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….
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.
- 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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