Why You Won’t See The Full Phase 2b/3 Data Any Time Soon.

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I will fill in the gaps here where Dr. Grimmer has left out some details or I will arrive at clear conclusions. As it stands right now and maybe for a very long time, neurodegenerative diseases like Alzheimer’s or Parkinson’s can not be cured. Why is it? Because there are three processes concurrently at play in the brains of the patients. The onslaught of the disease precedes the symptoms probably by a decade. The disease affects the health of the neurons causing them to slowly die off. The plasticity of the brain compensates for the die-off. Yet, soon enough the brain which works like a network of nodes suffers disruption due to the overwhelming loss of critical nodes in the network, and the patient loses the ability to perform tasks. Plasticity hides the consequences of the die-off till it can not cope with the onslaught. The final result is that no drug can bring back the patient to the original state once the symptoms are apparent. The see-saw between the plasticity of the brain and decimating neurons disease can be the source of patients scoring higher on cognition tests during the trial than during the recruitment phase. The therapeutic effect of a drug can bring the patient’s cognition up but there is an inherited limit to it. The phenomenon can be seen in the increasing recruitment of patients with higher MMSE scores in cognition tests in the latest trials. All this is done in search of a greater therapeutic effect but this is in my final conviction illusory as it just pushes the limit to a higher cognition level. Of course, this limit is statistically distributed among the patients as is their individual condition.

Let’s face it. Cognition testing does not tell the whole story. It just indicates there is a therapeutic effect but this is limited by the above narrative of the natural progression of the disease.

The Story of Donepezil.

Donepezil is presently the Standard of Care. The Mechanism of Action reveals how it does not work on the root causes of the disease. Basically, Donepezil blocks an enzyme that under normal conditions of homeostasis would break down the excess quantity of a neurotransmitter responsible for processing memory. For short 12 weeks, it compensates for the loss of memory due to neuron atrophy. These are two different processes. One briefly hides the consequences of the other but changes nothing as after 12 weeks the deterioration of patients resumes. At its apogee of illusory efficacy, Donepezil scores -2 points ADAS-Cog11 improvement in cognition. It is more like cocaine than a real drug helping the health of the patient, a short “high” at the expense of long-term well-being.

The Final Test of the Plaque Theory

Dr. Grimmer said that it would be very interesting if the immunotherapy removing the plaque from the brains of Alzheimer’s patients would be successful enough so that they would experience no plaque brains. If they would deteriorate further then we would know that the etiology or root cause of the disease lies somewhere else. This is the quest of Phase 4 of the Lecanemab or other immunotherapies as they did not definitely have a significant impact on cognition. What is worth mentioning here is that the immune system can be both an extremely beneficial force and a destructive one. The experiment is in its final phase although results will arrive in a few years’ time to finally put this controversy to rest.

In Dr. Grimmer’s interview, the leading thread is the question of the missing etiology of Alzheimer’s. There are theories like the plaque theory but none of them has been effectively proved or disproved yet. I have to make a confession. I have pursued the importance of cognitive data and as I did this I learned something about the proposed disease’s etiologies. It is until recently that I realized that cognitive data is rather a small part of the story. Nevertheless, for a long time, I have been telling people that only after 3 years the true efficacy of Alzheimer’s drugs can be established without uncertainty. This is the result of a study on the natural course of the disease as it progresses in a clinical trial environment.

The Case of Missing Etiology

The only way to avoid becoming the victim of the Donepezil trap is to hit the real etiology of Alzheimer’s. Two outcomes are to be expected in a time of three years, the cognitive test should be relatively steady versus the declining placebo arm, and the second is a bonus and was identified with the trials of Blarcamesine, the other diseases of CNS are also affected due to similar underlying root causes. Dr. Missling proceeded to check the genome of the dosed people and the placebo to differentiate the active and silenced genes in both cohorts. Gross of the genes silenced in the diseased were reactivated in the dosed cohort. This is an oversimplified picture but at the core correct. Different genes were silenced in different diseases but by the MOA of Blarcamesine, they were reactivated. Alzheimer’s telltale is at least from a hundred to 40 years old, I mean amyloid plaque and tau. Most recently the science of genetics supported by computing power untangles the relationships between genes and disease, ever rapidly. From the data published by Anavex Life Sciences, it seems that the missing etiology has been found.

It Was All in Phase 2a

After phase 2a Open Label Extension has been conducted in the trial with the result that the eight patients declined negligibly in the span of three years versus the steep decline of the underdosed cohort that did not exhibit the therapeutic effect and could easily be taken for a placebo arm. Yet, for the science deficient this was not proof enough so they clamored to run with hundreds of subjects to have the total certainty of “statistically significant” results.

Dr. Missling Is a Genius

Dr. Missling has masterfully is managing the expectations of the science deficient, including me. The market and the analysts look mostly at the cognition results. Only when you comprehend the existence of the Donepezil Trap and the Missing Etiology combined with the limited cognition in the trial results, the focus shifts to the true efforts to achieve approval found in the genetic data, and the imaging of amyloid plaque and tau tangles reduction conducted by Anavex.

Let’s Crunch Some Numbers

See my videos of Phase2b/3 results. So the data from Phase2b/3 released on December 5, 2022, was formatted in such a way as to confuse the arithmetic deficient. I partially went over this in my video. If we assume that 80% of patients in 50mg cohort are on average -4.03 ADAS-Cog13 and the remaining 20% is declining on average 5 points on ADAS-Cog13 scale then the average result is -2.22 on ADAS-Cog13, that is the result reached by Donepezil at 12 weeks!!!

Did Blarcamesine Failed?

Of course not, it hit the limit of cognitive improvement but avoided the Donepezil Trap. The other thing is that the various measures of cognition are not comparable to each other, each is in its own domain. That is why Dr. Missling works hard behind the scenes to approve the drug before he has to release the data which would scare the retail investors into selling. Dr. Grimmer expressed optimism for Blarcamesine best when he said that he is very excited by the fact that Blarcamesine showed efficacy in the three CNS conditions currently tested. Indeed, Blarcamesine has avoided the Donepezil Trap, and rest assured it is the winner.