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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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Donate yearlyIt was suggested to me to comparing the hypothetical performance of Blarcamesine in phase 2b/3 to Donezepil. Hat Tip to @Trainguy1. I tried to compare the 3 drugs, including 9 months performnace of Simufilam, to Donezepil as it was formated or presented in Fig. 2 on Donezepil Label coming with the drug, and FDA approved.

Following fact have to be kept in mind.

Donezepil performance is at the apogeum, that is at 24 weeks or about 6 months. Later, it deteriorates and cognitive scores decline. The other fact about Donezepil is that the trial included patients below 20 MMSE points. Namely, 26 >= MMSE >=10. This is the mild and moderate dementia due to Alzheimer’s. I plotted only the performance of the 10mg dose.

Blarcamesine performance projection was based on performance in phase2a, genetic classes i.e. SIGMAR1 and APOE4, and statistical distribution of classes in general population of Alzheimer’s patients. There is no way to assess at this point the consequences of limiting the population intent to treat to only patients with mild dementia i.e. MMSE >=20 points. The phase 2a included patients with moderate dementia as well as mild. This change in enrollment might alter the shape of curve and its proportions. In other words, plotted is the worst projected case for Blarcamesine. Also, the curve is not very well defined as only few points are provided. I am going to return to this graph, once more data can be available after December 1, 2022.

Simufilam performance was plotted with limiting the number of sample point to 10 from 50. also the duration of study is 9 months, and the criteria for enrollment. I think that Simufilam Open Label trial limits the enrollment to mild cases as the mean MMSE score is 25.7 MMSE points. So, this can be taken to be comparable to Blarcamesine but should in principle provide Simufilam better chances of success. The tendency in the field of Alzheimer’s trials is to treat the disease as early as possible i.e. at higher MMSE scores than 20 points. It is thought that with advancement into dementia the patients cross the point of no return due to the atrophy of too many brain cells.

In case of Donezepil and Simufilam the information is solid and the number of points sufficient to plot the performance curve, on the other hand Blarcamesine represents a case of an educated guess.

Illustrations.

From the left to the right the ADAS-Cog11 scores of change from baseline move from improvement to mcognitive decline. As we move up on the y-axis we are given the percentage of patients who perform better than corresponding value of cognition for that point on the x-axis.

Plot comaparing the absolute performances of Donezepil, Simufilam and possibly Blarcamesine.

The black line represents the Donezepil 10mg 24 weeks trial with mild and moderate patients. This is the best donezepil can deliver. Violet line is the plott for Simufilam at 9 months of dosing. Subsequent results for Simufilam were not radically different from the presented 9 months data on changes from baseline for 50 patients. The red line is projection for Blarcamsine which was expalined in my previous posts, with methodology and other plots.

To my surprise, simufilam at 9 months has not been doing much better than Donezepil at 24 weeks. What we have to remember is that this is the best Donezepil can provide to a patients. After 24 weeks Donezepil can not hold these results. It will be seen if Simufilam could hold scores or even improve them over longer period of time. The lates is that simufilam has improved scores frommean of -3 ADAS-Cog11 change from baseline to -3.2 mean over additional 3 months, altogether 12 months of dosing.

Projcected Blarcamesine performance suggests that for up to 70% of patients the effect is better than for Simufilam or Donezepil, with the core of definitely better performance of some 55% as at the most left region the scores are converging for all 3 drugs, probably due to the ramdoness and repeatability of test scores over such sort time period. Then again, the most pressing question is whether these improvements can be held over time. Here, the key are the open label trial extensions. However the approval can be made on the relatively short time span performance, the real value of the drug lies in its extended performance which can only be evaluated over at least 3 years of dosing. Blarcamesine has already accumulated enough data to definitevly answer this question, but the company has not released detailed data on longevity of efficacy.

**I am actually shocked by the mediocre performance of Simufilam as compared to Donezepil. The only saving grace in this situation for Simufilam can be holding the scores over time. **

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Donate yearlyI came with an idea to plot in a given trial all the cognition changes from the highest score to the lowest. On a spreadsheet I arranged patients in this order with their corressponding cognition deltas scores. When you see a patient number on x-axis then you check the y-axis for his cognition score delta.

I was looking to get hold of some sort detailed data on placebo arm. I realized that I can use the CTAD Presentation detailed data on cognition loss from Phase2a Low and Mid Concentration Cohorts as approximation of real PLACEBO data. There was no therapeutic effect detected in those two cohorts.

I disregarded the Patient 1009 a a fluke. I got this plot.

There is a trend line which is a straith line with R2 equall to .9805 and line equation ΔΜΜSE=-.5963*Patient#+.7904. Isn’t it amazing? **My reading data off the chart or illustration with ruler introduces errors but the relationship between the ΔΜΜSE from patient to patient is remarkable.**

Then I have repeated the procedure for Simufilam, respectivaly reading from the chart below and plotting Δ ADAS-Cog11 and converted Δ MMSE points. Even with the introduction of errors at each step, the relationship holds.

**There is interesting relationship between The Simufilam plot (Δ MMSE) and Approximation of Placebo. If you take the Placebo plot line function and multiply the slope by 2 (2*.5963 = ~ .1208 for Simufilam) which is equivalent to rotating the slope counterclockwise, and then add 3.0978 to .7904, which is equivalent to moving the line up on the graph. These transformations make one line into another. Very interesting. **

**This makes for very strange therapeutic effect, as those at lower cognition score are so proportionately moved up by rotation and translation that the relationship holds for them perfectly. Indeed, amazing! **

Using the illustration with detailed data from phase 2a Blarcamisine study I made plot for the High Concentration cohort alone.Forgive me for the low number of patients, but this all I can work with.

As you can see for yourself, the curve fitting produces curve of equal fidelity (R2=.9687) but the curve is polinomial not a straigth line. The line is fourth order polinomial (x^4) and the R2=.9963.

Now, draw a straigth line from the Highest Score to the Lowest.

**The area above the red line is the therapeutic effect over the placebo straigth line. If the general shape holds for Phase 2b/3 Blarcamesine AD trial than the therapeutic effect is clearly there. Notice at the highest scores we have ceiling effect and that at Δ ΜΜSE 2.25 to 0 the effect is the greatest. **

**I realize that I get way over the head of an average investor. If you have any questions, please, leave comments. This is my children’s (youngest 16) mathematics and a bit of serendipity.**

**The spreadsheets can be provided upon requests, they are very simple.** **More Sh*t to come. **

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This is quick and dirty, I have no time for bibliography and references. I had been giving references links but now I have no time so if you want references I can provided them on request. For most of you the references for those illustrations are already known. I apologize for misspellings and gramatical errors.

I think that we are still far away from actual comparison as phase 2b/3 data for Blarcamesine has not yet been released and Simufilam phase 3 data is years away. Such comparison would be rigorous and definitive. The best insight into the performance of both can be only have by examining qualitatively and quantitatively the data released by both companies, which would be of the same quality and format. Otherwise certain assumptions are necessary to be made.

First assumption I make is that $SAVA ‘s 9 months is sufficiently advanced for these purposes as it slowly develops over time and the difference in scores between 9 months and 12 months is small.

Illustration:

Let’s see the best or rather most detailed data we have from $SAVA Simufilam for the 9 months of dosing in 50 subjects. This is the best detailed data yet. Blarcamesine doses for 11 months, that is 2 more months but the super responders react explosively to the drug in first 5 weeks with steady improvement over the rest of the dosing period. Other patient on Blarcamesine either hold their deterioration or deteriorate slowly, less than -2 MMSE points. For my purposes comparing 11 months to 9 is acceptable.

The data for each patient is the delta or change in ADAS-Cog11 scores defining the progress made by each patient The labels with MMSE scores are only for insight as I have a better equation now to transform ADAS-Cog11 scores into MMSE scores.. In the plot below data from convesion table has been plotted and a trend line through the points has been caculated. Equation of the line is the used to convert the scales. Notice that small error has been introduced but the conversion is necessary as each company’s data is in the other scale.

**After that I have calculated the Mean value for the 50 patients to be 25.7 MMSe points. This is very high comparing to phase 2a for Blarcamesine but it is comparable to phase 2b/3 for Blarcamesine.**

If we devide the results into classes or ranges of responces to the Simufilam as expressed in MMSE changes for each patient we get following graph. **It is very uncanny when such order emerges from the chaos of graph. **

**We can arrive at the following conclusions**

**The population of patients is spread evenly between Δ 3 < 2 ανδ Δ -1 < -2.****Super performers (Δ >3) are only 50% (n=5) average populations of other ranges/classes. and this is understandably low.****The lowest performers are just 22% (n=11) of population and are clustered at Δ -1 < -2 which we can consider the average decline for 9 months time for normal progress of the disease.****There are no members of population deteriorating below of the average natural progress of the disease**.

Image #1.

By examining the plot we can conclude that Group1 and Group2 are of great interest to us as they are all above MMSE 20 points. We expect that all patients in the phase 2b/3 are to be above 20 MMSE. The Group1 goes through explosive resonse in just 5 weeks of dosing. Group2 holds its scores for at least 52 weeks. The differense for these groups is the presence of APOe3 or APOe4 Alleles. All probabilities being equally represented following distribution of population can be expected.

**The following information is available for us to make guess estimate of the hypotethical perfomance of different populations in the phase 2/3. **

**I expect high number of super responders from the information supplied by the company. $SAVA ‘s performers are closely clustered with very few declining but Blarcamesine offeres explosive response for the selected majority, whereas it does not do much for the those mutated or carries of APOe4 allel. Blarcamesine results are highly dependent on genetic make up. Simufilam seems like “tailored for success” all over the spectrum. The real question is, will Simufilam hold this “dream performance” the next 3 years? ** ** If Simufilam can hold the candle long term it can be used where Blarcamesine can not deliver. **

**If you can do anything for me, it is to watch short videos about energy on my Youtube channel Energy Shock Tips. The longest is 5 minutes. **

**Please, leave comments, as this Simufilam performance graph is very interesting. I wonder what you think about it.**

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But only if you don’t know much about the implications of language in phase 2b/3 for Blarcamesine for Alzheimer’s.

Mr. Brodkin has published this tweet. Link: https://twitter.com/jesse_brodkin/status/1550477966123171840?s=20&t=MdTQ5Aes7PJyFbCFHRQQAQ

One of the points he makes is that Anavex has changed the wording refering to the primary endpoints which accordingly to him is a harbinger of coming sure failure of the the trial. illustration, please!

as the agency did not allow to limit the patients to only those with the wild type SIGMAR1 and COMT genes as we, the investors, thought should be the case. Phase 2b/3 is testing Blarcamesine on so called general public, that is anybody with the conditions written on the Clinicaltrials.gov page.

On the basis of statistical data about the icidence of both SIGMAR1 genes and APOEe4 incidence and the distribution of decline in Phase2a I have arived at hypotetical distribution of scores in phase 2b/3.

I guess this is the minimum Blarcamesine can do for humanity. 55% of patients after 1 year of dosing should not experience any decline, or rather shall improve, which we can set at about +4 points on MMSE scale, only 4 points, because of ceiling effect. 12% of patients should decline less than 2 MMSE points. And finally, 33% patients should should decline 6 points on MMSE scale. Illustration of phase 2a results.

If we put that together.

.55*4+.12*(-2)+.33*(-6)=2.2-.24-1.98=-.02

Which means that overall scores can be expected to declined even if the drug can rescue about 55% patients. Because of this I have always stressed that the most important data for the clinical success of Blarcamesine is the long trend in scores experienced by those who enrolled in the Open Label Extensions trials.

This is just the worst outcome scenario for the phase 2b/3 High Dose 50 milligrams/kg cohort. I want to stress here, it is also based on genetic distribution of the genes and the APOEe4 alle.

In the real phase2b/3, we have 3 cohorts: Placebo, 30 milligrams and 50 milligrams per kilogram body weight. The aforementioned wording change might have been caused by increased effort to communicate the results from combined dosed cohorts, and not alone the 50 milligram per kg cohort, on which all the hope and attention is focused.

**I can command Mr. Brodkin’s for keen attention to the change in langauge, yet in order to investigate a progress of a company or a drug a more thorough analysis is needed, as they always say the devil is in the detail. **

**I am starting a new effort and make short videos about comming energy crisis. My channel on Youtube is called Energy Shock Tips. I am going to list links to them here two videos. **

links: https://youtu.be/dVWqd99IsNc https://youtu.be/sowV1rNfil4

**Next post is going to be on my missgiving on $SAVA ‘s data. ** Sorry for all those spelling mistakes.

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Donate yearlyI hope that things would be so simple as just calculating IC50 and blood concentration and then passing a judgement on the therapeutic effect of the drug. Things happen in time, there is the liver, Brain Blood Barrier, intestines, stomach juices all contributing to the level of SIGMAR1 occupation. I do not know in detail what happens when SIGMAR1 is occupied by Anavex2-73. What is the the timing of the response. I do not know at what rate SIGMAR1 receptors are produced. In light of this sort of ignorance, demanding that 100% occupation of SIGMAR1 receptors by molecules of Anave2-73 for emerging therapetic effect is surprising.

Anavex2-73 is not simply an inhibitor of a single point in a pathway as is the case with Donezepil. SIGMAR1 agonist set in motion complexity way beyond the four operation of arithmetic. On my blog I presented number of papers describing hypotetical mechanisms of action for the SIGMAR1 agonists. When I studied biology in preparation for medical school, I had to make the discovery that pathways or cascades leading to some physiological mechanism had sometimes negative feedback loops. You overstimulate them, they shut down. Many cascades would be like conjoined twins, feeding into others. That is why there is always a considerable risk of serious side effect in drug development. You cure the disease but cause another,. Therapeutic effect might not be connected to occupancy as much as sensitivity and specificity. In some cases you want occupancy to be as large as 100% but in others cases this can lead to serious side effects.

The concept of homeostasis is experienced in its simplest form in the existence of balance between stimulating and inhibiting compounds. Example of that can be the homeostatic balance between GABA and Glutomate, both neurotrasmitters of opposing action. The complexity of these interdependencies can be seen in scientific papers. Hey, we inhibit (or otherwise increase or exite) something and let’s see how it will cascade into changes in a number of places, hopefully desirable.

For every 11 drugs in development only one gets approved. Had the process been without surprises and serendipity I guess four arithmetic operation would suffice. Complexity makes things impossible by arithmetic, at least in biology, possible. One of the most interesting scientific mysteries is the emergence of life and its thermodynamics which eludes the one taught in engineering schools for running power plants. The term homeostasis was invented to describe this thermodynamic impossibility, that is life. Had Mr Brodkin been talking about shutting production of a mutated toxic protein I would gladly agree to concure. Yet, this is a receptor setting in motion large number of processes improving cellular homeostasis. Could it possibly overstimulate the cells? This possibility exists.

Long time ago, Anavex2-73 was used to dose healthy volunteers so that maximum safe dose could be established. At certain level headaches and vomitting was induced. This was recognized as a sign that the drug crossed Brain Blood Barrier and was occuping the SIGMAR1 receptors. The later studies on mice confirmed this.

Let’s again review Mr Brokin’s numbers. So, I calculated that at the 6 nanog/milliLiter (the highest concentration in patient) is equivalent to 30milligrams. Let’s look at another fact, the highest concentration in a patient was almost double that i.e. 60 milligrams. **These values correspont to highest level for some time and do not represent doses.** **These can be approximated or estimated by intergrating the concentration curve over time**. The highest dose given to the patients is 50milligrams per kg. If you weight 70 kg you recieve 3,500 milligrams into your stomach. The the slide of corporate presentation I can see that occupancy is just about 70% for 30milligrams per kg. Anavex does not provide information for 50milligrams per kg. Is 70% occupancy sensitive enough to induce a therapeutic effect? We find our soon.

**Mr Brodkin gave the occupancy range between 1/100 and 1/10. Unfortunately, his calculations do not agree with the experimental data as he made wrong assumptions about the dose delivered by confusing concentration with dose. **

**For a scientist it is hard to not understand the difference between peak concentration and the area under the curve of concentration over time that is the cumulative dose. I hope, Mr. Brodkin that you will update your tweet as soon as possible. ** **This would benefit the investing public,thank you!**

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