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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Alzheimer’s, Due to Fatal Infection? Cortexyme vs. Annovis Bio $CRTX $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!

The Most Important Question in Alzheimer’s Investing

The question is a simple one. Is Alzheimer’s a disease or a syndrome?. If it is a disease then it shall have one particular etiology with one drug to it. Of course, this is a great exaggeration but serves its purpose of illustration the difference between a disease and a syndrome, which is a set of symptoms that can have varied etiology. Talking more in terms of game theory, investing in Alzheimer’s drugs can be zero sum game or game where many are going to be winners, although fractionally. This view has been already expressed by Dr. Missling. I have also previously raised the question of disease vs. syndrome.

In very simplistic way the Alzheimer’s disease can be explained as the onset of cognitive impairment, followed by the plaque deposits and finally appearance of the tau tangles, all with continued decline in cognitive abilities. That is at least the scenario followed by the murine models of AD. Humans have a bit different response, as 30% those who had been diagnosed with AD at death had no amyloid plaque deposits. In regards to dementia itself and AD, we can see “three diseases”. The early onset AD, let’s say at age of 50 years and up to 10 years of duration, leading to death. Second, gradual cognitive decline with age. The third, with advancing old age and already age related congnitive decline, diagnosis of AD and the usual precipitous cognitive deterioration, often cut short by death due to other morbidity. This is the extremely simplified view of the epidemiology of dementia and AD. For reference see post link: https://piotrpeterblog.com/2021/04/11/the-ideal-dementia-drug-and-dementia-patients-population/

Etiology is the fancy name given in medicine to the cause of a disease or a condition. There are hundreds if not thousands of papers written every year about dementia and AD. Some are just reviews of literature on some aspect of the disease, some bring genuine new knowledge. But none of them are the full and complete answer to the question what are the causes or a cause of AD. Let’s for the sake of an argument claim that AD as a disease depends upon 100 interactions. A researcher can not follow all of them in vitro or in a murine model. He will concentrate on one or perhaps few to get a partial view of the disease. It is the clinical part of the search for new drug to give the final verdict on the benefits of the drug. The more limited is the scope of the study the less ambiguous are the results of the study and the more convincing they are. the caveat here is that much can lost in effort to limit the scope in order to lessen ambiguity.

I have written about some of the studies on AD. The etiologies given by them range from genetics mutations, epigenetic changes in genes during the life time of patients (chromatin remodeling), mitochondrial health, oxidative stress, neurotransmitters, misfolded protein, and neurotropic signaling molecules. They all can be aspects of one disease. The latest, I read about the possible etiology of AD due to infection by P. gingivalis, the same bacterium causing periodontal disease. If you shop for one and only cause of the disease it seems to the right place. Scientists at $CRTX claim that it is so and give studies to support their view. Indeed, it is a compelling evidence. It would explain the amyloid plaque failure and appearance in later times of tau tangles.

From ALZHEIMER’S DISEASE-LIKE NEURODEGENERATION IN PORPHYROMONAS GINGIVALIS INFECTED NEURONS WITH PERSISTENT EXPRESSION OF ACTIVE GINGIPAINS. JOURNAL OF ALZHEIMER’S DISEASE 2020.

Conclusion: P. gingivalis can invade and persist in mature neurons. Infected neurons display signs of AD-like neuropathology including the accumulation of autophagic vacuoles and multivesicular bodies, cytoskeleton disruption, an increase in phospho- tau/tau ratio, and synapse loss. Infection of iPSC-derived mature neurons by P. gingivalis provides a novel model system to study the cellular mechanisms leading to AD and to investigate the potential of new therapeutic approaches

Bacterium P. gingivalis might colonize the brains of the infected persons and stay there dormat for decades as expresed by researchers in words “viable but not culturable”, meantime the bacterium produces proteases which are sources of its virulences. Collectively, they called gingipains. Proteases are enzymes which cut proteins and peptides into parts, functionally destroying them or even producing toxic residue. These can also be found in the CSF (celebrospinal fluid) of infected persons. The in-vitro models provided by $CRTX suggest that the amyloid plaque and tau tangles are direct results of the infection.

About 50% of population of The US after age of 30 years is infected with the bacterium. The picture that the scientists at Cortexyme paint is that of bacterium taking a ride on some cells of the immune systen through brain blood barrier, and slowly spreading from neuron to neuron. Virulence of P. gingivalis causes neuroinflammation leading to production of A-beta amyloid plaque as defence mechanism and later on dissolution of microtubules resulting in tau tagles. Here, we can talk about the disruption of axonal transport, and loss of synapses. Ultimately, neurons are driven to cellular death called pyroptosis. The definition of pyroptosis says that it is the type of programmed cell death taking place in the event the cell has been infected and cannot be rescued.

This is a picture of low level infection which can be dormant for 30-40 years, which correponds to the murine model of 22 weeks incubation period to symptoms of AD. The murine and in-vitro utilize very high ratio of bacterium to cell ratio which makes the infection highly probable. Under real conditions these can never be achieved in a living person. Nevertheless, some people can be susceptible to the infection, as well as can have high levels of neuroinflammation. The authors conceded this truth.

The number of people infected with P. gingivalis is vast. Only minority develops Alzheimer’s. Let’s run the numbers. I estimate the population of the US after 30 to be at least 150,000,000. Out of that only 5 million have AD. So one in 30 develops the disease. Nevertheless, the infection is a risk for cognitive decline in general and AD in particular. The population which best illustrates the validity of Cortexyme’s claim is the Down Syndrome patients incidence of Alzheimer’s. I quote from a paper on the science section of Cortexyme home webpage.

PORPHYROMONAS GINGIVALIS IN ALZHEIMER’S DISEASE BRAINS: EVIDENCE FOR DISEASE CAUSATION AND TREATMENT WITH SMALL-MOLECULE INHIBITORS. SCIENCE ADVANCES, 2019.

In addition, sustained high levels of antimicrobial Aβ driven by chronic P. gingivalis infection of the brain may be toxic to host cells, and therefore, reduction of Aβ levels after treatment of the P. gingivalis infection should be beneficial. Furthermore, Down syndrome (DS), the most common genetic cause of mental disability, has been used to support Aβ as a therapeutic target because of the notably high prevalence of dementia with Alzheimer-type pathology in DS patients (greater than 50% after the age of 60) and the fact that the amyloid precursor protein gene, which gives rise to Aβ, is present on chromosome 21, which is triplicated in DS (65). However, in support of our hypothesis, an aggressive form of periodontitis with rapid progression and onset as early as 6 years of age is associated with DS, but not age-matched normal controls or other mentally handicapped patients of a similar age distribution (66). The occurrence of P. gingivalis has been found to be significant in the subgingival plaque of DS patients beginning around the age of 5 years when compared to age-matched controls, indicating that P. gingivalis abnormally colonizes DS patients in early childhood (67). The reason behind DS patients being susceptible to P. gingivalis infection at such an early age is unclear but may be due to the immunodeficiency that is associated with DS (68). Research is needed to determine whether P. gingivalis and gingipains are present in DS CSF and brain.

In the same paper the authors conclude that:

In summary, we propose that genetic polymorphisms of innate immune system genes in essential immune pathways may result in defective clearance of P. gingivalis and gingipains from the brain, resulting in chronic, low-level infection and neuroinflammation in susceptible individuals.

We are in the middle of Etiology Wars. There might be hundred and one things going on in AD patients physiology, one of them can be the infection with the bacterium which causes periodontal disease. Just beyond natural susceptibility, there might be other mechanism triggering onset of AD. For us, as the investors the most important thing is place our bets on a winning drugs. The AD and dementia etiology is so vast and complicated that it can be already plain to see that few drug at almost the same time are going to emerge as winners. Predicting where the money goes can be even more daunting question. I am not going to touch upon this.

Atuzaginstat (COR388) is the leading drug of Cortexyme. The drug binding to the gingipains thus making them defunct, leaving P. gingivalis infection toothless (pan intended). The infection itself is intact as no antibiotic has been found to reduce the numbers of the bacterium in brain or other colonized tissues. In other words the drugs has to be continuously dosed to have effect. This is going to be difficult to justify unless FDA conditionally approves the drug or a schedule will be given to dosing because there have been a liver reaction to the dosing of the drug over the course of the study (48 weeks). The company claims that these are transitory problems but FDA has put partial clinincal hold on Open Label Extension of the Phase2/3 GAIN study. More information can be found here, link: https://www.cortexyme.com/cortexyme-provides-regulatory-update-on-development-program-for-atuzaginstat-in-alzheimers-disease/.

Even as approved the drug would make it a duty of a physician to check on status of certain liver biomarkers making the drug cumbersome to dose. That in itself can be no surprise as Atuzaginstat binds to P.gingivalis proteases which might be similar to some liver enzymes. On the other hand, would the result in November 2021 (Q4 20121) be good enough and the climate politically accepting of AD drugs the NDA is not out of question.

I run by some notes on other drugs. Upon reading the material from Cortexyme $CRTX I realized that how limited is the terapeutic target of $SAVA. $SAVA Simufilam takes on a side show in the physiology of the AD as Cortexyme papers suggest demage to cytoplasme skeleton, and Simufilam acts on Filamin A cytoplasm skeleton element. The CEO of $SAVA has been awarded $3 million cash, it seems that options would be too long shot for him. One suspects that $SAVA’s result might be not on par. Nevertheless, it could be a good drug to add to drug cocktail a AD patient can use.

Another drug for those who think that infection with P. gingivalis is the way to go is the AVNS401 by Annovis Bio $ANVS. Reference to this can be found in this press release. https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=d75fe079-a291-4623-83a1-7c760a2c8907

It seems that the results from $CRTX are not much different than from $ANVS.

The most interesting is the Winterlight Assessment (Prepositions & Conjunctions) showing real improvements in the use of language in just 28 days. I think it is a more sensitive way to measure some aspects of cognition.

When you compare the results from both studies they seem to agree on the cognition measures like MMSE and ADAS-Cog, but I think that ANVS401 is a better drug as it does not have yet any problems with adverse effect and presents comparable improvements. See Press Realease. To get MMSE scores from ADAS-Cog (rough estimates) divide ADAS-Cog by 2.33. The ANVS401 MMSE score is 1.88 points which is about the same for COR388. Link: https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=364451b1-06a7-4b96-a389-016f3ef3e6e3

Nevertheless, as it is in the realm of phase2 studies in the Alzheimer’s disease most of them are conducted on samples size so small that the some results are not statistically significant.

I hope that the rally in AD stocks resumes as the uncertainty with FDA approval will be sorted out. There are great many stocks to invested in this field.

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AAIC 2021 July 26-30 $SAVA $ANVS $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!

Etiology Wars

The Aduhelm fiasco brings about the realization that it certainly isn’t a A-beta the reason for the dementia of Azheimer’s. The press still touts its sister the tau tangles. This narrative now goes through trasformation into the story of neuroinflammation with which are bound the two above-listed companies $SAVA and $ANVS. The transformation is simple, both of them are connected witht the A-beta physiology as a gateway to the neuroinflammation narrative. $SAVA indirectly, through Filamin A (illustration below).

$ANVS by the way of binding to messengerRNA for the precursor protein APP for A-beta, and some other enzyme related to it. quote from Alzforum on posiphen.

Posiphen, also known as ANVS-401, is the pure (+) enantiomer of phenserine. Both compounds were originally developed by Torrey Pines Therapeutics and licensed to QR Pharma in 2008. Both Posiphen and phenserine reduce production of amyloid precursor protein by blocking translation of its mRNA. Phenserine also inhibits acetylcholinesterase, while Posiphen does not. It is dosed by mouth and enters the brain.

Posiphen acts on iron-response element sequences in the 5′ untranslated region of APP mRNA to inhibit protein synthesis. It reduced APP and Aβ in neuronal cultures and brains of wild-type and AD transgenic mice (Lahiri et al., 2007Marutle et al., 2007). The drug was reported to be neuroprotective and neurotrophic in AD mouse models (Lilja et al., 2013Lilja et al., 2013), and to normalize memory impairment, learning, and synaptic function (Teich et al., 2018).

Posiphen reportedly also blocks translation of α-synuclein mRNA, implying potential application in Parkinson’s disease (Rogers et al., 2011Mikkilineni et al., 2012Yu et al., 2013). The compound reduced α-synuclein expression in brain and gut, and improved intestinal function in the A53T α-synuclein transgenic mouse model of PD (Kuo et al., 2019).

By a whole battery of biomarkers these drugs lower the level of neuroinflammation. I have to confess that upon viewing video, where a physician has injected AD patients with approved anti-inflammation drug into the neck, in order to have it then flow into the brain to make then partially recover from cognitive decline, I was so impressed that I thought it was the end of the search for AD cure. Unfortunately, the physician has been stopped from doing it by FDA. But for reasons given below this is not the end of pursuing AD cure.

Now, the etiology wars come to decisive battle, so it seems. It is not yet clear in the press and the among the laymen but the battle order in this war comes to two choices: Neuroinflammation or Epigenetics. I wrote about the Epigenetics and chromatine remodeling. Link: https://piotrpeterblog.com/2021/03/05/novel-etiology-of-alzheimers-linked-to-neuronal-loss-of-function-due-to-changes-in-cellular-transcription-mechanism-and-dna-chromatin-complex-avxl-sava-atha-biib/ [1].

I stole an article posted by Amateur17 on iHub. Post #319819. Link: https://www.spectrumnews.org/news/autisms-link-to-chromatin-remodeling-explained/ [2]. The aticle draws partly wrong conclusion as it suggests that CRISPR could help, whereas CRISPR is a method of gene editing and not fixing epigenetic chromatin remodeling. As I posted in the post [1] SIGMAR1 receptor agonist like cocaine alteres chromatin remodeling. Link to paper is inside post [1].

Nevertheless, I want to make certain predictions as new elements in this puzzle emerge. I think that neuroinflammation is just a symptom of neurodegenerative diseases. One fact is that, those who attack neuroinflammation do it indirectly and do not affect such wide spectrum of indications as $AVXL does, all by the virtue of addressing a symptom not a root cause. And even if it would be direct, it would be just only treating a symptom vs. wider systemic action (including chromatin remodeling) of Blarcamesine spread across many diseases. In this light the drugs which just temper neuroinflammation should produce immediate results with stagnation in the therapeutics effect with time, or even reversal. Blarcaesine should on the other hand produced slower and steady (to a point) recovery.

I will be watching the data from AAIC 2021 with that in mind. I am particularly interested in $SAVA’s data. If it shows any weakness I think this might bode poorly as well on $ANVS prospects, but only might.

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Parkinson’s Drug Delivered, Not Just Parkinson’s Disease Dementia Drug! $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!

Etiology Battle Won

The first paragraph says it all.

ANAVEX®2-73 treatment resulted in significant increase in the expression of the SIGMAR1 mRNA biomarker that significantly correlated with improvements in the primary and secondary clinical efficacy endpoints CoA (p = 0.029) and MDS-UPDRS Part III (p = 0.024) and MDS-UPDRS Total (p = 0.038)

Wherever Blarcamesine has been treating patients increased SIGMAR1 messengerRNA has been detected, this direcetly connects the drug with the biomarkers and the therapeutic effect. Clear and known Mechanism of Action has been established. Blarcamesine is a pathblazer for other SIGMAR1 drugs making iself the first of a new class of drugs. This warms considerably the icecold feet of FDA.

Parkinson’s Disease Dementia Addressed

.……which correlated with clinical efficacy as measured by primary cognitive efficacy endpoints, CDR system Continuity of Attention (CoA) (p = 0.029) and CDR system Power of Attention (PoA) (p = 0.015),….

Broad and statistically significant improvements in CDR system Cognitive Domain of Attention assessed by Choice Reaction Time (p = 0.039) and Digital Vigilance (p = 0.008) and CDR system Episodic Memory (p = 0.047), representing complex cognitive tasks with impact on quality of life such as making a choice between similar objects and remembering daily personal experiences, which are mostly impaired in both PD and AD.[15] 
Statistically significant dose-dependent (p = 0.003) improvement of Episodic Memory, which has been shown to be highly correlated (70%) with the Alzheimer’s Disease Assessment Scale–Cognitive score (ADAS-Cog; r = 0.7).

See my previous post on Episodic Memory as was reported initially. link: https://piotrpeterblog.com/2020/12/04/after-conference-of-3rd-of-december-2020-on-alzheimers/ . I have calculated the Effect Size for Episodic Memory which in my reckoning was supposed to be about 1.40. We don’t have and other data than what is given in the quotation. Firstly, CDR is composed from few subtests like Continuity of Attention, Episodic Memory, Choise Reaction Time, Digital Vigilance and Power of Attention. Those subtests measure errors and speed of response. The only metric given here is the p-vales of each subtest. P-values refer to the probability of the results being part of the characteristic dispersion of data among the placebo cohort. The lower the number the better results, or data points are better separated from placebo. They are both statistically significant, with Power of Attention being the best. Nothing more can be said at this moment. This calls for deeper research than done by me at this time, and a separate post.

Did Blarcamesine Put Parkinson’s in Its Bag of Tricks?

I shall not engage in speculation right now. (Just for a moment) Let me quote from the PR.

….and secondary Parkinson’s efficacy endpoints Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)[4], MDS-UPDRS Part III (p = 0.024) and MDS-UPDRS Total (p = 0.038).

Let’s us analyze the MDS-UPDRS test. It consists from 4 parts. I read through the questionnaire and tried to evaluate the maximum score obtainable which equates with scoring the worst on all measures. I can approximate the number of points to be about 230-240. The average Parkinson’s patient in the Phase2 PDD trial scores about ~77 points (1/.189*14.51= 76.8)(at the end of 14 weeks). Quick search revealed this to be about right.

Let us engage in pure speculation. We have the two mean values at 14 weeks and one of the standard deviations. We could explore the possible values for the dosed cohort standard deviation in order to calculate Effect Size for the Blarcamesine as Parkinson’s disease drug.

  • The placebo score is 77+/-32.8
  • Dosed score is 62.5+/-30 (assumed sdandard deviation of +/-30)

The Effect Size @ 14 weeks is 0.45. This is almost enough to approve the drug (minimum) but we would expect this to increase witht the duration of the trial as Blarcamesine Effect Size in progressive neurodegenerative diseases increases with the duration of the dosing. We have to remember that Donezepil was approved with Effect Size of 0.28 after six months of dosing (24 weeks).

Not without a reason, Dr Missling singled out the Part III (p-value of .024) from the MDS-UPDRS Total (p=.038). Part III is the motor examination which loss of is characteristic for the disease. Here, the implication is that patients on Part III score “better” than on measures of dementia and daily living, and the drug is engaging the core etiology of the disease.

Additionally, Blarcamesine improvement has been twice the empirically established cutoff score for spurious improvement of -7.1 points of MDS-UPDRS. We have remember that all this is happening at 14 weeks of dosing. As I previously pointed out, Parkinson’s is a progressing condition so even staying in place makes for larger Effect Size with time. A relatively small Effect Size is due to large size dispersion around a mean. The same reason might be behind the empirical cut-off of -7.1 points as such small difference in between the two mean is not sufficient to separate the two dispersions for any meaningful effect. After pluging the numbers into the formula for Effect Size we arrive with the number of 0.22, which qualitatively is below small. I guess many trials produced somewhere below -7 points only ultimately to disappoint. One might compare it to gravitation and Blarcamesine breaking away from it to leave its pull permanetly.

The Phase2 PDD has given us enough of data to claim that Blarcamesine is not only able to treat Parkinson’s dementia but also Parkinson’s disease itself. The experience with the extension of Phase 2a Alzheimer’s give us confidence that the effect of the drug will not wane with time but might reverse the ravages of the disease.

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