 2a for Blacamesine (ANVEX2-73)

If the amplitude and latency be equal and the duration of 12 days comesurable with the 8 days then we have almost the same relative rise in measures. For Blarcamesine it is from 6.5 millivolt to 7.8 millivolt so its is raise to 120% at the end of second period. It is impossible to compare the amplitude as P3b is just one component of P300. Under ATH-1017 latency is reduced from 390 milliseconds to about 300 millieconds latency, raise to 130% in improvement. Upcoming Lift-Ad and ACT-AD pahse 2/3 and phase 2 respectively will reveal the extend to which this similarity in this auxiliary measure is going to pan out as valid indication of durable increase in cognition for Alzheimer’s patients as data will be collected in ADAS-Cog11.

$AVXL’s Blarcamesine is on verge of proving itself to tackle Alzheimer’s like no other drug till now. See my other posts, and this one in particular.

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/

Blarcamesine is a SIGMAR1 agonist, ATH-1017 is a modulator of a growth factor. The former has been almost validated as a potent AD drug and other neurodevelopmental and degenerative diseases drug, probably being first in a new class of drugs. The same might happen will ATH-1017 as it can become a first growth factor drug, and the first competition to SIGMAR1 agonists. Whether this be the case we shall find out in two years time. For now I can voice some doubts, recervations, misgivings, but most of all hope.

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Novel Etiology of Alzheimer’s linked to neuronal loss of function due to changes in cellular transcription mechanism and DNA Chromatin Complex. $AVXL $SAVA $ATHA $BIIB

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.

Many neurodegenerative and neurodevelopmental diseases might have a similar mechanism. These might be Parkinson’s, Rett syndrome, Fragile X syndrome, and Autism.

The Amyloid and Tau plaque theory has been superseded but will die slowly. ($SAVA $BIIB)

New types of drugs will emerge to address this paradigm change.

AVXL already has drugs to address the new etiology. Large Effect Size proves that it is on the right track.

On November 13, 2020, a paper has been published in Science Advances magazine presenting a novel etiology of Alzheimer’s Disease. The link to the PDF of the paper is here Dedifferentiation and neuronal repression define familial Alzheimer’s disease

Before we delve into the article content we should first acquaint ourselves with few concepts and their implications.

The acronym EOFAD stands for Early-Onset Familial Alzheimer’s Disease. This is the form of AD (Alzheimer’s Disease) caused by inherited genetic mutations, which run in families. A number of those families were researched and gene mutations were identified. Further confirmation of the genetic etiology of EOFAD can be found in transgenic murine models engineered with the above mutations and following the pattern of EOFAD in humans with such fidelity that the early onset corresponds to the same age in mice years as in humans. In one such model named 3xTg, at 4 months of mice life (35-40 years in humans years) first signs of mental deterioration appear, and at 6 months (50 years in humans) telltale sign of AD amyloid plaque appears in the brains of mice. The model suggests that mental deterioration predates the Amyloid plaque occurrence and the plaque is a secondary effect that has synergy with mental deterioration, but it is not the primary cause of AD.

Most of AD sufferers (95%) succumb to LOAD (Late-Onset AD). There has not been found overwhelming evidence to connect its etiology in this population to a specific genetic mutation. APOEe4 mutation can be connected to the severity of the disease progression but it is unnecessary for a patient to carry the mutation in order to develop the disease. At this point in time LOAD has been vaguely connected to environmental causes.

The researchers have collected cells from EOFAD subjects and healthy control group, then by turning certain genes on they matured them into adult neurons. This technic is named Human Induced Pluripotent Stem Cells. During embryonic development single fertilized cell containing the new DNA divides repeatedly and the resulting cells differentiate selectively by expressing specific genes to mature among others into neurons. This is what is called cellular fate. The process of maturation follows the evolutionary tree of life where not all stages are present or have a function in the fully developed organism.

The presence of mutated genes at one point in time caused the mature neurons to devolved partially to an earlier stage in cellular differentiation creating a kind of Franken cells. These cells have lost all synaptic function as they can’t synthesize protein to “build” synapses and operate them. It can be expected that for a living organism this would mean onset of mental deterioration, just like in transgenic murine model 3xTg at 4 months of mouse’s life. The experiment was conducted in vitro so this is only speculation on my part. The devolved neuron cells produced signals inducing inflammation response from the microglia, marking themselves for destruction by the immune system. The inflammation is so destructive in AD and it is an intrinsic part of the disease that few therapies have been proposed to use agents controlling it. A graphic representation of the state of neurons in EOFAD can be seen in Fig 6 of the above-mentioned paper.

Both amyloid and tau proteins are part of healthy working neuron physiology. I can speculate that the loss of function by devolved neurons can trigger the disturbance in the physiology and precipitate accumulation of the aforementioned plaque. This is confirmed by the reported changes in Amyloid and Tau physiology of the devolved neurons, with this the Amyloid and Tau plaque theory has to be if not altogether abandoned then at least modified.

By running an experiment versus the healthy controls researchers have documented the interaction between genes ultimately leading to changes in Chromatin.

The sole purpose of Chromatin is to provide structural support and package the DNA double helix for reading by the cellular transcription machinery to synthesize proteins. In other words, the Chromatin complex is the gatekeeper of the information contained in the DNA. Chemical changes to its structure determine which genes can be read and which can be inaccessible to the cell at its particular cellular fate.

Those chemical changes can be either due to the expression of specific genes, their fate or can be due to environmental causes which are called epigenetic.

In the case of the EOFAD cells, the devolution was caused by mutations in the key genes. The progress of the disease in the familial EOFAD type and LOAD type does not differ with the exception of the onset of the disease. A next step in the scientific pursuit of AD etiology might be to seek the epigenetic nexus between the two forms of the disease.

Since the end of the nineteenth-century plaque has been connected to dementia, by the early science of histopathology. In 1985, the chemical structure of the plaque has been identified and it became later the primary therapeutic target. As in any field, new tools open new horizons and new insights into the etiology of previously unsolved mystery diseases. Once a while, a study upends years of research in a case of scientific “creative destruction”. The insight present in the paper could not have been elucidated had it not been for HiPSC and a myriad of other methods not available in 1985. No doubt, the content of the paper is the seminal work in the field of Alzheimer’s disease, introducing a new paradigm, and entirely dismissing the Amyloid or Tau plaque as a therapeutic target. The only unanswered question is the relevance of the work on EOFAD to LOAD. Epigenetic changes in the structure of chromatin can serve as a potential conceptual bridge. Other studies point to a similar set of affected genes in LOAD patients. Reference to these studies can be found in the Discussion section of the paper.

As investors, we are much more concerned with the relevant consequences of scientific discovery to define therapeutic targets, so that effective drugs can be designed, than the science itself. Currently, I see few types of drugs ready to address this novel etiology of AD. One is growth factors, then RNA interference, finally are Sigma 1 receptor agonists. Growth factors are usually compounds coxing stem cells to divide and transform into specific types of cells. In the Alzheimer’s field, Athira Pharma ($ATHA) comes to mind. Growth factors are present in embryonic development as well as in wound healing. So-called autologous stem cells are present in all kinds of tissues and can be called on to assist in the healing process. They are undifferentiated and waiting to assume some limited cellular fates. RNA interference can mute the expression of a gene at the point of protein synthesis. Yet, the most comprehensive drugs are the sigma 1 receptor agonists. Aptly, one researcher has called the capabilities of the SIGMAR1 receptor “pluripotent”. The SIGMAR1 receptors are located in the endoplasmic reticulum where protein synthesis and protein folding takes place. Since the endoplasmic reticulum is an outgrowth of the cell nucleus it is not surprising that SIGMAR1 has been implicated in affecting the Chromatin complex and by this the expression of certain genes as is in the example of cocaine being an agonist of SIGMAR1 and its interference with the transcription of MAOB protein. Link to the paper Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

There is no single definitive agonist for this receptor, its specificity is kind of amorphous. It can have a high affinity with different compounds but the effective agonists are few.

$AVXL has two such compounds in the pipeline. Anavex3-71 is a future development, just looking to enter clinical trials soon. Blarcamesine is currently in Alzheimer’s phase 2b/3 trials and few others.

The design of phase 2b/3 builds on the results of phase 2a, which in the High Concentration Cohort bifurcated into those who succumbed to the disease and the group in which basically the course of the disease has been reversed, the so-called Super Responders. Anavex Life Sciences is in pursuit of precision medicine and Artificial Intelligence was used in analyzing all the possible connections between the genome of the subjects and the measurable in the trial. The Super Responders tended to be the carriers of the wild type SIGMAR1 gene, roughly 80% of the general population, and certain variants of the COMT gene, with lesser benefits. Also, they tended to test on MiniMental State Examination above 20 points. MMSE test goes from 30 points for a healthy individual to zero for somebody incapacitated. The following illustration is a slide from CTAD 2017 presentation with the results of the 57-week dosing.

pastedGraphic.png

The numbers at the position of each patient are is the change in MMSE score from baseline after 399 days of dosing. Y-axis is the slope of the line to the 57 weeks score in MMSE points per day. The High Concentration Cohort roughly corresponds to a 50mg/kg daily dose.

The task which is set before us is to determine how likely is Anavex’s Blarcamesine to obtain approval for its Alzheimer’s drug?

When you have a drug trial you measure a variable in two populations, placebo, and the dose cohort. Both populations can be described by the mean and the distribution around the mean. The first question: Is the distribution of data on the dosed population part of the placebo population distribution? Second question: How far removed are those two distributions from each other? Both these questions are partially answered by Effect Size Cohen’s d. We will try to arrive at a somewhat objective measure of Blarcamesine performance versus other drugs via this statistical tool. In order to do so we need to make some assumptions and calculations.

Phase 2b/3 pivotal Alzheimer’s trial #NCT03790709 recruits subjects inclusive MMSE scores 20-28 but with proven Alzheimer’s hallmark of Amyloid deposits. Patients are not selected on the basis of carrying the genes tending to cause a better response. They represent the general population, where about 16 to 20% carry the mutation lowering response.

Let us now make the assumptions.

  1. From calculations of phase 2a data, we got the mean and SD deviation for the Super Responders annual change in MMSE scores +3.5+/- 2.6. Let us disregard the small sample size.
  2. We assume that the trial responders will follow this performance metric. 80% percent of the dosed population to be Super Responders, 20% placebo equivalent responders.
  3. We assume that the combined dosed cohort will have an average change in MMSE scores +2.4+/-3.2
  4. The baseline score will be MMSE 23.
  5. As the trial uses ADAS-Cog11 as a primary cognitive measure we assume that the calculations are equally valid for MMSE scores.
  6. We assume that the placebo arm will follow loosely the synthetic placebo arrived by the ADNI industry consortium for the purpose of eliminating the placebo arm in Alzheimer’s trials with MMSE annual change of -2.2 +/-1.2. We prefer to set the SD to 1.2 instead of 0.31 as it seems to be more realistic and in line with the experience from phase 2a.
  7. We assume that patients in phase 2b/3 will respond to Blarcamesine just like the few in phase 2a, disregarding the sample size. `

The formulas for calculating Effect Size Cohen’s d are available on many pages on the web. No adjustments are taken into considerations as the trial sample size is above 50 subjects. We need to compare the Effect Size numbers for Donezepil, Cassava Science Simufilam and for Blarcamesine (projected) to give the insight into possible therapeutic effect which might be reached in phase 2b/3.

pastedGraphic_1.png

The clear winner is Blarcamesine with an Effect Size of 1.89, which is qualitatively given as “very large” versus Simufilam’s .37 or “small”. Donezepil has been approved with ES=.28, so the hurdles are set low. A similar range of Effect Size metrics has been achieved by Blarcamesine in Parkinson’s Disease Phase 2 (ES~1.20) and Rett Syndrome phase 2 (ES~1.20 with only 5mg/kg daily dose as of now).

The Rett Syndrome has been linked to a similar mechanism of cellular degeneration but involving a mutation in the gene MECP2 which among others regulates the expression of genes during neural maturation and development. Link to paper MeCP2 as a genome-wide modulator: the renewal of an old story The success with Rett Syndrome confirms the moniker of “pluripotency” in regards to Blarcamesine, which at least partially is restoring function where the transcription mechanism is at fault. Similar mechanisms are being identified in other degenerative diseases of the central nervous system.

Just like Rett Syndrome Autism Spectrum Disorders (ASD) are neurodevelopment diseases. The aforementioned “pluripotency” of Blarcamesine might be proven true in the next market by entering with Fragile X Syndrome the field of ASD. Visit anavex.com to see the pipeline of its drugs.

There is a concept to refer to the almost miraculous self-regulations of life in spite of the prevailing entropy, it is called homeostasis. The phrase of “restoring homeostasis” has been often used in reference to SIGMAR1 receptors therapeutic action.

The rapid progress the drug is making in Rett Syndrome and the lack of effective medication in this rare disease bodes well for timely approval of the drug to hit the market in early 2022. The company already is talking fo developing its own marketing of Blarcamesine for Rett syndrome as other companies have done with rare diseases drugs.

Anavex has been dosing, through the vehicle of Open-Label Extension, patients with Alzheimer’s for the last 3 years without any serious adverse effects. Currently, Phase 2b/3 is 86% enrolled and randomized and the release of data is expected to take place in the first half of 2022.

To summarize, AVXL presents unsurpassed and yet unrecognized by the market opportunity with wide therapeutic reach and unparalleled efficacy of its drugs. Timing-wise Blarcamesine beats Cassava Science ($SAVA) and Athira Pharma ($ATHA) by at least 3 years.

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