Why You Should Count On Cortexyme To Deliver The Alzheimer’s Drug! $CRTX

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!

Jitters of The Biotech Investors and Their Cure

In most PRs companies give some measure of improvement of patients, with the number of subject and the p-values. The certainty of the improvemnts are judged mostely throught the prism of p-values as it is a number with a threshold once attained a semblence of certainty is holly assumed. Alzheimer’s trials are the widowmakers of too many hopes to count. Many a times a promising phase 2a drug turns into disappointment in phase 3 trials. Companies, therefore make their phase 2a trial just as light on subjects count, to cut costs, as proverbial trial baloon. These results are short on certainty and make the investors to look for clues in the bevavior of the management which can be faked or genuine. The hopes connected with $SAVA’s drug Simufilam in the eyes of investors carry higher certainty than those from phase 2a by companies like $AVXL or $CTRX. I have tried to evaluate their chances to deliver the Alzheimer Drug. Maybe, such a drug does not exist but everybody believes that their favorite CNS company has the best horse in the race. A sign of pure lack of certainty, is to hold them all.

Power Of A Trial And One Patient’s Story

The management of $CRTX is fond of saying, or rather all they can say about the trial, that it is powered to detect 50% decrease in the rate of decline among the Alzheimer’s patients treated with Atuzaginistat. When I parse this assertion, it occures to me that this is the least of benefits to patients the management expects to detect with p-values smaller than .05 but this is my interpretation. The hint is “it is better than BIIB drug”. I might be wrong on this one, at least in the second part.

I have already looked into the APOE4 allele and its connection with allegedly increased virulences of P. ginvivalis in brains of some Alzheimer’s patients. $CRTX and the papers on the interacton between the bacterium and the APOE4 protein give the most plausible explanation of the accute character of dementia in individuals carring the APOE4 allele. They are the most quickly declining patients and are the most likely to drop out from trials.

However, you would try to discount the 28 days and n=9 phase 2a and short on duration and subjects number trial, there is very interesting effect of Atuzaginistat on the launguge abilities of the 6 patients who were in the dosed cohort. Let’s see the slide from the $CRTX AAIC 2021 Symposium.

The Winterlight Assesment of Propositions and Conjuctions achieved p-values smaller than .05 just after 15 days and the p-values decreased to less than .001. Would that suffiece to engender certainty in investors? We have here the one from the three (p-values). Missing is the good n number and the measure of efficacy as Winterlight is a black box. I had very few tools to assess the efficacy of Winterlight, because I did not know anything about the inner-workings of the test. Nevertheless my understanding was that there was a consistent separation between the two cohorts, both in magnitude of change and the dispertion around the means for both groups. Ergo, low p-values and high Effect Size, which I calculated to be about 3.8. This is way beyond huge. Fortunately the company published something to giving us insight into the Winterlight Assessment. Let’s see next slide.

The inriched lauguage examplifies the speach pattern of an elderly patients treated with Atuzaginistat over period of 28 days. The patern present in many trials is to exhibited immediate therapetic effect followed by either decline or slower movement toward improved cognitive scores, the latter has happened in the case of Blarcamesine by $AVXL. A similar early effect has taken place with Atuzaginistat where in just 28 days the patient experienced such change in speach pattern that the only conclusion to be drawn here is that we deal with deep recovery of severly deteriorated language and cognition patient, not just 50% decline in the rate of deterioration. The recruitment requirments listed the patients as being between MMSE-2 14 and 25. From the speech pattern one would expect the patient to be closer to the lover limit of recruitment.

As a person myself struggling with disability, especially with language, I recognize here somethig akin to phase change in physics in the language pattern of that patient. For those who have never suffered mental deterioration this might seem trivial or constitute marginal improvement. I consider these two slides anecdotal evidence of very strong therapetic signal. No doubt, that this is the strongest example $CRTX mangement could choose. Nevrtheless, for me it is a very strong argument to expect better results than just 50% decline in the rate of deterioration.

For investors to reach the comfort zone, the troika of n number, p-values and clinicaly meanigful effect has to be present in the data. Otherwise, tea leaves reading of mangement maneuvers, statements, or comings and goings issues. Sometimes, for some, all it takes is to present anecdotal evidence by just few patients to dispell the statistical uncertainty. In case of $CRTX we have it all save the respectfull duration, p-values on known measures and n numbers in the trial. For certainty, this is just incomplete picture. For me the language improvements or rather the phase change in cognition associated with the language of those dosed presents a very persuading argument to make me lean towards expactations of large therapeutic effect. $CRTX second market (periodontal disease) might be so large that the Alzheimer’s is just a fraction of it. Nevertheless, the seond market might not be of the same urgency as Alzheimer’s it can make up for it in numbers, so the bet is kind of asymetric but inherently safer than many others.

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Can Blarcamesine Catch Up to Simufilam and Surpass it? $AVXL $SAVA $CTRX

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!

This is the final installment of three parts in the same question. Two previous installments are;

link: https://piotrpeterblog.com/2021/08/09/cassava-science-results-vs-anavex-life-sciences-projections-sava-avxl/

link: https://piotrpeterblog.com/2021/09/27/why-sava-simufilam-might-not-have-any-advantage-over-avxl-blarcamesine-sava-avxl-crtx-snpx/

The Proper Mix

If we are to assess the chances of Blarcamesnie to better its results in Alzheimer’s phase 2b/3 then first we have to list the known factors impacting the response of the patients. These are;

  1. The baseline MMSE score of a patient
  2. Presence of the Wild Type genes for SIGMAR1 and/or right version of COMT gene
  3. Being a carrier of APOE4 alleles or allele

In sundry remarks during the time from phase 2a to present Dr. Missling has revealed that “we can rescue anybody above 20 MMSE score”. The phase 2b/3 recruits only those with the MMSE score above 20.

In another remark Dr. Missling has thrown light on the unexclusive character of the SIGMAR1 gene as the fact of being the carrier for the mutated gene does not preclude the patient from responding, just makes the response less pronounced.

The last but the most impactful point concerns the APOE4 allele. From the illustration below it is clear that APOE4 affects the chances of a patient to resond to Blarcamesine the most.

Source [1],
see bibliography

When read, this graph makes clear that in phase 2b/3 the predominant class will be Group1

  • SIGMAR1 Wild Type
  • Both APOE3 or other than APOE4 alleles

We are only looking into high dose cohort so we assume that all patients are all High Concentration. The same applies to MMSE scores, as they are all to be above MMSE 20.

As the patients number move from the smallest sample size in life sciences of 30 towards hundreds, the probability of mirroring the population distribution of these factors in the sample population grows.

Source [2], see bilbliography

The probability of having any other allele than APOE4 is 44%, combine this with 90% probability of SIGMAR1 WT and get ~40%. The suggested response is in the range of +3.5+/-0.7 MMSE as the illustration below suggests. Two highest scoring member of the set to be identified as member of this class of patients. This is 57 week dosing chart.

source [3], see bibliography

The class of patients in phase 2b/3 corresponding to Group2 minus Group1 that is carriers of APOE4 allele or alleles plus the conditions in Group1, which basically stand almost still. This Groups has been marked yellow. Probability of occurance .90*56=50%. The rest, that is 10% assumed as declining with palcebo or worse.

Assuming mean of 23 MMSE and looking at 16.6 +/-3.4 MMSE mean placebo with 24.5+/-2.4 MMSE mean projected for data after 57 (one year) weeks. Once we plug in these numbers into Cohen’s d formula we get Effect Size of 2.68.

Simufilam number from post number two were 1.63. The presented educated guess on Blarcamesine might not be on the money but I think it highly unlikely to fall under the number given by Simufilam. The difference is very large in terms of Effect Size.

The anecdotal “evidence” points to even larger Effect Size. Nevertheless I would like you to take these results with grain of salt. I do not know what precisely means Dr. Missling saying that ” We can rescue anybody above MMSE 20″. There seems to be contradictory evidence in source [1] but source [1] is not entirely clear on many aspects of the phase2a, at least to me. From the rudimentary probability calculations 40% of patients shall not succumb to the dreaded decline associated with Alzheimer’s. Further 50% shall dither between further decline or stable condition. 10% shall decline with the placebo or even worse.

The most significant factor in decline is the APOE4 allele. In article written on Seeking Alpha private blog link https://seekingalpha.com/instablog/20791881-gordon-gecko-was-a-commie/5613017-cortexyme-s-gingipain-theory-of-alzheimer-s-disease-pathogenesis , there is the only worth of attention explanation of the pathogenesis of AD connected to APOE4 allele. Let me quote the gist of it. I strongly suggest reading the post.

From this post it becomes obvious that Alzheimer’s might have very complex etiology and Atuziginistant might affect some aspects of the disease as well as Blarcamesine and Simufilam. It is possible that all three of these drug will be necessary to tackle the disease. I think it is worth to wait for the CTAD 2021 in November to see the data from $CRTX phase 3 GAIN study. Atuziginistat offers ways to cut virulence of the bacterium which might be involved in AD etiology, Blarcamesine starts regenerating mechanism reaching well beyond CNS diseases (my opinion), and Simufilam repairs the cellular scaffolding. All three might be necessary.

BIBLIOGRAPHY

[1] link: https://pubmed.ncbi.nlm.nih.gov/32318621/

[2] link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854133/

[3] Corporate Presentation on AD Phase 2a 2017.

Why $SAVA Simufilam Might Not Have Any Advantage Over $AVXL Blarcamesine $SAVA $AVXL $CRTX $SNPX

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!

So called previous post link https://piotrpeterblog.com/2021/08/09/cassava-science-results-vs-anavex-life-sciences-projections-sava-avxl/

This post is rather a continuation of that post.

$SAVA, The First in The Race Contender

The share price of $SAVA has taken some beating over the alegations of, let’s say it outloud, fraud. Nevertheless, the price has been staging some comeback. Either, due to short memory of the market participants or the flimsy character of the accusasion. The data presented for Simufilam 9 months duration trial will be here compared with $AVXL phase 2a trial data which was presented in similar manner. There is a 3 months mismatch between those two sets of data, but our excercise is to gain an insight into any substantial future advantage to be achieved by any of those companies in the future.

The Differences Are Important

There are substantial differences between the general level of deterioration of the patients in both of those trials. In previous post I pointed out the discrepancy between both mean base point as they where expressed in MMSE and ADAS-Cog11 by $SAVA. I used the graphic calculator by Steve Balsis et al. (see previous post) to assess these. In terms of MMSE scores there is a rather substential difference between 24.3/22.6 MMSE and $AVXL phase 2a 21 MMSE. This discrepancy will be addressed in $AVXL’s AD Phase 2b/3 due in second have of 2022.

On the other hand $SAVA presents just 9 months of data vs. $AVXL’s 57 weeks. If the deterioration vs. therapeutic effect accelerates with time the advantage goes to $AVXL. From the data the therapeutic effect of seem to have a steady progress with just 1/3 of patient lagging for Simufilam and in case of $AVXL phase 2a only the 1/2 half of the High Concentration Cohort responds but with very strong therapeutic effect. Simufilam seems to affect all but in very mild manner.

The illustration to both of these characteristics of response have been presented in previous post.

Effect Size: Cohen’s d

Cohen’s d measures the effect size of a drug vs. the placebo arm. It is proportional to the distance between the means of distribution of the two bell curves. It is also inversly proportional to sizes of the standard deviations of those two bell curves.

This is a special case when SD of control group and experimental group is the same, otherwise we use pooled SD.

The Question of the Choice of the Placebo Arm

Neither the $AVXL phase 2a or the Simufilam data contain any information on a placebo arm. We could use the industry standard ANDI 2.1+/-.4 MMSE but we have a different population in case of $AVXL phase 2a, the lower concentration cohorts. They can be seen on the illustration in the previous post. If we take the entire High Concentration Cohort 8 patient group and measure it performance to the Lower Concentration Cohorts the Effect Size Cohen’s d is equal to 1.39

If we use as the placebo arm from the reference [2] on the previous post with decline of -3.4+/-6.1 MMSE and run the same calculations we get Cohen’s d equal to 0.95.

Once we have done this we can look at the $SAVA data. Again we have question of the placebo arm. I decided to use the annual decline from the reference [2] and use the Steve Balsis et al. graphic calculator for transfering the measure of dementia from MMSE scale to ADAS-Cog11. I settled on +10+/-11 ADAS-Cog11 points. The use of annual data, 3 more months of decline might enhence the Effect Size for Simufilam. I am not worried about this error since I am looking for insight, not predictions or forecast. The Effect Size Cohen’s d for Simufilam (9 months data vs. 12 months decline) is 1.63.

Discussion

Simufilam has on its side the higher baseline MMSE scores, less advanced into demntia patients. This might be a decisive factor in the pursuit of higher Effect Size as it seems that the more advanced people are into dementia the therapeutic effect is all that smaller. $AVXL phase 2a gave the same indication as in the High Concentration Cohort patients who responded to Blarcamesine were all above 20 MMSE. In contrast Simufilam trial has average MMSE score above 22.6 MMSE, at least. It is unceratin how this is spread but possibly it can include some below 20 MMSE. In $AVXL phase 2b/3 all the patients shall be above or equal to 20 MMSE. That is why a whole set better results are expected from $AVXL Alzheimer’s phase 2b/3.

In the case of $SNPX and $ATHA we discussed the appearing distinction between “preventative” and “regenerative” CNS drugs. https://piotrpeterblog.com/2021/08/20/neurotrophic-factors-in-curing-alzheimers-and-other-neurodegenerative-diseases-snpx-avxl-atha/ .

The distinction might not be clearcut, some overlap is possible. $SNPX is trying to develop narrative of pure regenerative drug. Yet as I further researched, the SIB (Severe Impairment Battery) can be as well as a 133 point scale. In the light of this any translation of performance into MMSE score card is even more dobtful. Initially, I thought it could be 80 points. Bryostatin can provide a signal in a sea of noise, but the signal can be almost drawing in the noise making it clinically insignificant. So, unless I am entirely wrong about Bryostain, I would wait for more data.

We are still waiting for data from phase 3 of $CRTX drug which as I was reporting holds the only scientific explanation of the mystery of APOE4 alle and higher incidence and severity of Alzheimer’s among the carriers. Very well researched article can be found under this link https://seekingalpha.com/instablog/20791881-gordon-gecko-was-a-commie/5613017-cortexyme-s-gingipain-theory-of-alzheimer-s-disease-pathogenesis .

Dr. Missling has been changing the narrative around Blarcamesine from neuroregenerative drug to neuropreventaive drug. I also ventured into pure speculation when I published post where I stipulated that Blarcamesine has not only removed the morbidity due to Alzheimer’s or dementia but also improved overall life span on the small initial sample of 32 patients. link: https://piotrpeterblog.com/2021/06/12/is-there-more-than-just-alzheimers-parkinsons-and-rett-syndrome-in-blarcamesine-bag-of-tricks-avxl/ .

Let us return to the leader ($SAVA) and the ugly duckling ($AVXL). $SAVA has produced 50 subject study and the n=50 did the trick, it instilled confidence in $SAVA when competition has been timidly dipping toes in phase 2a trials with just a tens of subjects. What was suspicious about $SAVA is its management structuring a large payout when stock price would have reached certain value. Fortunately for the stock holders ((?) equivocal statement) the market just spooked before the share price was reached. It seems like get quick rich scheme. On top of that, add accusations of use of doctored images in publications.

From the above calculations of Effect Size Cohen’s d for both drug, Simufilam has not have an upper leg on Blarcamesine. Equivalent study of Blarcamesine is still in the making, double blinded. I would like to see ~18 months duration of study of Simufilam to compare both in the most direct way it is possible.

Neurotrophic Factors In Curing Alzheimer’s and Other Neurodegenerative Diseases. $SNPX $AVXL $ATHA

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!

When It Rains It Pours…

We are witnessing outpouring of excellent phase 2 results from many corners of the Alzheimer’s and neurodegenerative field. The question now is; who is the best bet? The capital behaves like a loose cannon ball on a ship in rough seas, swinging from one company to another.

I am primarily concerned with Alzheimer’s as it is the most common and the most difficult to tackle disease. It doesn’t mean that it can’t be just number of varied factors leading to the same result for the patient. The sheer number of companies pursuing the golden fleece of neurodegerative field beyond the already discredited amyloid plaque theory grows exponentially. In some sense there seem to be two ways to fight neurodegenerative diseases. One being, preventing the loss of neurons and synapses. The other, the second way, attempt to regrow what has been lost. $AVXL turns more with every step of its trials into prospective preventative, whereas $SNPX and $ATHA try the second way in dealing with Alzheimer’s, and not only Alzheimer’s. Blarcamesine by $AVXL solidifies the image of its MOA into the consequence of releasing broad array of proteins and signaling compounds into cellular machinery and intercellular space. This multipronged assault on the disturbance in the cellular homeostasis might be much more beneficial when the system is not yet advanced in its destruction. The purpose of doing the above is to stop the death of neurons and to correct the cellular homeostasis. The Mitochodria Associated Membranes which release these compounds also release certain quantities of BDNF helping to regrow the depleted neurons. BDNF stands for Brain Derived Neurotrophic Factor. Synaptogenix ($SNPX) Bryostatin works in a cascade involving BDNF, the implication being that large amount of this factor are released by Bryostatin. Bryostatin might not be exclusively limited to BDNF but this seems to be the most immediate explanation of its efficacy. The efficacy of Blarcamesine seems to support the efficacy of Bryostatin and the reverse might be true too. A third company mentioned here is Athira Pharma which attemps to regrow the neurons by amplifying the a growth factor present. Please, read my posts on $ATHA for expalnations of its effects on the patients.

The most used tool in accessing cognition in MCI and mild Alzheimer’s patients is Mini-Mental State Examination, ADAS-Cog11 or ADCS-ADL. SIB (Severe Impaired Battery) is a finer measure of moderate to moderately severe dementia. These scales are not easily to be converted from one to the other. Had you been reding my blog you would have known about this. Nevertheless, we have to try to compare the performance of one company to another even if these are expressed in varying scales. The understanding is that as we might be gaining something in perspective but at the same time something can be lost in conversion. In measurments of cognition precision is sometimes missing and uncertainties abound.

There is a following discussion of Bryostatin performance….

Link: https://www.synaptogen.com/wp-content/uploads/2021/07/ESCIOBAADP.pdf

Just to begin I would like to point out that the p value for the first trial was larger 8 times than for the second trial which suggests that there is a clear-cut separation between placebo and dosed cohorts in the second trial which had higher MMSE scores (ergo better cognition) yet the separation between means was almost the same. My immediate problem was that I am habituated to think in terms of cognition prevalent among patients between MMSE 28-20 points. Byrostatin patients have been severly impacted by dementia and their improvement has been described in measure I have no experience with. After short search I found a source of information on SIB link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930878/ .

I figured that SIB is 80 point scale that can be roughly converted by factor .38 into MMSE scale. Of course, this is gross over simplification as locally the scales might not be related by this factor. If we subject the results from Bryostatin to conversion we get +1.55 MMSE gain for patients between MMSE 14 to 10 over 13 weeks. These results are extremely good as most patient at this stage are not even dosed in phase 3 trials. Bryostatin proves its mettle at very low MMSE scores prompting us to ask about performance in MCI and mild Alzheimer’s patients. These are unanswered questions. The fact is that $SNPX has a drug with performance similar to Blarcamsine in MCI and mild patinets but acting on severely to modereltly severely afflicted individuals.

I have written extensively about Blarcamesine. In some of my posts I suggested that the dropout rate from the 32 patient phase 2a trial suggests that the morbidity due to Alzheimer’s has been removed from this small sample size population. I went even further, claiming that due to the ambiguity of Dr Missling statement (21 to 10 patients left in trial) there is possibility that Blarcamesine acts as ‘regeration” drug – improving the survivability of the treated above the statistically background morbidity. This claim might be far fetched. Nevertheless, the company ($AVXL) has started talking openly about the “regenerative” prospects of the drug. It seems that Bryostatin and Blarcamesine are connected at one point in their MOA of upregulating the production of BDNF.

Conclusions

  • Bryostatin by $SNPX has shown ability to improve severely demented patient
  • No other company as of yet has show that to be the case
  • The field of treating neurodegerative disease expands rapidly beyond amyloid plaque theory
  • There are nascent “preventatives” and “regeneratives”
  • Blarcamesine can straddle both of them
  • Bryostatin can takes its due place as one of the better “regeneratives”
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Cassava Science Results vs. Anavex Life Sciences Projections $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!

Baseline in $SAVA data and the same in $AVXL Phase 2a data.

Picture first.

There seems to be a discrepancy from calculated ADAS-Cog/MMSE baseline numbers. By ADAS-Cog11 numbers the patients in $SAVA’s trial are a bit better off than the data on MMSE tests would suggests. It is difficult to interpret the data as these two scores can give quite varied results, nevertheless it is worth to mention it here, especially in the context of comparison with $AVXL data. As the sample data here is 50 one would suggest that the discrepancy would be smaller. The calculated data comes from this graphical calculator.

Source bilbliography [1]

In the $AVXL results there is a bifuraction of results in the same time frame. There is a group of 4 patients exhibiting therapeutic effect and group of patients declining as if there would be no therapeutic effect for them. Of course, we are talking about the high concentration cohort. Those who showed improvement are well documented by the company to have average baseline MMSE scores of 23 MMSE. This is compatible with the $SAVA numbers. The high concentration cohort has rather small sample size but the pattern exhibited by the bifurcation is telling of undoubfull therapeutic effect, though limited to certain population. In the illustration I have tried to determine the mean of the second latter group of patients but this is more or less impossible, that is why there is a question mark.

Dispertion and Therapeutic Effect

$SAVA data shows the dispersion to narrow by so few points on ADAS-Cog scale that it is insignificant (or due to my error in calculations and reading the slide). Calculated results are average of Delta 3.2+/-6.1 vs baseline score 16.6+/-7.7. It seems that Simufilam just rises all boats with well distributed terapeutic effect but nevertheless milder than $AVXL. I wonder how it would perform had it have the same mix of MMSE scores as Phase2a of Blarcamesine (MMSE 21). Let’s see the slide for $AVXL.

the same illustration as above.

The combined average and standard deviation for both groups of high concentration cohort is Delta MMSE -.46+/-4.3 or recalculated ADAS-Cog11 +2.7+/-19.2. Notice the very wide dispesion. This is due to bifurcation of response to Blarcamesine. When we calculate these for two separate groups they turne to be much different. The therapeutic effect group have Delta MMSE +3.5+/-0.7, notice very narrow dispersion about the average. This suggests very strong and uniform therapeutice effect. The other group basically follows the decline in the placebo. Reference [2] gives the rate for annual decline for large group of patients to be -3.4+/-3.7 MMSE. If we compare the other group’s declining annual scores ( -4.05+/-3.2 MMSE), the deteriration does not stand out from the annualized fall in scores in reference [2]. Recalculating the results for the group with therapeutic effect we get Delta ADAS-Cog=-9.7+/-1.8 (vs Simufilam’s Delta ADAS-Cog=-3.2+/-6.1)

Demographics

Source: Bibliography [3]

The group who carries the therapeutice effect up to 3 years without decline is defined in “Group1”, let’s estimate probaility for a patient to be in this group.

Source bibliography [4]

The carriers of APOE3 alleles are 87% of the stricken with Late On-set Alzheimer’s Disease. There is certain amount of ambiguity here. Does it include e3e4 carriers, or these are e4 carriers and therefore excluded from the group. It seems that they are excluded, as we know that 75% of high concentration group is APOE4 carriers. This would make 35% of patients to be protected from farther decline over 3 years (combined probability of SIGMAR1 WT and APOE other than e4). If we include APOE e3e4 carriers we can see that that would cover additional 35% patients with considerably slowed decline after 70 weeks (~1.5 years).

There is always the question of interpretation what the companies say or what info they release really mean. $SAVA has reported that after 6 months of dosing, if memory saves me well, 93 or 96% of patients responded to Simufilam. At 9 months there is a visible deterioration in these numbers, if I interpret them correctly, as 33% still decline. This would indicate deterioration in the quality or strength of response. $AVXL has the data on 3 years of dosing, though on very small sample size, but then it has been partially validated with the genetic and other biomarkers.

The reference [2] concludes that due to distribution and dispersion of the testing scores for large number of participants, to have a truly validated insight into efficacy of a Alzheimer’s drug, at least 3 years of data collecting is necessary. Let’s have a look at their data supporting this conclusion.

For the first 3 years, the scores as they are presented in the graph can spontaneously become positive or increase vs. the baseline scores. By about 3 years time, this phenomenon atenuates so much that the judgement on the efficay of a drug can be made without excessive ambiguity.

Conclusions

  • Simufilam produces widely spread but mild therapeutic effect (vs. $AVXL)
  • Simufilam widely spread therapeutic effect becomes narrower with time (?)
  • There is very litle information on dropouts from Simufilam trial (<10%?)
  • $AVXL presents narrower therapeutic effect with greater strength peristing for 3 years
  • $AVXL has problem with uncertainty due to small sample size but holds data for 3 years
  • Combination of biomarkers validate the $AVXL data, creating groups whose members respond similarly
  • Simufilam needs to report at least for 18 months and $AVXL needs to release data on Phase2b/3

BIBLIOGRAPHY

[1] https://pubmed.ncbi.nlm.nih.gov/26617181/

[2] https://pubmed.ncbi.nlm.nih.gov/10404988/

[3] https://pubmed.ncbi.nlm.nih.gov/32318621/

[4] https://pubmed.ncbi.nlm.nih.gov/22068907/

I have to confess that it took me some time to reach these conclusion. The number cruching takes few hours so please take it into considerations.

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A Bit About MDS-UPDRS $AVXL $ANVS

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor!

Data on Parkinson’s MDS-UPDRS Measure from $ANVS.

There are 4 parts to this test. Part 1 deals general mood. From the slide it is obvious that there is improvemnt in the placebo like the dosed cohort; conclusion strong placebo effect. The difference is large as it is about 9%. Part 2 is asking patients for their daily living activities, and again placebo effect is large with minimal difference odf 1%. Part 3 monitors the deterioration in the eponimous with Parkinson’s patients motion capabilities. the improvent here is absolute 2% and relative to placebo 3%. Forth part deals with complications in the therapy, patients are usually on some therapy, and there is lower incidence of perceived therapy problems in dosed cohort by 3%.

The consequitive parts have a ratio of the mean partial scores making up for the total over all mean score: 12.2:14.5:34.4:3.5 [1]. The part 1 and part 4 a can be connected by the improvement in cognition, ratio is 3.5. The part 2 and 3 are similarly correlated with ratio 2.37 as they are different take on the basic motion and dementia ability.

The ratio of all improvements is 9:1.1:3:2.8. This implies former ratio to be 3.2 and the latter to be 2.7. If we recalculate this we get (12.2*.09)+(14.5*1.1)+(34.4*.03)+(3.5*.028)=~2.4 points improvement.

Let’s make another assumption. The trial took 25 days, what if the trial is extended to 14 weeks and the progress in improvement is linear (my foot, but for a lack of better model this will do in this exercise).

(14*7)/25=3.92 3.92*2.4=~9.4 points improvement in 14 weeks (linear)

I bet, God is laughing now!

Let’s compare this to $AVXL’s Blarcamesine. See the results at this link: https://www.anavex.com/anavex-life-sciences-announces-anavex2-73-blarcamesine-improved-both-primary-cognitive-and-secondary-mds-updrs-efficacy-endpoints-with-significant-biomarker-correlation-in-placebo-controlled-p/

Blarcamesine did in 14 weeks 14.51 points of improvement.

This is all great but the unpredictable thing is the waning off the placebo effect which seems to be in full swing at 25 day of the $ANVS trial.

One thing is how the numbers make a partial sense, and the other thing is that there is a danger that the improvement in motion abilities of patients is smaller than one would expect because of the disproportionally better scores in parts 1 and 4. This can be blamed on the better mood and cognition these drugs induce in the patients. No doubt that the parts 1 and 4 are partialy tied to each other, as might also be the case with parts 2 and 3. $AVXL has not released such data. It would be very interesting to see it presented in some way similar to $ANVS. On the other hand, it just suffices to keep the motion abilities of the patients from further deterioration so that with time the patient will stabilize as they are mostly mild or moderate at this stage of the disease.

Data on composition of mean Parkinson’s score comes from paper Differences in MDS-UPDRS Scores Based on Hoehn and Yahr Stage and Disease Duration [1] link: https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mdc3.12476

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ANNOVIS BIO, Mirror Mirror on the Wall…. $ANVS $AVXL $SAVA

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!

How good are results from 25 days exploratory trial in Alzheimer’s and Parkinson’s?

For those accustomed to measure of dementia in MMSE (Mini Mental State Examination) it comes as a shock that the actual Posiphen score are lower than placebo in MMSE. This is due to two unrelated facts.

FACT 1: MMSE is notoriously insensitive to dementia among patients near healthy or MCI (Mild Cognitively Impaired)

This is illustration of the sensitivity of the scales in the range in question. Arithmetically, scale of 70 points divided by 30 gives 2.333 ADAS-Cog11 points per one point MMSE. In fact these scales have different ratios between them at different ranges.

For $ANVS Blue takes MMSE 25.4 initial baseline mean to ADAS-Cog11 15.0. Green takes ADAS-Cog11 10.4 (-4.4) to MMSE 26.8

FACT 2: Among the people sick with Alzheimer’s the MMSE scores can spontaneously improve, especially among the MCI (MMSE ~25).

The difference in MMSE scores interpreted from ADAS-Cog scores is +1.4. This is comparable to Blarcamesine scoring +1.2 MMSE in initial 5 week. Compare this with the tests on the dosed cohort of AD patients which is just +.8 (~60% of interpreted value, I came to the conclusion that $ANVS became victim of the random statistical events which we try to fend off by both spreading the tests in time and having large enough sample size. There is also the fact that the newly diagnosed sometimes spontaneously score better on the MMSE test in the first three years of the duration of the disease. By pure fluke the patients in placebo scored better than 25 days ago. See this illustartion from reference link https://pubmed.ncbi.nlm.nih.gov/10404988/

Now let’s compare this with the six months results from $SAVA. First see the Press Release https://www.cassavasciences.com/news-releases/news-release-details/cassava-sciences-simufilam-improves-cognition-and-behavior . This PR states that there was improvement -1.6 ADAS-Cog11 and that improvement was 10% from baseline over 6 months. That gives the baseline mean score to be 16 points.

For $SAVA over 6 months Green takes initial ADAS-Cog11 score of 16.0 to MMSE score of 24.9. Blue takes improvement of -1.6 ADAS-Cog11 to MMSE 25.4.

The interpretation of this chart suggests that the MMSE scores improved only +.50 points. This is on a bit lower than the performance of the whole n=8 High Concentration Cohort in $AVXL Blarcamesine exploratory Phase2a at the same time. But there are also conspicuous differences. Simufilam treats population on average ~25 MMSE whereas Blarcamesine treated one at ~21 MMSE. The High Concentration Cohort ,had as it members subject moving up 2-3 points and those declining 3-4 due to prevalence of 75% of APOe4 carries and scores below 20 MMSE. Had the cohort had more people over MMSE 20 and less APOe4 (50% of population) carriers it would have been few points above the baseline at this point. The cognition improvements of Posiphen are larger than those experiences by Simufilam in much shorter time frame save the spontaneous event. This bodes well for $ANVS drug as similar pattern had been developed by $AVXL Blarcamesine. After first 5 weeks the mean on the almost 30 patients went up +1.2 MMSE points. Unfortunately, some of these patients years later declined, yet the initial reaction to Posiphen is similar to $AVXL Blarcamesine. See my blog for more information.

I would like to make few remarks on the particular AAIC 2021 presentation slides.

You probably wonder what those numbers after ADAS-Cog name are? These are number of chapters added to the test. ADAS-Cog14 consists from 14 parts and is used to assess patients who are most mild Alzheimer patients like those who are participating in this trial. The scores for ADAS-Cog11 range from 0- to 70. THe range for ADAS-Cog14 is 90. the graph translate from percent to points as -3.3 points of ADAS-Cog14.

The improvement in part 3 is the smallest as it is only 2.7% that is about 1 to 2 points on the total MDS-UPDRS part 3. Part 3 deals with motion. Part 1 deals with behavior and mood. Part 2 deals with Activities of Daily Life. Part 3 is assessed by properly trained staff and concerns the motion status of a patient. Part 4 deals with complications of the therapy. It is obvious that the parts 1 makes the most progress. Part 1 is more connected with the well being than with motion improvement. I bet more information will coming soon on those 40 Parkinson’s patients in cohort 3. Though the bars convey visualy something different, the greatest disparity is between placebo and Posiphen in part 1 (~10%), I expect the the nascent change in the part 3 will increase with time. It is just right now almost 1/3 of that in part 1. I would say that part 1 is most likely due to placebo effect as patients expect to get better, of course, on top of therapeutic effect. This is confirmed in very small difference in the placebo vs. dosed in daily living part 2 which is very close to the 2.7% observed in the part 3. With time we can expect this to reject the distortions due to placebo effect.

Where Posiphen shine is the cognition improvement. Notwithstanding the problems with testing for MMSE and the distortions in testing scores in placebo cohort, the WAIS Wechester Adult Inteligence Test elucidates the tremendous change in cognition with the drug. One has to make an observation here that the improvements speed of movement and thought has been exposed with better sensitivity than it was done in MDS-UPDRS part3. Here again, placebo improved, so the placebo change was happening due to the possibility of the subjects in short time interval to improve spontaneously, especially that that placebo is just few subjects (AD n=6, PD n=5).

Cognition changes are the key to tackling Alzheimer’s. I think it was a mistake by $ANVS to have a n=6 placebo cohort. It was a right decision on part of $AVXL to dispense with it as in those exploratory trial distortions like this can happen with low n=6 and 25 days of dosing. Up to this moment I would place $AVXL first in effiacy, $ANVS second and then $SAVA. Remmber that that picture can change tomorrow evning.

How good are results from 25 days exploratory trial in Alzheimer’s and Parkinson’s?

For time being they are second best but stil can l improve.

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How to Digest Alzheimer’s Data from AAIC 2021 $AVXL $ANVS $CRTX $SAVA

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!

Stock Markets Reaction Is ……..

There are two very basic reactions from stock market participants. A kee-jerk one where everybody buys in the rush of enthusiasm and damned be the price. “I just want to get hold of it at any price”. And the measured one where the price and acquisition are weighted against each other as the market digests the pros and cons slowly.

It is very hard to predict the extend of knee-jerk reaction. This is kind of the “madness of the crowd” moment. I am not going to predict either one, but I am going to provide information helping to digest the incoming information with background of results from the most advanced player in the field.

Let’s jump to it.

$AVXL has conducted trial of its drug Anavex2-73 later known as Blarcamesine to assess dosage and explore efficacy. The trial initially involved 32 patients, in three years this number dwindled to 21 patients. The illustartion divides the patients into the groups or classes based on MMSE scores, SIGMAR1 receptor and APOE mutations. The plot y-axis is in ADCS-Activities of Daily Living (78 points scale) and it follows the patients over period of almost 3 years (148 weeks). The numbers represent the improvement from baseline. Out of cohort of 8 people, with 75% carriers of APOE4, two without APOE4 (carriers of APOE3) responded very abruptly in just 5 weeks with jump of 6.5 points (9.3% improvement over base of 70 points) [1]

Source [1]

Conclusions on Efficacy Paterns

  1. The only take way point can be that a drug with efficacy against AD should make a very steep and quick recovery possible in just few weeks if they are to hold this patients steady.
  2. A second conclusion is that if it did not do that, after two years it should only slow the progression of the disease as it happend when the APOE4 patients were added to the mix.

Nota bene, in the population of Alzheimer’s sick the Group1 should include from 50% to 40% of patients.

If these two patterns are worth anything and we intend to view the other palyers through this lense tthen…

$ANVS

It shows the pattern number 1, to verify this see the Press releases from $ANVS. links: https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=364451b1-06a7-4b96-a389-016f3ef3e6e3 ;

https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=b6b5cfe1-123f-45fa-9ab2-fd42c8960048

$CRTX

As the picture conveys thousand words so the language improvent does. I would say that $CRTX displays the pattern number 1.

$SAVA

The improvement of -1.6 ADCS-Cog points over 6 months breaks away with the pattern number 1. We need to view more data from $SAVA to say anything conclusive. Nevertheless, $SAVA has been touted as the first company achieving something more than lowering or delaying the deterioration. The record does not corroborated this assertion.

It is actually $AVXL and $CRTX which are in head to head competition. At this point $SAVA is a PR darling. It has been reported that $ANVS drug might be involved in treating the infections such as P. gingivalis giving a competition to $CRTX. In the conclusion I can only say that $AVXL,$ANVS and $CRTX share similar pattern of responces in phase2. $SAVA is the odd man out, but that is not saying that it is better than former three. It will be very interesting to read data from $SAVA.

What $SAVA has going on for it is that its phase 2b dosed size cohort is ~50 patients with first reading of interim results and kind of serves as surrogate for phase 3.

Bibliography

[1] https://pubmed.ncbi.nlm.nih.gov/32318621/

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AAIC 2021 as Viewed Through My Prism of Expectations $SAVA $CRTX $ATHA $AVXL

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor!

Monday 10:00 AM Eastern Time

$SAVA

  • Poster: “SavaDx, a Novel Plasma Biomarker to Detect Alzheimer’s Disease, Confirms Mechanism of Action of Simufilam”
  • Sounds like more of “curing Alzheimer’s with biomarker” or the best left for Thursday? Is there a change in narrative towards proteopathy? Proteopathy – Sickness of the protein making machinery. A bow in direction of those who are presenting at AAIC 2021, like $AVXL?

$CRTX

  • Poster: An update and baseline data from the Phase 2/3 GAIN trial of COR388 (atuzaginstat), a novel bacterial virulence factor inhibitor for the treatment of Alzheimer’s Disease
  • Of great interest to me, as I want to compare the data to $ANVS and $AVXL data.

$ATHA

  • Poster: Quantitative EEG as a translational measure for the assessment of ATH-1017 neurophysiological changes in mild-to-moderate Alzheimer’s disease
  • I hope for some new data. It would be very interesting to review it vs. the information I have already compiled on ERP/EEG.

Tuesday

  • $CRTX: Symposium, Dinner 5:30-7:30 PM MT – Wining and Dinnning in search of investors/buyers

Wednesday

  • $ANVS:

On Wednesday, July 28, at 8 p.m. ET, Annovis Bio will host a panel presentation which will include new efficacy and biomarker data from an interim analysis of the Company’s ongoing Phase 2a trials. The data presented will include:

·        Neurotoxic protein levels

·        Marker of axonal damage 

·        Inflammatory markers

·        Efficacy

Thursday

  • $SAVA:

On Thursday, July 29th, at approximately 11 am ET, simufilam will be featured in a live podium presentation at AAIC, including a brief Q&A session. This oral presentation will announce results of an interim analysis on safety and cognition for the first 50 patients with Alzheimer’s disease to complete 9 months of open-label treatment. Scientists for Cassava Sciences will also present biomarker data analyzed from cerebrospinal fluid (CSF) collected from 25 study subjects at baseline and again after completing 6 months of open-label drug treatment, including:

  • Biomarkers of Alzheimer’s disease: amyloid beta42, total tau, P-tau181
  • Biomarkers of neurodegeneration: neurogranin, neurofilament light chain (NfL)
  • Biomarkers of neuroinflammation: YKL-40, sTREM2 and HMGB1

If there are any comparable competitors these are in pairs:

  • $AVXL and $CRTX: both soon presenting top data on phase 2b/3 or phase 3. $CRTX Q4 2021; $AVXL H2 2022 Lifting Heavy Weights
  • $ANVS and $SAVA: battle of the phase 2 results; who looks better? Beauty Contest

As there seems to be some proteomic overlap between narratives of $AVXL and $SAVA, $AVXL in general faces more competition from $CRTX on basis that $CRTX reports phase 3 data first and that etiologically it presents completely different narrative. Yet, the $AVXL’s wide range of possible elements of MOA does not preclude possible partial acceptance of $CRTX etiology of Alzheimer’s. $AVXL MOA improves or rights some of the same cellular mechanisms the virulence of P. gingivalis affects. The real quest is to find a medication keeping people cognitevely fit longer than it happens now. Currently, the average MMSE score at diagnosis is 18.2+/-6.6 points. If the diagnose can be made before scores drope to the lower edge of this range the possibility of rescuing the patients increases. Also, this means that a slow decline in the aged population needs to be stopped or slowed down. Since I am best acquainted with $AVXL record I see it possibly fulfiling this requirement. Nevertheless, I want to get as soon as possible anything hinting as prospective performance of $CRTX.

The market’s darling is $SAVA at this moment. It would have to present relatively better data than it had presented till now. Even if it doesn’t, it might soar on lackluster performance, as it is common with the “beauty contest” stocks. The real heavy lifting is between $AVXL and $CRTX.

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Why Blarcamesine Might Be Working Against P. gingivalis $CRTX $AVXL $ANVS $SAVA

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!

I have been directed by the author to an article about $CRTX and the evidence that Alzheimer’s might be caused by virulence of the bacterium P. gingivalis. The bacterium can hitch a ride from the mouth on cells of the immune systen and enter the brain through the Brain Blood Barrier. Then it slowely makes its way infecting neuron after neuron. The article documents in exquisitely detailed manner many aspects of this infection. Indeed, the evidence is compelling.

Nevertheless, drugs like $AVXL’s Blaracamesine do make difference in the progress of the disease. If truly the disease had been caused by germ infection then how a drug which was an agonist to SIGMAR1 receptors and in very general terms worked by restoring autophagy, homeostasis and doing some work around chromatin remodeling seems also to work on a bacterial infection?

The answer is that the P. gingivalis is interacting with humans in very insidious and complex manner. It takes about 25-30 years from infection to the manifestation for the infection. But what is most interesting that the action of gingipains, that is the proteases which the bacteruim produces cut proteins into smaller fragments and feed on them. The P. gingivalis bacterium is not an ordinary prasite, it downregulates genes and upregulates gene on its feeding preference. The article beautifully documents this. Let me quote the author Gordon Gecko was a Commie (SeekingAlpha privet blog): link: https://seekingalpha.com/instablog/20791881-gordon-gecko-was-a-commie/5613017-cortexyme-s-gingipain-theory-of-alzheimer-s-disease-pathogenesis

  • Pg / gingipains display an astonishing ability to toggle our genes in ways that benefit their survival. A recent paper[xxiii] shows that of 15K genes studied, Pg upregulates 942 genes, and downregulates 1247 genes. Interestingly, this paper documents how Pg tends to upregulate the genes that code for proteins containing arginine or lysine, which are the sources of food and nutrition that gingipains can chomp on. The reverse is also true—Pg downregulates that genes that code for proteins lacking arg or lys that gingipains cannot attack. These upregulated and downregulated genes tend to be concentrated in the hippocampus; it is often observed that hippocampal volume shrinks in AD patients. The evidence seems to show that gingipains are especially active in this brain region, which would seem to explain why hippocampal shrinkage is so commonly seen in AD patients MRIs.

It is richly researched article. My admiration goes to the author for his deep knowledge. Had the alteration to chromatine be done by the bacterium would the suspected or rather documented chromatin remodeling by Blarcamesine would change this? We only have circumstantial evidence for the involvement of SIGMAR1 agonists with chromatin remodeling throught the results in the phase2a, the work on SIGMAR1 agonist cocaine, and its therapeutice effect on sufferes of Rett Syndrome. In previous post I gave link to paper documenting in research which concluded that cocaine block transcription of and the enzyme which broke down dopanine – feel good neurotransmitter.

Other papers (can be found on $CRTX website) described disruptions in autophagy and accumulation of proteins in the cytoplasm. Here again, the research on Blarcamesine show that it can clear the path to cellular health.

It might also be that the drugs from $CRTX, $ANVS, $SAVA and last but not least $AVXL can create a potent cocktail to cure Alzheimer’s once and for all. It seems that $CRTX drug binds to its proteases, $ANVS works in some unexpalined way still or cuts inflammation, $SAVA addresses the Filamen A and the cytoplasmic skeleton damage, and $AVXL reverses the chromatin remodeling done by the bacterium and also removes the barterium with its metabolism products.

I am not a scientist. This is both an advantage and a curse, since I barely have any detailed knowledge but I can see what escapes those who are entangled in mass of details, someties even contradictory. I am free to explore possibilities as I am unencumbered by amassed knowledge on any particular paradigm. This is both a strength and a weakness just the same applies to the mirror image of this dilema.

Please, take this post with grain of salt. Nevertheless, Dr. Missling himself has said that it is entirely possible that there will be a few drugs addressing Alzheimer’s as it is a very complex disease. I think that the results from the clinical trials shall prove Dr. Missling right.

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