Cassava Sciences, Hit or Miss? $SAVA $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!

Cassava’s target is the good old Amyloid plaque, the only difference between the other amyloid palque targeting drugs and Sumifilam is that instead removal of the plaque the sumifilam blocks production of amyloid plaque in its misshaped state and therefore the whole cascade of other biomarkers are controled, especially those direcetly involved in inflammation and released in neuronal death. The Unified Alzheimer’s Theory claimes that there is a hypothetical event causing homeostsis disturbance, in response to which the plague is produced and finally the inflammation does is irreversable damage. This is the short vesion of it. As knowledge of biochemistry of amyloid plaque grows so do opportunities to disrupt the process. This slide expalained how the discovery was made.

Slide 5 from CTAD 2020 Presentation

First the target protein gets discovered, later the physiological process in which it was involved i.e. processes in which it binds with other proteins or catalyses some processes. All within some cascade of reactions leading to produce some final physiological effect. This opens an opportunity to either bind to this protein to lower its impact or block it altogether, that is to remove it, or supplement it with the drug to increase its impact. In point 3 of the slide 5, a small molecule by trial and error has been found to bind to altered version of the protein taking part in the cascade of events leading to deposits of plaque. Restoration to healthy state of A-Beta-42 lowers the neuroinflammation by removal of misshapen ABeta-42 otherwise acting on TLR4 toll-like receptor. Homeostasis is restored at least in this cascade.

The tau tangles are accumulating in the interstitial space between the cells. The best indicator of deposits of ABeta plaque (Amyloid) inside the cells is the P-Tau181. See this reference. https://pubmed.ncbi.nlm.nih.gov/29626426/
This very protein is considered a potential target for biomarker to detect levels of Abeta plaque and Tau tangles to screen patients for signs of early ABeta deposits indicating onset of Alzheimer’s, that at least is the intension of the authors of the above mentioned paper. Yet, as the reference acknowledges the screening has little efficacy in finding the patients with MCI (Mild Cognitive Imparaiment) but its power lies in predicting whether patients develops deposits of ABeta and Tau better than APOE4 allele and age. This is inline with the observation that 30% of diseased Alzheimer’s patients carry no sign of Abeta plaque deposits at autopsy. The significance of this is that $AVXL and The Unified Alzheimer’s Theory seem onto a better path to tackle the CNS diseases, as the cause to be addressed seems to be up stream from Abeta (Amyloid) and Tau physiology. This is due to the old story that murine model first develope cognitive decline 2 months before onset of the plaque. The lifespan of a mouse is about 11 months. This corresponds to 70 to 80 human years. 6 months corresponds to 42-48 years in humans but 4 months to 28-32 years. Of course these are not absolute numbers but they are presented here to give you insight into the timeline of events. See post https://piotrpeterblog.com/2018/08/10/the-winning-combination-for-anavex-2-73-and-is-it-all-about-inflammation/

The 10% drop in P-Tau181 indicates that the Sumifilam works as designed and lowers the biomarker for Abeta and Tau. Slide 19 confirms that Abeta-42 (the healthy form) has increased. I would like to turn your attention to slides 22 & 23, because they present the evidence that the neural death has been lowered substantially by the drug.

Antibodies that neutralize HMGB1 confer protection against damage and tissue injury during arthritiscolitisischemiasepsis, endotoxemia, and systemic lupus erythematosus.

This quotation comes from Wikipedia page on HMGB1. The protein is in positive feedback loop of inflammation. As neurons are dying, macrophages that digests them relase this companound which works like a signal to other receptors in the inflammation pathways. Reducing its levels in the cerebral fluid lowers the destructive effects of neuroinflammation.

The Brain Blood Barrier gets “rebuild” too as the levels of the most ubiquitous protein in blood which indicate the health of BBB gets lowered.

Sumifilam shows all the presented biomarkers going its way, on biomarkers this drug should have cured the Alzheimer’s already. All the ducks are in row for a big show of secondary measures of cognition. Before we get into this, let us remember that on basis of 57 weeks the greatest progress done by Blarcamesine was during first 5 weeks of dosing. After that the progress among 6 Supper Responders was a steady paced improvement. Here, the dose was provided for 28 days that is 4 weeks. Dr. McFarlane once said that Blarcamesine had 110% (1.1) Effect Size when run against placebo. I calculated that the effect size can go from just ~35% to ~300%, it all depends on the performance of the placebo arm and the subgroup of the patients taken for analysis. Patients in AD Phase2b/3 can be anywhere in between those two limiting cases. Of course, the above analysis pertains to patients in the first 57 weeks of AD Phase 2a. Now let us see the performance of Sumifilam on cognition.

The Effect Size for Sumifilam is large enough to assure an approval as it is above ES=.28 of Donezepli though it is a bit spotty with the 50mg cohort having 37% Effect Size vs. 23% 100mg cohort. I guess this is the best data Sumifilam could muster which overlaps with the worst case for the ES for the entire High Concentration Cohort (including the worst performers) in ANAVEX2-73 Phase 2a vs syntethic placebo. If Dr McFarlane’s remark that Blacamesine has exhibited 110% Effect Size in Australian trials is true then $AVXL still comes ahead. The PDD Phase 2 had 33% of patients to SIGMAR1 mutated variant, the reminder was SIGMAR1 Wlid Type. That was even larger incidence of the mutated version than in the general poplulation which is about 16-20%. I wonder whether the same composition will be retained in AD Phase 2b/3 or will the results be adjusted for the genetic composition of the cohort. https://piotrpeterblog.com/2020/11/10/preview-of-possible-effect-size-in-alzheimers-phase-2b-3-avxl-blarcamesine-anavex2-73/

  • My impression is that Sumifilam did not that much improved the lot of the patients through removal of the plaque what it did just by stopping the inflammation associated with the process. It is rather the proof of the destructive force of neurinflammation than the theory of plaque removal as a way to help Alzheimer’s patients.
  • The fact that 98% of trial population have improved indicates that there is no genetic aspect to Sumifilam efficacy unlike in Blarcamesine’s case. They work in two different ways and could be combined, hopefully. Blarcamesine can tackle the 80-84% of patients carrying the SIGMAR1 Wild Type gene.
  • There is almost instantaneous effect (4 weeks) just as it was in the case of Blarcamesine (5 weeks). Bodes well for both drugs.
  • Blarcamesine’s trials by Dr Missling design never looked into biomarkers (at least the same way as Sumifilam) since Dr Missling looked to control cost and concentrate on final outcomes that is cognitive measures. The consequence of this is that we do not know the impact of Blarcamesine on inflammation besides the global cognition impromement. One can be infered from the other, yet we lack numbers to make a direct comparison.
  • The reach of Blarcamesine is wider as there are multiple indication it can be used. Sumifilam actually is limited to the patients with Amyloid plaque, the telltale sign of Alzheimer’s disease, as it at least is now accepted to be.
  • Blarcamesine Rett Syndrome trials point to earier approval than Sumifilam’s but do not discount a partnership to speed up Sumifilam approval or $SAVA’s buyout.
  • $SAVA is just a variation of the theme of Amyloid removal and as such might get quicker acceptance than $AVXL with much more novel approach and still unknow MOA.
  • On the other hand unknown MOA makes $AVXL have a solid moat. Rather it is not the MOA per se but the unknown way ANAVEX2-73 interacts with SIGMAR1 receptor.
  • The cost of measuring 11 biomarkers must have been excessive and it follows the pattern of scientists to be in the driving seat. Seeking validation through biomarkers seems to be the approach taken by many Amyloid Theory trials as the biomarkers “proved” the theory valid while the cognitive tests were disappointing. Ultimately, what you “sell” is the cognitive improvement.
  • $SAVA is looking toward ~$75 million offering, compare it with the financing conducted by Dr Missling.

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Preview of Possible Effect Size in Alzheimer’s Phase 2b/3. $AVXL Blarcamesine ANAVEX2-73.

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!

Hat tip to Tom Dean.

Let’s start with a pretty picture.

I broke down the “variety” of patients into two groups 6 Patient SUPER RESPONDERS and 9 Patient HC Cohort. What can I say about HC Cohort:

  • In light of other developments it seems that HC Cohort contains some SIGMAR1 Mutated Variants patients who basically behave like under placebo.
  • The “performers” in HC Cohort should be all SIGMAR1 WT type carriers.
  • Among the “performers” and “placebo like” are spread carriers of APOEe4 allele which contributes to severity of decline. There is 75% of APOEe4 carriers so the results are skewed toward under performance. In general population the number of APOE e4 carrier is about 48%. See info on impact of APOEe4 at a post on my blog at this link https://wp.me/p2IvqX-7q
  • The distribution of performers to “placebo like” patients is such that we can assume it to be the worst case for accessing the possiblity of approval by FDA it is even worse than natural distribution of SIGMAR1 WT gene. This has been made void by use of Precision Medicine by $AVXL.

What can we say about the SUPER RESPONDERS:

  • It seems that all 6 patients are carriers of SIGMAR1 WT who respond to Blarcamesine in significant way.
  • Among them might be scattered carriers of APOEe4 allele whose severity of decline is affected by the genotype.
  • We assume this to be the best case for application for approval from FDA known to us at this time.

What “statistically significant” mean:

It is similar to the phrase beyond “reasonable doubt”. If p is greater than .05 then there exists reasonable doubt to the hypothesis trufulness and for all pratical purposed it should be rejected. Otherwise the hypotesis find itself beyond reasonable doubt. Still, p-value might be below .05 and the effect might be not satisfctory. Results can be have low efficacy but valid statistically. Enter Effec Size into the picture.

What effect size is:

We can calculate Cohen’s D between two samples with defined mean and standard deviation to assess the Effect Size of a drug in trial.

The biggest hurdle is to assess the decline per year and standard deviation since number of studies exist and in case of annual decline I have seen numbers like -2.15, -3 and -5.7. They all are very sensitive to the mix and match in the placebo cohort of the MMSE, age and genetics. The same applies to standard deviaton as I have seen -2.15+/-.31 through -3+/-3.4 and -5.7+/-8.2. The closes to the ADNI Syntetic Placebo (standard of the industry) is -2.15+/-.31. I assume that the extremely narrow standard deviation in this model should be changed to at least vaule of 2 so that allow some not to decline even after one year.

BEST CASE
WORST CASE

How to interpret these findings?

The Best Case. 2.98 Size Effect is well beyond the .50 acceptable level for drug approval “no questions ask”. This is the same magnitude (2.8:1 “therapeutic signal” to “placebo noise” ratio) effect as was conveyed by the slide 17 with the placebo SIGMAR1 WT patients “noise” vs. SIGMAR1 WT dosed patients “signal”. Donezepil showed in highest dose cohort Size Effect=.28 and was approved. Even at the severe disadvantage Blarcamesine has 125% of ES of Donezepli, and this is done ove the period double that of Donezepil’s beneficial effect, of just 6 months. The ES=.35 is strongly influenced by decline from average, I assumed this to be the 21 MMSE points and decline of -2.15+/-2.00. If the placebo decline is just one point more, we get following change in ES result. This proves how sensitive is ES to placebo model.

  • One should be very appreciative of the management by Dr. Missling, as instead of pursuing outright a decisive trial which could possibly disappoint and shatter the company and prospects of ANVEX2-73 he probed all possibilities and collected enough data to create a juggernaut of a drug. For a small company and a giant in waiting that is not a small feat.
  • Once Dr. Missling said once we get approval we will understand why he went this way not another (paraphrase).
  • The emphasis on Precision Medicine is the exapmle of the sentiment I expressed in above point. Without it the we would not be unaware of the real healing power behind this drug.
  • Placebo and its composition (initial MMSE scores, age and genetics) is very important as it determine the deterioration of its patients. As ES is very sensitive to placebo metrics so is the approval process but at ES=.28 (Donezepli) the hurdle is low.
  • Yet, if ES=.63 even at being unaware of Anavex2-73 would have had a clear path to approval. Without Precision Medicine all depends on placebo relative performance.
  • The SIGMAR1 WT show the same performance in PDD Phase 2 as the same genotype in AD Phase 2a.

The question whether there will be an approval has been answered; all the ducks are in a row. The rest is in the nature of the game of being a biotech stock, the science has spoken, it seems to be settled.

I am planing to partial change profile of my blog so I am not going to blog about $AVXL mostly, may be there is some cash in other subjects.

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GOING ONE SLIDE AT A TIME.. CTAD 2020. $AVXL BLARCAMESINE

SLIDE 15.

Slide 15

It is long standing tradition that $AVXL formats the data in such way that only a scientist can quickly recognoze the revelance of the data to currrent paradigm of the disease in question. The individual investor is left holding in his hand something so bewildering that I don’t dismiss the calls that there is nothing to it just cherry picking or “no good data” to be dismissed as another trick played on the individual investors.

Let us get down to it and elucidate as much knowelde as possible. The note on the bottom left relates to statistical method. J-T test stands for ;

The Jonckheere-Terpstra test is a rank-based nonparametric test that can be used to determine if there is a statistically significant trend between an ordinal independent variable and a continuous or ordinal dependent variable. The Jonckheere-Terpstra test tests for an ordered difference in medians where you need to state the direction of this order (this will become clearer below). It is also known as the Jonckheere-Terpstra test for ordered alternatives.

The ordinary independent variable is the dose the ordinary dependent varaible is the count of right or wrong aswers in the test of Episodic Memory. Most questionares are available on line, but CDR-CA Continuing Attention is available in software form only and is being controlled by private company. In light of this I do not know how many counts there are to be found in the test. All I know that the test takes about 18 minutes. I am not even cartain whether this is pertains to the particular battery tasks in question.

If we assume 100 counts then the improvement is about 20% from base line and 42% of the scale diffrence between outcomes. This seems to be too big a difference to be relevant in the context of procentages of assumed scale because there is some sort of nonlinear situation here as probably the test units are of varing difficulty to extend the scale from mild symptoms to severe.

The only conclusion we can make is that during the period of 14 weeks the deterioration of those on placebo arm is sufficient to detect the trend down and the same 14 weeks is sufficient to exhibit the trend up. (up = improvement) in both dose cohorts and placebo. There is no way we can say anything more at this point as we do not know enough to anchore it to some absolute value. To make a meaningful plot one needs the number of misses as well of hits. All we have is relative number of hits (mean) with bar of distribution.

Slide 17

Another slide with no absolute numbers but uses absloute vales of the changes from baseline of all the patients in population to arrive at realtive contribution of given populations. As you might remember absolute values do not have a minus sign and are always positive, it is just magnitude of change without direction. In the left side of the slide the contributions are changing in very small ways toward the dosed cohorts composed of SIGMAR1 Wild genotype and SIGMAR1 mutated genotypes. They all seem to be consitent with distribution of patients to cohorts (2:1). Then on the right side the population of SIGMAR1 Wild genotype in dosed cohorts (unmutated SIGMAR1=the good responders) increase their relative contribution. This proves that it is dosed SIGMAR1 WT who respond with greater magnitude of signal than the background of placebo. This gives greater confidence the dosed cohort privide statistical significance as they separate the signal from the background noise. As I said this does not measure the direction of change just its magnitude. From this plot one can see that average dosed SIGMAR1 WT is “improving” (if we assume that this only due to improvment, so we assume direction) 12.5% more than average SIGMAR1 WT undosed patient in placebo arm 6 weeks ago, compare this to 4.5% greater contribution of all dosed cohorts with both genotypes for the same period of 6 weeks. This makes the magnitude of change in 6 weeks 3 times larger for SIGMAR1 WT than between placebo and both dosed cohorts. One can say that SIGMAR1 WT signal to noise is 2.8:1. One has to remember that individual subjects due to variation in and nature of human performance will move up and down in zig-zag motion along some trend line, so there is noise and this can up as well down but will register in this measure as a positive value regardless of direction. There is one more piece of info to ponder here, as this is done within the confines of 95% confidence level, meaning the there is 95% chance that the result are repeatable, namely our beloved phrase “statistically significant”.

First thing which is a surprise is that that subjects have the SIGMAR1 Wild genotype in only 87 cases, these are the Good Responders. Remaining 47 patients are the mutated SIGMAR1 gene carriers. They are basically 1:2 represented in the test population. In other words the mutated version carrier represent 35% of trial population almost double that what is represented in the general poplulation. That is double overrepresentation of the 16 to 20% in general population. Does that mean the sufferers of PDD are more likely to be carriers of mutated SIGMAR1 gene? That would have two consequences, first that Population Intent To Treat would be a bit smaller due to greater mutated version of SIGMAR1 incidence among patients with PDD, second might be that mutated gene is innately connected with succumbing to PDD which supports thesis that the SIGMAR1 Wild genotype has protective properties.

Slide 11 with the timing of dosing

Question of timing. From the Alzheimer’s Phase 2a we know that Blarcamesine given in lage enough doses results in sudden large changes in measured outcomes for the first 5 weeks then the pace of improvement, at least in the Super Responders became less steep but continued for few years. From the dosing on slide 11 and the info on the slide 17 it seems that in Parkinson’s Phase 2 the week 8th is comparable to week 5 in Phase2a and week 14 to week 11, Just keep this in mind.

Slide 18.

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TREND LINES to visualize difference in time between Dose Cohorts and Placebo

In the above plot I wanted to convey the difference which grows with time when these trends as measured will continue. The slide 15 suggested 100 misses and 100 hits. this might be possible as the one test unit might be just few seconds (ten’s of seconds more likely). The scale here is just 50 misses. The 20 misses in just 14 weeks seems to be a very rapid decline, I think that the subjects range from those with MCI (mild cognitive impairment) to mild dementia so the decline in aggregate might persist.

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Indication Parkinson’s! $AVXL Blarcamesine

For next month I will go over the CTAD data in detail. Please, subscribed. I will post at least 3 post a week.

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!

Page 8 of CTAD 2020 Presentation.

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I downloaded copy of the paper listed on the slide 8 and that is what I learned.

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Connectivity of working memory in human cognition slide 12 CTAD 2020 Presentation

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Blarcamesine has the making of a drug which can become the first choise for patients with Parkinson’s, either slowing progress of the disease or even reversing it for some. The prospects here are even beter than they are with Alzheimer’s

I am sorry for multiple log-in buttons, I am learning how to use the editor, but the same login should be used for all paragraphs. I apologize.

CTAD 2020 Delivered Goods List. $AVXL

List of delivered goods.

For the list of goods to be delivered see http://Goods to be delivered

  1. Goods delivered. The dosed cohorts beat the placebo with hands down. Analysis coming.
  2. Placebo “slower” than the dosed. Goods delivered.
  3. Dr Missling talking of other demantias to be soon tackled by Blarcamesine. Point Delivered.
  4. Not yet delivered. One out of five, not bad.
  5. Goods delivered. Analysis coming up.

From other signs in just a sweep of the presentation, FDA is being informed or rather has taken notice of Blarcamesine. I bet there is a rush to approve Blarcamesine within the timing constrains of the system. I am convinced of it as I looked at the timing of the Rett trials. I don’t want to set any dates for approval as these are always sooner than the bureaucracy of the process allows, but you have to live within this sysyem as it the law of the land.

Kudos to Dr Missling who plays the long game, never overextending the companies finances in order to provide one toss of dice approval, and then turn to toxic financing when the resources are low. Combining cohorts of different dosing is one just way to play this game as statistical significance is maintained with efficacy. My immediate takes is that in few years it will be Blarcamesine given as drug of first choice to Parkinson’s patients after early diagnosis by computerized mental testing.

What to Expect from CTAD 2020 Boston. $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!

Let us go from the most likely to the least likely.

  1. Cognitive Drug Research – Computerized Assesment System – Continuing Attension confirms the AD Phase 2a Phase 2b/3 results with decreased timing in psychomotor skils (relevant to both PD and AD, but mostly for PDD) and cognitive skill as tested by CDR-CA.
  2. Background of previous point; dementias, both in PDD and AD are connected with increasing the latency in phenomenons like P300 (wave of reverseing polarity on synapses after an event like startling sound), which translates into what we laymen say about others like “he is slow”. LOL. It might be almost anecdotal but the speed of synaptic response of your nervous system is positively correlated with your IQ. So speed up and your are brighter, that what in essence measures CDR-CA, and does it in milliseconds. This is positively as much as possibly you can get to the most objective measurment of mental abilities.
  3. If such outcomes are to be reported then Blarcamesine becomes the Universal Drug to Go in Dementias.
  4. 78% of PDD patients develop dementia and some develop psychosis just beyond the mental ability of impairment (dementia). The impairment of mental function are called the negative symptoms, the psychosis on the other hand are called the positive since they are an “addition” to the mental condition of a person afflicted. In some sense PDD leads to dementia (negative symptoms) which then leads to psychosis (positive symptoms) not unlike schizophrenia. Is this bridge to treating schizophrenia? Does PDD Phase 2 report on these symptoms?
  5. The etiology of PDD is being connected to the death of neurons in substrata nigra and resulting dopamin deficiency causing the motor skils negative symptoms. What if Blarcamesine can restor the homeostasis to those neurons and prevent neuronal death, but above all restore the levels of the neurotrasmitter in question, dopanime that is. In this way Blarcamesine becomes the drug for PDD. We only will know if the dopamine levels are direcetly measured otherwise we can reason it out of the CDR-CA results.

Published 9:52 AM on 11-6-2020 so few minutes before the presentation.

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Suddenly, Aducanumab (again)! And Biogen Adds Billions in Market Cap. $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!

Before I lose my train of thought…the title should have been; “at 3,285 patients even the dead can walk…”. Another of my gross exaggerations.

The intrepid Aducanumab adds another $X billion to $BIIB market cap. New analysis claims that there is a glimmer of hope for the drug. I am not a statistician or did I see the study. All I can do is to look for differences in measurements and trials between Blarcamesine and Aducanmab, and there are some great differences. FDA’s clinicaltrials.gov lists both Biogen studies as almost identical and terminated upon futility study on 1,748 patients. Yet once the data on the full the set of 3,285 patients has been gathered a new life has been blown into Aducanumab’s claim of efficacy. Let’s look at some aspects of it Aducanumab’s trials and results.

Selection of Subjects

Both studies recruited patients between MMSE scores 24 and 30 but with positive amyloid Positron Emission Tomography, ergo the guy or gal can be normal but have deposits of amyloid plaque. If you have read my posts in the pasts you probably remember that I had learned that about 30% of deceased Alzheimer’s sick don’t have plaque and that some people have plaque but are perfectly normal. These people have either MCI or mild AD but at MMSE 30 they can fall into the category of “healthy + plaque”.

The other aspect is that APOE genotyping has been conducted which means that the carriers of e4 can be excluded but this has not been asserted when they talked about a subgroup of responders. Though the science on APOE e4 is not conclusive it is taken to be true that the single carriers have 20% probability of developing AD and much earlier, the progress of the diseaes is also much faster than for none e4 carriers. See my post on APOE genotyping Anavex2-73 Phase2a. https://wordpress.com/post/piotrpeterblog.com/460 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118550/

It has been reported that some subset of patients has responded positively to treatment with Aducanumab. Are carriers of APOE e4 excluded? What is the average MMSE score of those responders? One is certain that the drug has caused removal of plaque, which is deemed to have synergy in causing further deterioration in patients, so removal can be expected in some way to help the patients, theoretically. It could not have been found in 1,748 patients but was somehow conjured at 3,285.

It is very hard to compare Blarcamesine data and Aducanumab as the starting MMSE scores are different and the onset on Alzheimer’s is not linear which is explained in this reference. https://jamanetwork.com/journals/jamaneurology/fullarticle/775209 The data from this reference has been presented graphically beneath.

Outcome Measures

CDR-SB is not the same measure as used in $AVXL PDD Phase2 trial. This is just a very subjective questionaire with just 4 different outcomes. See it for yourself https://sites.cscc.unc.edu/aric/sites/default/files/public/forms/CDS%20Clinical%20Dementia%20Rating%20-%20Summary%20and%20QxQ.pdf

CDR-AC, which was used in the PDD trial, is a computerazied assesment for cognition and motor skills to be used in both Alzheimer’s and Parkinson’s diseases where some of the reuslts are measured in milliseconds. These are not the same measures. One is very objective and quantitative and the other is much more subjective and qualitative.

The reported 23% increase in the scores of CDR-SB is basically lowering the score by 25% in most subjects. This can be significant but the next measure that is MMSE scores paints rather different picture. The data on MMSE scores was supposed to be better than the placebo by 15%. MMSE is not perfect but it is a better measure as it it less prone to subjectivity.

Extrapolating from this graph MMSE scores in the initial period of the disease after 18 month should be lower on average by 3.38 MMSE points. Average MMSE score is let’s say (assumed) 27 points, including drop it is 27-3.38 points=23.62 points so after 18 months and 15% improvement (115% of placebo score) this is MMSE 27.16 points therefore improvement can be seen as illusory as that subset of early patients could have not deteriorated yet. These are the paients who postpon their slide into dementia for just a year or two. The power of the study is at p=.06 which means that 6% patients in the select group could be counted in the dispersion about placebo mean. See the plot and read that at 78 weeks there is still some 10% of patients who did not deteriorated at all in the background of other 90% who did, some even significantly. I present here a models of deterioration from other post as there always is a group with delayed deterioration which over years dwindles with accelerated rate as years progresses.

This depicts deterioration for patients on average at MMSE 20 points, that is on 60% percent of the scale (healthy). MMSE of 24 is 80% percent of scale and MMSE 30 is 100% of scale. Also these patients had been already followed for one year prior. The disease can have very nonlinear progression with large number of patients detriorating quicker than other and some lingering for quite some time. The above illistration drives the point in easy to see manner.

See this paper for source data https://jamanetwork.com/journals/jamaneurology/fullarticle/775209

By contrast the MMSE scores of the Super Responders in ANVEX2-73 AD Phase2a can be seen on this graph

If we talking selected groups the 4 assending patients have imporoment of MMSE 4 points which over placebo give improvent of 170% over placebo in span of 78 weeks, the same as the $BIIB trials.

If we try to compare oranges to oranges and apples to apples which anyway can not be perfect in he field of Alzheimer’s but at least semblence of such comparison is called for here then the improvement by Blarcamesine in MMSE scores over Aducnumab is almost ~5 times greater for selected groups

Biogen claims efficacy by separating th patients into selcted groups, subsets, the question is how valid is such division? Can it be justified on some bio marker grounds? Or is it just another case for crafting the trial to the drug vs. the drug to the trial?

I read following article https://www.statnews.com/2020/11/04/fda-scientists-appear-to-offer-major-endorsement-of-biogens-controversial-alzheimers-treatment/ . I would like to highlight following quotes. One of the authors here is no other than Adam Feuerstein https://twitter.com/adamfeuerstein

In Conclusion

  • $BIIB is picking and choosing studies and group of patients, and with the exclusion the fast and furious down the 6 feet down slide and at 3,285 patients much can be claimed.
  • If the claim that the blinding of the study has been compromised and the fact that on qualitative and subjecive measures Aducanumab improved most the we can stipulate that the CDR-SB was affected by this.
  • The improvement in MMSE scores puts in doubt the scenario of significant efficacy as applying the same criteria to Blarcamesine trial Phase2a gives 5 fold advantage over Aducanumab to Blarcamesine.
  • The above point was made in face of assumed average initial MMSE score for Aducanumab of 27 point versus that of 22.5 for the Super Responders of Blarcamesine. Relatively healthy vs. Already diseased and rescued.
  • Starting with almost healty subjects (MMSE scores 24 to 30) might distort the trial as the fast deteriorating patients are excluded and the duration is only 18 months. See illusration above.
  • The incidence of ARIA still present vs. almost none on Blarcamesine side.
  • Just another attempt to rescue the amyloid hypothesis for Alzhiemer’s on closer examination doesn’t hold water.
  • The simplest expalaination of Aducanumab strategy is to remove the worst offenders and still compare to placebo arm containing those worst offenders but your claim rests on the fact that relatively healthy rest of the dosed arm do not start to deteriorate untill much later.

I beg for money here but I have the impression that had I stood on the corner I would get more money. Just drop a fiver!

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About Rett. $AVXL ANAVEX2-73 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!

The study of Anavex2-73 in Patients With Rett Syndrome NCT03758924 being just a repeat of AD Phase 2a that is expolaratory turned out to be a shocker. A measure of behavioral “disruption” droped 30% from baseline which is 21% of the entire scale of 70 points. Even at just 6 patients the drop is statistically significant p<.05. Two measures RSBQ and CGI-I both moved in the same direction with steady correlation. Neurotransmitter Glutamate deacreased by 40% from base, GABA, its antagonist, increased, in inverse relation. All of this was achieved on 5mg daily dose. Or is this a typo? The results come from 6 patient which comprised a pharmakinetics cohort of the study. This reference gives the values for glutamate concentration in Rett patients and healthy controls. https://pubmed.ncbi.nlm.nih.gov/8916158/

In the patients with Rett syndrome, the mean of cerebrospinal fluid glutamate concentration was 355.2 nmol/L (SD +/- 109.2 nmol/L). In the controls it was 203.9 nmol/L (SD +/- 55.5 nmol/L). … Glutamate may therefore play an important role in the primary pathogenesis in Rett syndrome

After drop of 40% the concentration shall be ~213 nmol/L which comparable with healthy controls. There is great divergence in those number bewteen ages as at age 20 young healthy person might be around 2.5 that much what is the concentration in brain of a 35 year old mature person. The numbers given where for girls in ages spaning from 3 to 13 years old with average about 8 and similar thing for controls. The subject in the study are all over 18 years old to 45 years old so this calculation can only give us certain amount of insight. And their level of concentration is 250 times than normal given in the above reference as reported on page 14 of ANAVEX Corporate Presentation, February 2020. Drop of 40% lowers this to 150 times. This is indeed a stunning development as the levels are brought to almost normal levels, at least in the context of the above reference but not the presentation numbers. I think that measurment methods can be different here, or is this a typo? Only long term dosing will tell how far Rett syndrom sufferes can be rescued. How quickly can we know the results of 14 weeks extension? Through my own experience I can imagine the mental torment these poor souls go through. Your brain can be affected by chemical and even a “better” ways is through microelectronics or direrctional electromagnetic waves. Russia for example boasted of a naval weapon, an electromagnetic beam, able to disrupt the sight of naval personel. The stories in the news have not reached a threshold of widespread public awarnes. They are just dripping not yet pouring. Microelectronic implants are the next wave of dealing with CNS disorders but your privacy is gone after implanting.

Since I am a lay person, what is not seeming to scientis might be quite forgivable to the one not worshipping at the altar of scientific ortohoxy. From referrence on RSBQ I learned that one of the telltale sign of RS is unconsloable crying at night or screaming, and seizures. If indeed operation of locus coeruleus (location of “circuit” regulating panic and fear) is out of balance due to the mutation and it causes flooding of the brain with neurotrasmitters like glutomate and they return to almost normal levels, so it seems, the question is how deep is this homeostasis restoration ability of ANAVEX2-73? In some posts I advanced the idea, the Romans used to say “paper never blashes”, the Blarcamesine’s MOA is connected with embryonic development when rapid growth requires increased “quality control” of all processes in the cell. The earliest you can see the onset of Rett is about 6 months after birth, no indicationas are present in the prenatal period. The implications are that Blarcamesine can work just like gene terapy if introduced early enough.

iHub user Xena left a comment with a link to a paper about leads into the mystery of autism. The paper listed pletora of neurotrasmitters with deregulated levels and other neurvous system compounds with information from studies attepting establishing links to autism spectrum disorders. The Rett Suprise might be repeated on Autism, which is the conviction of Xena, and with some dose of incredulity of it all, mine too. Thank you, Xena!

  1. Study NCT03758924 puropose was to explore the dose and pharmakinetics of Anavex2-73 in Rett Syndrome, hence 5mg dose, probably driven by mouse studies. Duration is interesting 7 weeks dosing and OLE extesion of 12 weeks. Would we be soon informed about the results of the extensions?
  2. Recruiting for Australian study NCT03941444 (AVATAR) proceeded before completing of NCT03758924. Is this the “Fast Track” designation at work?
  3. The Clinicaltrial.gov page listed 31 patients for NCT03758924, in the presentation we have 21(!) and the study is conducted in the US. It is possible that study is suspended in light of reaching statistical significance?
  4. AVATAR study has 22 girls in dosed cohort, but what is interesting is that Primary Outcomes Measures are all Pharmakintetics, also dose in not given. Is the drug is effective but optimal dose has to be determined?
  5. Study NCT04304482 ANAVEX2-73-RS-003 (EXCELLENCE) is the Phase3 study due for completion July 2021. 46 dosed to 23 placebo. 12 week duration plus 48 weeks extension. 5-18 years old.

This is so called “telescopic development”; each trial is nested in previous one, timewise, the information cascades to next level once it is obtained. We are on the Fast Track.

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CTAD 2020, PDD Phase2, way to partnership? $AVXL ANAVEX2-73 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!

Alzheimer’s trial as widow makers

Dr Missling by choosing to have only 32 patients in Alzheimer’s phase2a proved that he was very conservative with company’s resources and not overly enthusiastic about ANAVEX2-73 prospects. Ask questions first, shoot later. The run up to $14 on hopes of “quick cure”=”quick riches” was indeed a disappointment to shareholder or speculators (not much I think, at least to the experienced ones) in $AVXL stock. On the other hand Dr. Missling tactics of incorporating genetics, Ariana’s AI, microbiota and ingenuous financing, just to mention few, are a proof of strategy aiming to build lasting value.

The Parkinson’s Dementia Disease study phase2 has about 44 patients per cohort. By looking back, one can see that the initial miserly 32 subject spread over 3 cohorts dwindled to 9 patients in High Concentration Cohort who could be used to prove the hypothesis of ANAVEX2-73 efficacy, but they were too few to do it outright, they did it over span of few years. When looking at the PDD trial phase 2 every cohort has ample number of participants to end up with at least ~30 patients needed for minimal sample in life sciences. This alone suggests that Dr. Missling as much as trying to economize on sample size has now full confidence in Blarcamesine. Remember, for 20 or so years 95% of trails for Alzheimer’s drugs ended up as failures, making AD a proverbial widow maker. I guess that on 9 patients in High Concentration cohort you can discount any chances on an approval or partnership in the world so intensely afflicted with bipolar disorder of hype, dashed hope and failure. The bipolar condition afflict the small companies to a greater degree than the Big Pharma companies, who are more observers than actors in this field. Though those who speculate bet more on Big Pharma. However strong the signal was in AD Phase2a most of the people in the field plus the pundits were skeptical as “great discoveries” can be had a dozen at a time and even cheaper a 2 years later.

Let us go over in details why and how PDD phase 2 is relevant for Blarcamesine and $AVXL.

  1. Duration of trial: 14 weeks. In AD Phase 2a the patients who responded positively to ANAVEX2-73 did it over period of 7 week in very rapid fashion and then they split into one group slowly improving and one slowly descending in their MMSE scores. Repeating this pattern in 14 weeks would corroborate AD Phase2a with at most 44 patients and had it been weighted statistically as significant when seeing the same strength of the signal this would be complete. The therapeutic result can even be greater as Dr Missling pointed out that even the 30 mg cohort responded.
  2. The use of Cognitive Drug Research Computerized Assesment System Continuining Attension measurest among others reaction time both in mental aspects as well as motor skills. Nice name comes here to mind, psychomotor. Wikiepedia pages lists the know etiology of Parkinson’s:
    The motor symptoms of the disease result from the death of cells in the substantia nigra, a region of the midbrain, leading to a dopamine deficit.[1] The cause of this cell death is poorly understood, but involves the build-up of proteins into Lewy bodies in the neurons.[4] So another undetermined primary cause neurodegenerative disease with the most conspicuous cause (dopamine deficiency) and neuron death located in one region due to homeostasis deregulation spreading from origin to Lewy bodies in particular. Is Lewy Bodies Dementia next target? This is kind of like a cross between AD and Rett. On conceptual level only.
  3. If CDR-CA would measure the amount of rescue extended to motor neurons on global level, just beyond pure dopamine deficiency, at least in the context of Blarcamesine study, anti-neurodegenerative properties of Blarcamesine would be buttressed. CDR-CA was also validated as a measure in AD. Dr Missling mentioned that notable strong signal was detected in memory measurement. If response in psychomotor skills would be statistically significant and would be better or equal to the existing therapy, we have killed two birds with one stone. This is another evident reason to think of ANVEX2-73 as neuronal broad-base homeostasis drug than one working on one single chemical reaction in a cascade like most of the old guard drugs do, or SOC.
  4. Members of the Ariana team are co-authors of the presentation. Are we again pursuing the genetic signature of perfect PDD patient? I am not a scientist so I do not know a lot of details about the genetics of the disease. The approach taken by $AVXL is not to only concentrate to bring the drug to trial but to create knowledge base so that a drug like ANVEX2-73 can be assured to beat all possible ways FDA can find to make life difficult to $AVXL. Dr. Missling creates a franchise not just a one wonder-drug company.
  5. PDD phase2 with very brief exposure of just 14 weeks corroborates AD Phase2a the exploratory trial. I called AD Phase2a “exploratory” because with the least of money Dr Missling was trying to find out whether there is anything in the AD field for $AVXL. The extremely low number (in absolute terms) of very strong responders determined the way forward without destroying the company financially. The penalty is time. I don’t think that anybody in FDA would risk giving, even at this junction, green light for approval without a partnership; a foot into the door of the club.
  6. The coming Rett results and PDD Phase2 results to be broadcasted at CTAD 2020 in Boston validate the attractiveness of $AVXL to join with Big Pharma company in partnership, or rather they quicken the time for it. On how Dr. Missling will play this out will depend the future of the company.
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