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! And I am long $AVXL.
Discovery Brings About the Therapetic Taget of the Day and Damned be the Complexity.
Thousands of researchers study and write papers on number of different physiological processes. Some compounds discovered at one place are used to do quite different job somewhere else in the matrix of physiological maze. A layman like me reading the papers recognizes at first that in this maze of connections the possible cross-referencing points to number of connections beyond the ability to be grasped by a mind of a single human being. Human mind likes to simplify this multitude of connections with some ordering thought. In search of therapeutic targets the modern medicine man has to place his hopes on one compound at the moment to carry him to point at which he can claim that he succeeded in bringing benefit to the sick. Any new discovery is viewed with this hope in mind. Complexity of these connections can defeat him by bringing about crushing side effects, or the irrelevence of the compound to the over all health can dash the hopes.
EIP Pharma (private) hopes to address CNS system diseases with targeting p38 Alpha (MAPK14(gene)). This gene expression is connected to “programed cell death through network of signaling molecules and trascription factors” . Also p38 alpha was identified to play role in “proliferation, differentiation and trascription” . The picture which emerges in my mind is that of molecule mediated through trascription of MAPK14 gene to bring about cascade of changes, all entailed by occurance of some form of prior cellular stress. This should lead to apoptosis (cellular suicide) of cells stressed beyond the recovery and starting mechanism of replacing the dead cells with new ones through “proliferation, differatiation and trascription”. This mechanism can cope with mild stress introduced to the cells but when overwhelmed by it, it adds fuel to the fire. Would p38 alpha downregulation (inhibitor) stop the apoptosis and lower the resulting neuronal death and inflammation? Or would it stop the “prior cellular stress” which theoretically might be found upstream?
I crossed referenced ref.  witht the list of genes p38 alpha interacts with (ref ). The etiology of reference  is tracing the Alzheimer’s disease to the genetic mutation mostly in PSEN1 gene (), and by extension to some undisclosed yet epigenetic change in those with LOAD (late on-set AD). Indeed, p38 alpha interacts with two genes which are the same as in ref , STAT1 (inflammation) and SRF (serum responce factor-neuronal apoptosis). This implies the possibility that p38 alpha is triggered downstream of the PSEN1 etiology . See link to post talking about the PSEN1 etiology. 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/
The reference  placed the fault in EOFAD (early on-set familial AD) on genetic changes in the trascription mechanism in the cells nucleus (chromatin DNA complex – (histone+acetyl group)). There is arising evidence that that is also the case with LOAD (late on-set AD) through egenetic changes. This might be the reason that all the means of assaulting the disease has up to this point in time where aimed at “periphery” of its etiology or even outside of it. The results presented by EIP Pharma might be proving my point, and the altest new from Dr. Missling corroborates the etiology given in referenc . The results for Phase 2b for the EIP Pharma drug Neflamapimod was presented under this link on the corporate slideshow https://www.eippharma.com/wp-content/uploads/2019/12/CTAD-REVERSE-SD-Presentation-Final-5-December-2019.pdf .
Let us view the slide on recruitment for the trial. It is earily similar to the Anavex’s phase 2b/3 Ad trial (pivotal).
The same MMSe score range and the presence of amyloid and tau plaque. In case of EIP Pharma this is Celebral-Spinal Fluid bio markers but Anavex had the brain scan made in order to eliminate any doubt of the amyloid plaque deposits existance. This might explain the long recruiting period. It sems that FDA might be doubly cautious with Anavex as it leaves no possibility of so called random event skewing the results because as a lay person would say they are “unbelievably” good. (too good to be true) (beyond the range of prrevious trials).
The primary measures are total disasters. Let’s see the secondary.
The secondary ones, which are more familiar to me follow the suit. So what EIP Pharma did was to turn to Plasma Drug Concentration as covariance. (covariance is a variable of secondary importance (possibly))
At the 75th precentile 18 patients show slight improvenet. As far as I can read this plot the least suare mean of those patients is .075 (7.5%) standard deviations above the least square mean of the inintial scores for all measures combined. You indeed need a degree in biostatistics to fully understand what is going on here. Z-scores are the values for each data point in relation to the mean expressed in the multiple of Standard Deviation. The Least Square Mean is a version of mean where a covariance (or few of them) is kept constant. This mean can be different from the mean but not much different. And what the conclusion of the management was after this debacle? Need to increase the dose to 150%. Let’s compare it to plot of delta of MMSE scores vs. concentration for Anavex2-73 Blarcamesine in phase 2a at 57 weeks. This study preceded the Phase 2b/3 AD (pivotal) which is due to present top data in summer of 2022.
These are the Effect Size calculations for the same high concentration patients after 3 years for dosing. This is much more transparent to an averge Joe like me than “the least square mean of Z-scores of all the measures of 75th precentile of plasma concentration after 24 weeks of dosing”. EIP Pharma futility in Alzheimer’s Reverse-SD study is rather obvious. Nevertheless its Lewy Body Dementia study Phase2 AscenD-LB was able to produce Effet Size of above 0.50 values, theoretically sufficient for approval. You can read the Press Release at this link https://www.eippharma.com/news/eip-pharma-announces-presentation-of-positive-clinical-trial-results-with-neflamapimod-at-the-13th-clinical-trials-in-alzheimers-disease-ctad-meeting/
EIP Pharma eexpects to have Neflamapimod approved at least for Lewy Body Dementia, and in deed it just reached that point of efficacy where the approval is possible.
The etiology given to Alzheimer’s in reference  is becoming confirmed by further research into Sigmar1 receptors and their MOA in the cellular physiology. In this recent presentation link: https://wsw.com/webcast/needham107/avxl/2271566 (time sensitive) Dr Missling talks of new paper being review to be published and talking about the sigmar1 involvement in regulation of the chromatine-DNA complex besides autophagy and protein “uality control”. Alzheimer’s is indeed the thoughest nut to crack in the pool of CNS diseases but inevitably science has been granted the tools to look into the etiology of these diseases and new generation of drugs might mitigage the suffering and morbidity.
 Wikipedia artickle https://en.wikipedia.org/wiki/MAPK14
 Dedifferentiation and neuronal repression define familial Alzheimer’s disease
Andrew B. Caldwell1, Qing Liu2, Gary P. Schroth3, Douglas R. Galasko2, Shauna H. Yuan2*, Steven L. Wagner2,4, Shankar Subramaniam1,5,6,7†
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