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The graph on the left shows the plot of changes in the MMSE scores (cognition) over 148 weeks of Phase 2a and the Open-Label Extension. Because the graph values include MMSE scores, Standard Error, and n, we can calculate Standard Deviation to arrive at Cohen’s d Effect Size at 57 and 148 weeks.

The definition of Standard Error is SE = Standard Deviation / Square root ( n )

Once we obtain Standard Deviation, we can calculate Pooled STANDARD DEVIATION used in calculating Cohen’s d.

The definition of Pooled Standard Deviation is SDpooled = Square root(( SDdosed^2 + SDplacebo^2)/2)

To calculate Cohen’s d, we divide the difference between the cognition scores of the Placebo and Dosed arms by the pooled Standard Deviation. The result is the Cohen’s d Effect size.

Of course, since we do not have the accurate Placebo arm in Phase 2a, we assume that the Low/Medium Concentration Arm is not showing any therapeutic effect of Blarcamesine in Alzheimer’s disease and, therefore, can serve as a Placebo arm.

After going into calculations, we obtained the following results

**The Effect Size for Blarcamesine after 57 weeks of dosing was ES57= 0.38**

**The Effect Size for Blarcamesine after 148 weeks of dosing was ES148 = 0 96**

I cannot provide you with a quick answer to this question. Only partially, since we do not know the mean cognition and Standard Deviation results for the 50mg Cohort in Phase 2b/3. Let’s see what we know at this moment.

We are given Standard Error for the Placebo Arm and The Mean. We have the combined arms for the Anavex2- 73; 30mg and 50 mg. 30mg corresponds to the Medium Concentration Cohort from Phase 2a, so we assume there is no therapeutic effect in that cohort. The Odds ratio leads us to believe we can have a 70% / 30% distribution between those scoring on average -4.03 ADAS-Cog13 and those scoring +4.11 (Placebo-like) ADAS-Cog13. We can also assume that the maximum effect distribution might be 80% / 20%. We also have to assume the values of Standard Errors (by extension of Standard Deviations) to be the same as given in this slide of the December 1, 2021 Presentation. These assumptions introduce unknown errors in the Cohen’s d Effect Size estimation for Phase 2b/3. The results can only be used as general guidance. I will not present here all the calculations and will limit myself to results.

**The 80% / 20% distribution of results attained Cohen’s Effect Size of 0.57 after 48 weeks of dosing**

**The 70% / 30% distribution of results attained Cohen’s Effect Size of 0.50 at 48 weeks of dosing**

Similar results were calculated for 48 + 96 weeks per Attention-AD trial (clinicaltrials.gov), assuming 2% deterioration in dosed arm with Placebo Arm deterioration of the same rate as in the 48 weeks.

**The 80% / 20% distribution of results attained Cohen’s Effect Size of 1.15 after 144 weeks of dosing**

**The 70% / 30% distribution of results attained Cohen’s Effect Size of 1.10 after 144 weeks of dosing**

**Two observations can be readily made. The error in my assumptions is not leading to a significant divergence between the results from Phase 2a and Phase 2b/3, and with time the Effect Size has roughly doubled. ** **Also, Phase 2b/3 validates Phase 2a even against arguments to dismiss it due to its small n. **

To put these numbers in perspective, I will calculate the Effect Size of Cohen’s d for the 12 months (52 weeks) for $SAVA Simufilam. We have almost all the data available on January 24, 2023, Press Release from Cassava Sciences except for Placebo arm deterioration at cognition score of 19.1 ADAS-Cog11. Previously done analysis led to this plot of baseline cognition numbers related to expected Placebo deterioration. link https://piotrpeterblog.com/2023/07/26/beware-of-lower-adas-cog11-baseline-scores-when-compaing-drug-performance-blarcamesine-vs-simufilam-avxl-sava/

When converted from ADAS-Cog13, the baseline cognition for Blarcamesine is ~24 ADAS-Cog11 points. Still, for Simufilam, with a higher level of baseline cognition at 19.1, the rate of Placebo arm deterioration seems to be about 2.25 or 2.5. Plugging all the numbers into the EFeect Size Cohen’s d formula gives the following results for Simufilam.

**Cohen’s d Effect Size for Simufilam at 52 weeks of dosing at a baseline of 19.1 ADAS-Cog11 is ES = 0.18**

**Cohen’s d Effect Size for Simufilam at 78 weeks of dosing at a baseline of 19.1 ADAS-Cog11 is ES = 0.22**

From the clinicaltrials.gov (link https://clinicaltrials.gov/study/NCT04314934?intr=blarcamesine&rank=2), we can read that the Attention-AD trials add another 96 weeks of dosing to the already accrued 48 weeks giving altogether 144 weeks of dosing which is about 2.77 years. A trial that long, at least for Alzheimer’s disease time, eliminates all who would spontaneously test cognitively higher than the baseline, leaving no doubts about the drug’s efficacy. This was the conclusion of the paper I gave a link to (link. https://pubmed.ncbi.nlm.nih.gov/10404988/). **The trial is to be completed by 7/31/2024. **

- Phase 2b/3 improves over the Phase 2a results. We must remember that Phase 2a had over 70% APOE4 carriers, while the statistical Alzheimer’s population holds only 43%. They deteriorate 22% faster than other Alzheimer’s patients.
- With time, Cohen’s d Effect Size increases in both Phases. Releasing the results later has the advantage of erasing doubts about the drug’s efficacy as 2.77 years trial duration purges any patients who could spontaneously score better than at baseline.
- Simufilam is not competing with Blarcamesine. If it reported its Effect Size at 3 years at present deterioration rates, its ES would be only about 0.34 versus Blarcamesines ~1.00.
- Any values present here are approximate, as the respective Standard Deviations may change with time. They only give insight into general trends.
- Stocktwits community members speculate regarding the release of full Alzheimer’s trial data. It seems that the latest the data can be released is after 7/31/2024, as the accrued Effect Size will be most remarkable. This generally agrees with Dr. Missling’s words of surprising the market. In this case, data would show unquestionable Blarcamesine’s efficacy.
- The baseline of the Blarcamesine trial in cognitive terms is so low that compared superficially to other drugs, it suffers from a comparative disadvantage in the eyes of investors. The lower the cognitive baseline, the faster the deterioration of patients, and the stronger must be the drug’s therapeutic effect to overcome deterioration.
- This phenomenon is not lost on the people in the field, but investors are not accurately aware of it. That is why KOL are enthusiastic about Blarcamesine’s prospects.
**As Investor, I realize that the full release of data on Alzheimer’s trials will likely happen the following year (2024). I suggest forbearance and focusing on Rett’s results.**

**Please, donate. I just bought grammar software to improve my writing **

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Donate yearlyIn general, these diseases are a constant struggle between the adaptive capability of the brain to injury and the process of neuronal death or impairment. The greater the progress of the disease the lesser the margin by which the adaptation or plasticity of the brain can cope with the devastation of the brain tissue. This progressive character of the neurodegenerative disease explains the phenomenon of the increased rate of decline with the onset of symptoms that are preceded by neuronal death by about a decade. On the other hand, there is a glass ceiling on the amount of recovery every drug can provide, as no full recovery is possible, only partial due to the amount of damage already done.

Reference [2] on Table 3 lists the rate of deterioration for individuals at the age of 75 years, APOE4 negative based on their ADAS-Cog score. If we plot this we get this picture.

The plot from about 10 ADAS-Cog points to 30 is almost a straight line. The rollover at ADAS-Cog 35 points to such devastation already done that the rate of deterioration starts slowing. See reference [2]

Since this is the plot for individuals, I compared that with empirical data from a number of trials and this is the approximate rate of decline for whole populations involved in trials based on their mean baseline ADAS-Cog11 scores.

So if you want to know how fast the trial population shall deteriorate from the baseline you select on the x-axis the baseline number and read off the y-axis the rate of deterioration.

Again, in general, in every trial, there is a play between the forces of deterioration, which strength can be expressed in the deterioration rate, and the therapeutic effect of the drug. Following that logic, trials with different baselines are not equivalent. Their results should be adjusted by the ratio of their deterioration rates. that should be done in principle, for greater fidelity of comparison.

The graph above was arrived at by dividing the rate of deterioration for the baseline of ADAS-Cog11 equal to 25 points by all the rates of deterioration for any other baseline. In this way, we arrived at a very imperfect but informative relative strength of the tendency to self-recover as some patients core better with time than at the baseline.

**In light of this relationship, the lower baseline is selected for trial the the lesser drug therapeutic effect might be to achieve the same result**.

**Due to the above-noted relationships and phenomena, it is very tough to compare or assess the absolute performance of trials for different drugs. The latter is much more difficult than the comparison between drugs with trials with similar baselines. ** **Such differentiation can be much easier to achieve than absolute reckoning. **

My approach was that Odds Ratio gave the number of those improved in cognition below -0.5 ADAS-Cog13 points (negative is improved) to the number of those who naturally are still improved at one year into the trial started at the baseline of ADAS-Cog13 29 points. The unknown was the latter. I used two different estimates. I estimated the number of patients below -0.5 points by calculating it from the placebo Standard Deviation. Alternatively, I used the estimate given in reference [1]. I settled on the average of the two i.e. 29% of the placebo population. I will refer you here to my video on the subject. Link: https://youtu.be/Jj6Px_XhhLU

I estimated that the 50mg cohort would be composed of 70% of those who improved ADAS-Cog13 -4.03 and 30% of those who declined 4.11 ADAS-Cog13. The precedent is Phase 2a. The better case is if the split goes 80%/20%. then we need to convert the results into the ADAS-Cog11 scale by multiplying by 70 and dividing by 85.

These trials’ results can be found on January 24, 2023, Press Release from Cassava Sciences, Inc. and July 5, 2023, Press Release. Blarcamesine Phase 2b/30 had a baseline of about 29 ADAS-Cog13 points so we can equate this to 25 ADAS-Cog11 points. Smufilam on the July 5 Press Release had The Extension and Semi-Placebo respectively at 19.3 and 21.1 ADAS-Cog11 points. That baseline should give a slight advantage to Simufilam as we can read it off the graph of **Relative Strength of Self Recovery in Alzheimer’s Disease**. The number is 1.23 vs. 1 for Blarcamesine. Let’s see the plot of the performance of both drugs.

The Extension of the Open-Label trial had two legs. The dosed one has a slope of 2.05 versus the Semi-Placebo 2.53. That is just 81% of deterioration for Dosed versus Semi-Placebo. Comparing the performance of Blarcamesine to Simufilam the difference is in quality not only quantity. Blarcamesnie does not impede the deterioration but reverses it.

This is the most of the like comparison between the two drugs. Blarcamesine was supposed to be tested under lower ADAS-Cog11 baseline scores, and I think this did not happen as the stringent requirements to keep the trial population have an amyloid plaque in their brains pushed the baseline mean up.

Meantime investors in $SAVA Simufilam keep on comparing Simufilam’s performance only to Leqambi claiming better performance. User @Keroman (StockTwits) shared his plot of Simufilam performance at lower ADAS-Cog11 baselines (mixing baselines ADAS-Cog11 16.6 n=50 with 11.2 n=76 indiscriminately).

This is an impressive performance but it begs the question. How would other drugs perform under these baselines? The argument presented by Simufilam investors is that they only need to compete with the drugs like Leqambi or Donanemab. When the two latter are compared with Blarcamesine they seem to be almost frauds committed on the patients.

**In conclusion, I would like to stress that the baseline ADAS-Cog11 or any other cognition score must be taken into consideration when comparing different drugs. I was able to gather some empirical data listing the placebo arm deterioration but could not say anything as definitive as this about the percentage of patients testing above their baseline scores.** ** In general, I know that this number is increasing with the decline in baseline ADAS-Cog11 scores. This spontaneous improvement gives a false strong signal of drug performance at low ADAS-Cog11 scores. **

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**[1] Variability in Anual Mini-Mental State Examination Score in Patients With Probable Alzheimer’s Disease**

Christopher M. Clark, MD; Lianne Sheppard, PhD; Gerda G Fillenbaum, PhD; Douglas Glasko, MD; John C. Morris, MD; Ellisabeth Koss, PhD; Albert Heyman, MD; and the CERAD Investigators

**[2] Disease progression model for cognitive deterioration from Alzheimer’s Disease Neuroimaging Initiative database**

Kaori Ito, Brian Corrigan, Qinying Zhao, Jonathan French, Raymond Miller, Holly Soares, Elyse Katz, Timothy Nicholas, Bill Billing, Richard Anziano, Terence Fullerton; Alzheimer’s Disease Neuroimaging Initiative

]]>Select your subjects with so mild symptoms of Alzheimer’s that even a minimal amount of therapeutic effect can move the needle. That is because the disease starts decimating the neurons in the patient’s brain probably a decade before and the plasticity of the brain compensates for the loss of critical neurons till it can not, and patients show symptoms. There is a point when this struggle between the loss and plasticity of the brain is most conspicuous when patients score one day down and a month later up a few points. When this struggle is still relatively young the patients seem to be more sensitive to the therapeutic effect of a drug but this is an illusion. This has been an overall trend in drug trials to select patients with lower levels of dementia in search of indications of efficacy as they seem to be more sensitive to drug effects.

The first look reveals that the two lines are almost parallel in their descent into greater dementia. What is essential in this picture is the stated baseline dementia measures. I assume that the 30-point ADAS-Cog11 and 70-point MMSE scales start at the same point and end. This allows us to normalize them into percentages of scale. In terms of MMSE scores, we are 38%. In terms of ADAS-Cog11, we are at 31% of increasing dementia. But in order to supply its fun base with “proof of efficacy” $SAVA chose to select a subgroup that benefits the most from the purported efficacy.

Let’s proceed to do the same exercise with the normalized measures of the advancement of dementia in this group of patients. In terms of MMSE, we are at 20%, and for ADAS-Cog11 16%. The group consists of half that much deteriorated as in Figure 1. The red line denotes the performance of the cohort where the dosing has been withdrawn and shows apparent oscillation about the horizontal line. All by making the struggle between deterioration and brain plasticity younger and more even. This is ridiculous, at least in my mind. All this is in a last-ditch effort to justify a failed drug that does not perform much better than the vaunted LEQEMBI. LEQEMBI might bury the amyloid plaque theory forever. The picture shows ascending Simufilam plotline just to bait the gullible.

Reference [1] link https://alz-journals.onlinelibrary.wiley.com/doi/10.1016/j.jalz.2010.03.018

This link is to a paper I have referenced with compiled data from an ADNI project that collected data on some 800 subjects. Here is a link to a video with a short description of the papers and their content.

I made a plot of the variation of the decline rate in ADSA-Cog set at constant age of 75 years for different baseline dementia ratings. Since the ADAS-Cog scale goes from healthy or 0 to 70, the x-axis goes from left to right increasing the baseline dementia for a given rate of decline.

In Figure 1 the baseline deterioration is reported to be about 20 points ADAS-Cog11 so deterioration is about ~4.8 points per year But at 10 points it is 0.90 ADAS-Cog points per year. That is a remarkable difference. In this context, Simufilam data has to be evaluated. This plot is not absolute but it can serve as a guide for those worried about how their investment in $SAVA might be going. Wait but there is a piece of extenuating evidence. The reference [1] identified the age of the subjects as the second in magnitude after the baseline deterioration factor in the rate of decline, with the difference that with increased age the deterioration is lower. Here is the plot.

The $AVXL phase 2b/3 had the average age of patients at 75 years but Simufilam had the Open Label trial which was extended into the latest one for Simufilam at 65 years. Playing with the ratio again for 65 years old patients the decline is 1.3 greater than for 75 years old patients. If we selectively applied the ratio to the 0.90 annual decline we get ~1.2 ADAS-Cog annual decline vs. 4.8 points. These numbers are not absolute values but can be used as guidance in evaluating data and give a good insight into the mechanics of the data.

**At one point in time, I even considered purchasing $SAVA stock as an insurance policy, I am $AVXL investor, but I decided to wait till more results would be available. Simufilam proved to be a drug not much better than LEQEMBI. Actually, its only virtue is that it is a pill, not an infusion. Maybe, I am not entirely right on this. I know that I am a bit biased but not much.**

**In the next post, I will talk again about Blarcamesine versus Simufilam**. **Meantime, I would ask for donations. My last post has been visited by about 600 visitors. I hope that you find this post helpful and I would like to stress that the site is safe as is published through WORDPRESS.COM and all donations are funneled through WORDPRESS.COM. I don’t need large donations to pay for the site maintenance, yet even small ones are significant to me. I would prefer to see many small ones as this gives me an indication of how appreciated my writing is.**

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I will fill in the gaps here where Dr. Grimmer has left out some details or I will arrive at clear conclusions. As it stands right now and maybe for a very long time, neurodegenerative diseases like Alzheimer’s or Parkinson’s can not be cured. Why is it? Because there are three processes concurrently at play in the brains of the patients. The onslaught of the disease precedes the symptoms probably by a decade. The disease affects the health of the neurons causing them to slowly die off. The plasticity of the brain compensates for the die-off. Yet, soon enough the brain which works like a network of nodes suffers disruption due to the overwhelming loss of critical nodes in the network, and the patient loses the ability to perform tasks. Plasticity hides the consequences of the die-off till it can not cope with the onslaught. The final result is that no drug can bring back the patient to the original state once the symptoms are apparent. The see-saw between the plasticity of the brain and decimating neurons disease can be the source of patients scoring higher on cognition tests during the trial than during the recruitment phase. The therapeutic effect of a drug can bring the patient’s cognition up but there is an inherited limit to it. The phenomenon can be seen in the increasing recruitment of patients with higher MMSE scores in cognition tests in the latest trials. All this is done in search of a greater therapeutic effect but this is in my final conviction illusory as it just pushes the limit to a higher cognition level. Of course, this limit is statistically distributed among the patients as is their individual condition.

**Let’s face it. Cognition testing does not tell the whole story. It just indicates there is a therapeutic effect but this is limited by the above narrative of the natural progression of the disease. **

Donepezil is presently the Standard of Care. The Mechanism of Action reveals how it does not work on the root causes of the disease. Basically, Donepezil blocks an enzyme that under normal conditions of homeostasis would break down the excess quantity of a neurotransmitter responsible for processing memory. For short 12 weeks, it compensates for the loss of memory due to neuron atrophy. These are two different processes. One briefly hides the consequences of the other but changes nothing as after 12 weeks the deterioration of patients resumes. At its apogee of illusory efficacy, Donepezil scores -2 points ADAS-Cog11 improvement in cognition. It is more like cocaine than a real drug helping the health of the patient, a short “high” at the expense of long-term well-being.

Dr. Grimmer said that it would be very interesting if the immunotherapy removing the plaque from the brains of Alzheimer’s patients would be successful enough so that they would experience no plaque brains. If they would deteriorate further then we would know that the etiology or root cause of the disease lies somewhere else. This is the quest of Phase 4 of the Lecanemab or other immunotherapies as they did not definitely have a significant impact on cognition. What is worth mentioning here is that the immune system can be both an extremely beneficial force and a destructive one. The experiment is in its final phase although results will arrive in a few years’ time to finally put this controversy to rest.

In Dr. Grimmer’s interview, the leading thread is the question of the missing etiology of Alzheimer’s. There are theories like the plaque theory but none of them has been effectively proved or disproved yet. I have to make a confession. I have pursued the importance of cognitive data and as I did this I learned something about the proposed disease’s etiologies. It is until recently that I realized that cognitive data is rather a small part of the story. Nevertheless, for a long time, I have been telling people that only after 3 years the true efficacy of Alzheimer’s drugs can be established without uncertainty. This is the result of a study on the natural course of the disease as it progresses in a clinical trial environment.

The only way to avoid becoming the victim of the Donepezil trap is to hit the real etiology of Alzheimer’s. Two outcomes are to be expected in a time of three years, the cognitive test should be relatively steady versus the declining placebo arm, and the second is a bonus and was identified with the trials of Blarcamesine, the other diseases of CNS are also affected due to similar underlying root causes. Dr. Missling proceeded to check the genome of the dosed people and the placebo to differentiate the active and silenced genes in both cohorts. Gross of the genes silenced in the diseased were reactivated in the dosed cohort. This is an oversimplified picture but at the core correct. Different genes were silenced in different diseases but by the MOA of Blarcamesine, they were reactivated. Alzheimer’s telltale is at least from a hundred to 40 years old, I mean amyloid plaque and tau. Most recently the science of genetics supported by computing power untangles the relationships between genes and disease, ever rapidly. From the data published by Anavex Life Sciences, it seems that the missing etiology has been found.

After phase 2a Open Label Extension has been conducted in the trial with the result that the eight patients declined negligibly in the span of three years versus the steep decline of the underdosed cohort that did not exhibit the therapeutic effect and could easily be taken for a placebo arm. Yet, for the science deficient this was not proof enough so they clamored to run with hundreds of subjects to have the total certainty of “statistically significant” results.

Dr. Missling has masterfully is managing the expectations of the science deficient, including me. The market and the analysts look mostly at the cognition results. Only when you comprehend the existence of the Donepezil Trap and the Missing Etiology combined with the limited cognition in the trial results, the focus shifts to the true efforts to achieve approval found in the genetic data, and the imaging of amyloid plaque and tau tangles reduction conducted by Anavex.

See my videos of Phase2b/3 results. So the data from Phase2b/3 released on December 5, 2022, was formatted in such a way as to confuse the arithmetic deficient. I partially went over this in my video. If we assume that 80% of patients in 50mg cohort are on average -4.03 ADAS-Cog13 and the remaining 20% is declining on average 5 points on ADAS-Cog13 scale then the average result is -2.22 on ADAS-Cog13, that is the result reached by Donepezil at 12 weeks!!!

**Of course not, it hit the limit of cognitive improvement but avoided the Donepezil Trap. The other thing is that the various measures of cognition are not comparable to each other, each is in its own domain. That is why Dr. Missling works hard behind the scenes to approve the drug before he has to release the data which would scare the retail investors into selling.** **Dr. Grimmer expressed optimism for Blarcamesine best when he said that he is very excited by the fact that Blarcamesine showed efficacy in the three CNS conditions currently tested**. **Indeed, Blarcamesine has avoided the Donepezil Trap, and rest assured it is the winner. **

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Donate yearlyLately, I have been posting videos but there ia limited capability of videos to disseminate graphics or plots. I decided to do a post and video later.

The Anavex’s data release on the results of Phase 2b/3 included Odds Ratio versus Placebo arm for cognition (MMSE) and Activities of Daily Living (ADCS-ADL). Again, we assume that the Low and Medium Concentration cohorts did not exhibited any therapeutic effect or efficacy so that we can assume them to be a synthetic placebo arm in Phase2a. Let’s see the marked up illustrations/presentation slides.

The criteria for cognitive improvement will be the zero line. If we want to arrive at Odds Ratio for cognition improvement we count the improved cases on Low and Medium concentrations columns, namely population of 2. The population of those improved with the High Concentration can be taken to be either 5 or 4, one case on borderline. this gives tentative Odds Ratio of 2.5 or 2 for lower value when excluding the border case. If we compare it to the press release on Phase 2b/3 Odds Ratio of 1.84 we get very close value.

Now, let’s turn our attention to the ADCS-ADL. I bet it will get more interesting since we have never anylyzed daily living results.

The values for ADL are within round parenthesis and the corresponding to patient MMSE (cognition scores) are within square brackets. First thing to notice here is that the border criteria for performance in ADCS-ADL is set at minus 2 points. Notice that all the 4 cases of synthetic placebo belonging to the Low and Medium Cohorts are almost exclusively negative on cognition. The Odds Ratio for ADCS-ADL seems to be 4 to 6 or 1.5., or 150% improvement. If we move the border criteria for improvement up to zero line the Odds Ratio becomes 2 to 4 or 2, 200%. Compare this with 2.67 (267%) Odds ratio in the Phase 2b/3. On very superficial level Blarcamesine in Phase 2b/3 has repeated the performance of Phase 2a. Notice that there is high correlation between general improvement in cognition and improvement in daily living scores.

Another aspect of the data from Phase 2b/3 was that the cutoff criteria was +3.5 ADCS-ADL points, not zero or -2 points. Just a remainder that positive is the direction of the increased ability to carry on the daily living. This suggests much stronger response in Phase 2b/3.

If indeed the Low and Medium Concentration cohort or rather only the Medium Concentration Cohort corresponds to the 30mg dose then one should expect very low performance in this cohort versus the higher dose 50mg cohort. This being the case the 50mg cohort would have higher concentration of better MMSE and ADCS-ADL scores. I touched on this issue in the video below.

The reason for combining the cohorts is a mystery. However, the theory of Lane Simonian published in Seeking Alpha article that the combining of cohorts was done to support achieving statistical significance does not seen to be a valid as the calculations to arrive at it do not involve directly the n of the dosed cohort. Since the Standard Deviation of the Placebo arm is set and its Standard Error as well it leaves only the mean of the dosed cohort to be given a consideration. If the mean of dosed cohort is outside (to the right of) the value of 1.96 Standard Error plus Mean of Placebo then we have statistical significance. Including the 30mg cohort with the expectation of lower efficacy should rather move to the left the value of the mean for combined cohort versus the 50mg cohort mean which could be more to the right. That is only the case , if our expectations are correct. In other words, at this point of my knowledge how p-values are computed I think that Lane’s idea is false.

**In conclusion, the results from the Phase 2b/3 as they are posted to the public give a picture of performance compatible with the results of the Phase 2a. Yet, the combining of cohorts on the face of facts known at this point of Phase 2a dosing seems odd at the least. **

**See more videoes on my YouTube channel @TheLomLom9 or Energy and Alzheimer’s**

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The following post is in reference to paper tilted:

link: https://alz-journals.onlinelibrary.wiley.com/doi/10.1016/j.jalz.2010.03.018

The purpose of this paper is to establish realtionship between covariates like baseline severity, age, APOE4 genotype and gender, and the slope of yearly decline in ADAS-Cog cognition measure.

- The mean slope is dependent mostly on baseline severity and age.
- The individual slope is dependent on APOE4 genotype (incease of ~22% deterioration) and the gender; male decrease of ~10% in deterioration vs. females.

To illustrate the impact the baseline severity and age can have on the first year decline slope can have one can peruse or parse the table 3 from the above paper.

If we are to compare results from** Blarcamesine ($AVXL)** Phase 2b/3 and Open Label **Simufilam ($SAVA)** following information can be gathered from the data published by the comapnies.

Fo**r Simufilam**: Baseline Mean ADAS-Cog 16.7(+/-7.86); Age 69.6 (+/-6.4)

For **Blarcamesine** (dosed Cohorts): Baseline Mean ADAS-Cog ~29.0 (+/-8.80); Age ~73.9 (+/-6.5)

Neither of these sets of values neatly fall into the ones listed in the table.

Blarcamesine is closer to record listed as 30 ADAS-Cog baseline and 75 years of age, where as Simufilam Open Label is closer 20 ADAS-Cog baseline and Age of 70 years. The disparity of the decline slopes is ~3.6 ADAS-Cog points with** potentially** **Blarcamesine **population declining faster than **Simufilam**. One can infere from the table that the baseline severity carries more weight than just the age. The difference between Blarcamesine and Simufilam is greatest in the baseline severity than in the age. **However, the only firm conclusions we can draw from the table is that studies are more difficult to compare if their demographics vary significantly and that they should be evaluated in context of their own placebo arms to avoid the bias introduced by the diffrences in demographics. **

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The fact that Phase2b/3 included 30mg cohort makes it just greater n Phase2a? If this question can be aswered in affirmitive than one would expect the 30mg follow placebo, or at least expect most of the responders to reside in the 50mg cohort. Notwithstanding the fact that Dr Missling has presented the data from Phase2a on basis of concentration in blood which somehow was suppose to follow the dose. **In this iteration of my musings on Phase2b/3 results I assume the 95% membership of performers in 50mg cohort. **

**The number of responders (cognition) in both cohorts was set at 1.84 of responders in Placebo Arm**.**The averege change of scores between baseline and 48 weeks for all the responders (-0.5 or less) (both cohorts) was ADAS-Cog = -4.03****The average change of scores between baseline and 48 weeks for all patient (both cohorts) was 2.26**

The first question which comes to mind is what was the number of responders in the Placebo Arm. That was not given. What we are left with is searching for some surrogate numbers in the literature. [1] Link to resourse https://pubmed.ncbi.nlm.nih.gov/10404988/

The paper states that after one year it was observed that 23% of initial number of patients retained their score or even had better scores. For our purposed we set this number to be 170*.23=39. If one of these is a dropout then is (39/161)=24% . Therefore the least number of responders in both chorts is 24%*1.84 = 44.2% which is 139 responders. If 95% of them are in 50mg cohort that makes to be 131. There is 169 people in the 50mg cohort so 38 are nonresponders. We assume these unresponders decline with average rate. **How to obtain the average rate? ** solve equation ((-4.03)*131+207*x)/2=2.26 therefor x=2.57. **Now we can compute the average change of scores in 50mg cohort. It is -2.54. **

That computation is not the only possible since we have the data on placebo arm in Donezepil as it is presented in the fig. 2 of the Donezepil label.

This is altered plot of donezepil placebo. Original plot was for 24 weeks duration of Donezepil trial. I moved the plot additional 2 points to the right to simulate additional 24 weeks. I think that additional move to the right is warranted by 1 point. If we so alter the plot we can read that 30% of patinets still are socring better than at baseline. 30%81.84=55%. 55% of 170 is 94. So in 50mg cohort there is going to be 95% of (2*94) = 178. The number is larger than the cohort so we assume 90% are reponders 10% are average patients. **How to obtain the average rate? ** ((-4.03)*188+150*x)/2=2.26 therefor x=5.08. This rate of decline for patients is commesurate with the average annual decline for ADAS-Cog in normal disease. This makes the calculation more probable than those given above. Calculating averge for 50mg cohort. ((152*(-4.03))+(17*5.08))/169=-3.11. **50mg cohort should have averge rate of change in scores -3.11**.

**It is rational to expect the 50mg cohort to have average improvement of -3.11 ADAS-Cog****In the rivalry betweeen $SAVA Simufilam and Blarcamesine there seems to be a tie for right now.**

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Donate yearlyThe presented data has been just released to Anavex and processed to be delivered just in nick of time to Dr. Farlane to be presented at CTAD 2022. Unfortunately, I had not saved the presentation slides as I initially downloaded them and they have been remoed now. If anybody has a copy I would be greatfull to receive a copy.

I have already mentioned that Phase2b/3 is repeat of phase2a with just larger sample size. In general remarks I can say that now we know why in data release in Phase2a the patients were listed by blood concentration. It was explained at the time that the dose and the concentration membership mostly overlaped. The problem is that for some 7.5% of patients there is the incidence of dizziness and confusion after dosage and that it might be so persistent that the members of the 50mg cohort never reach the required 50mg dose as the titration goes on. One way of mitigating this effect is to dose the patients before going to sleep, when the initial blood concentration is the highest after oral dosing. This is a widly practised way of dosing oral CNS drugs. About 48 patients suffered from this limitation, if I am right about it. In the light of that present situation the data merges the two cohorts of 30mg and 50mg into one.

**The first thing which struck me was that the Baseline average ADAS-Cog score when interpreted on the MMSE scale was near or about 21.5 MMSE points**. (Later I looked up the slides, and h measurment was 23.5 MMSE) The clinicaltrials.gov webpage for the trial listed the conditions, among others, to be MMSe score 20 to 28 and PET scan positive for Amyloid plaque. From the listed ADAS-Cog score I gather that the latter condition lowered the average score or rather brought the average down to 23.5 MMSE (updated per slides) making this very similar in number to Phase2a but not the same as they must be clustered about the mean or average without much dispersion. No wonder that the enrollment has taken so much time. **The other consequence is that versus $SAVA’s Simufilam with average or mean MMSE score of somewere about 24-26 MMSE, Blarcamesine treats a bit worse off patients. **

From the email released by Anavex at the time of presentation by Dr. Farlane;

ANAVEX®2-73 demonstrated visible improvement in patients with Alzheimer’s disease. Patients treated with ANAVEX®2-73 were 84% more likely, to have improved cognition by ADAS-Cog score change of -0.50 points or better from baseline to end of treatment than patients on placebo, Odds Ratio = 1.84 (p = 0.015). On average, patients, who improved cognitively with ANAVEX®2-73 treatment, improved by ADAS-Cog cognition score of -4.03 points. ANAVEX®2-73 treatment was 167% more likely to improve function compared with placebo, at a clinically meaningful improvement of ADCS-ADL score change of +3.5 points or better, Odds Ratio = 2.67 (p=0.0255). This reflects a robust improved and clinically meaningful outcome in cognition and function from baseline.

We have two pieces of information. First is the criteria for branding a patient a responder, the other is the incidence as related to the placebo cohort. Here, we have to dispell some misconceptions. For patients in the Mild cases of Alzheimer’s it is not uncommon to spontaneously improve cognition scores. With time this erratic behavior diminishes and with time disapears completely in a given sample. The best information on this I could find was in a plot of placebo improvement scores in the Donezepil trial that is included in the label for the drug.

The plot with white square is for the placebo arm. The fly in the oinment is that when it comes to my purposes the duration is just 24 week, whereas Blarcamesine trial was of duration of 48 weeks. Let’s make an assumption that we can approximate the passage of time by shifting the entire curve to the right and then read the percentage of those who still improve within the population of the placebo arm. The magnitude of the shift might be somewhere between 2 or 3 ADAS-Cog points. The choice of the shift magnitude was inspired by the 4.11 points deterioration of the placebo Phase2b/3 arm over 48 weeks.

For Delta = 2 there 48% patients improving therefore 184% of that will be 88% of 309 subjects of combined cohorts = 272

For Delta = 3 there 40% patients improving therefore 184% of that will be 74% of 309 subjects of combined cohorts = 229

After accounting for the dropouts of about 6% the average membership in either cohort is 155. The above membership numbers in the cognitive improvement or hold are larger than just either cohort. **That might mean that even the 30mg cohort has about at least 50% members who did not detriorate** **or just improved** **vs. the 48% or 40% of the same for the placebo arm**. ** This would be consistent with the results from Phase2a where no efficacy has been detected in the 30mg cohort**. By default the therapeutic effect or drug efficacy has to be very high in the 50mg cohort to produce such low p-value as reported. **Also, the average score for the responders is ADAS-Cog -4.03, so most of this improvement must be within the 50mg cohort with great strength. No wonder that the p-value of .015 is suggesting low probability of false positive or false efficacy of the drug. **

**User MayoMobile (stocktwits) had conversation with Dr Farlane discussing the existance of the super responders. I believe that they are the cause behind the low p-value of the combine cohorts even in face of possible lack of therapetic effect in the 30mg cohort.**

**However Cognition Improves the Real McCoy is Daily Living**

The odds are here greater over placebo but I have no data at this time assess this as I have no placebo data on ADCS-ADL. Though odds are greater but the p-value which determines the false positive is greater too. They measure two different things. One measures incidence or relative probability of incidence, the other probability of error in establishing efficacy.

**In conclusion, Phase2b/3 has validated the Phase2a therapetic signal.** **My personal conclusion is that there is a group of superresponders who basically are those at the highest dose or concentration in blood that can be turned back from the abyss of cognitive deterioration. They might be present in both cohorts by the virtue of concentration and these are going to be predominately among the 50mg cohort. They are the reason behind low p-value for the trial. ** **The problem with dizziness and confusion can be overcome by the late in the day intake so that the maximum dose can be administred to maximize the benefits**.

**First thing is to point to a mistaken plus sign of the Avg. Delta ADAS-COG11, which should be -7.21, not 7.21. **

- Green Line represents the performance of Donezepil Placebo from Donezepil Label Fig.2. But this is only decline over 24 weeks or 6 months, not 9 months as is the case for Simufilam. For both Blarcamesine (48 weeks or 11 months) and Simufilam (9 months) this would be move farther to the right.
- Red Line represents the performance of Donezepil at 24 weeks of dosing i.e. the apogeum of its performance
- Black Line traces the performance of 50 patients in the Open Label of Simufilam trial, dsed for 9 months.
- Blue Line is a hypothetical performance of Blarcamesine in the high dose cohort (50mg)
- How to read the plot? If you draw horizontal line and this line cuts a curve for given drug, on x-axis is the condition of conginitive perforamnce given cumulative percentage of patients are better off in the trial.
- So Donezepil cut through the X-axis zero line at 82% cumulatine number of patients, which means that 82% patients show improvement with remaing becoming worse off.
- If we draw a line from normal to x-axis we get the same cognitive improvement for all drugs as expressed in the cumulative number patients in the trial being better off.

The question we can have; is the performance curve for Blarcamesine Hig Dose at all plausible?

I have two pieces of information.

On this blog, I posted an interpretation of news piece by $AVXL that claimed average delta MMSE = to about 2 points. The news release claimed that pertained to those who were in the Open Label Extension of Phase2a. If by my skewed logic we assume that this was a way of comunicating progress in high dose cohort of Phase2b/3 and from this plot we calculate the average Delta MMSe to be around 2 to 3 points we are a ball park firgure.

Second thing is that the language change on the Clinicaltrials.com page does not preclude this to be a possibility as the 30mg cohort in phase2a behaved basically as a placebo. It is entirely within realms of possibility that the 30mg cohort is declining even more (Delta MMSE or rather ADAS-COG11) than the 50mg cohort is on average preserving them, all due to ceiling effect against the cognitive healthy. The measured decline ranges from Delta MMSE=-2.2 to even -8.2 points.

**We might be on arithmetical decline in overall score for the entire body of the trial, and at the same time much improve just one cohort. **

**The Judgement Day Cometh on December 1. I am curious,. How far off I am in all my analysis and prognostication? **

**Meantime, please, take it with grain of salt.**

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