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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