After Conference of 3rd of December 2020….On Alzheimer’s.

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Dr. Missling reveals internals of the phase 2a

Link to paper https://jamanetwork.com/journals/jamaneurology/fullarticle/775209

By the end of the first year the number of subjects dwindled from original 32 (would these 7 be below 20 MMSE and mutant SIGMAR1? – their genome was never read) to 25 (accordingly to Dr Missling) and among these 25, 20 had had there genome read. Those 20 then separated into 15 SIGMAR1 wild type and 5 mutated. Interesting would be to find out how many patients out of the 9 who were in the High Concentration Cohort were SIGMAR1 mutated and how many were below MMSE 20. From this illustration visible is the staying power of those dosed with Blarcamesine. It seems that the 21 who did not dropped out by the third year end are all SIGMAR1 wild type and are at the least dosed with 10mg/d, as we don’t know whether all patient got the highest dose. As I was saying, with time the Effect Size will increase between synthetic placebo and the patients on Blarcamesine, if this trend continues.

Dr. Missling on Phase 2b/3

FDA has not allowed for the patients to be selected by their genetic variants so the trial results are the same as for the general population including both wild type and mutated SIGMAR1 individulas. The break down is 80%/20-16% Wild Type/Mutated (low responce). Only after the trial the SIGMAR1 mutation can be taken into account in the analysis. Dr. Missling said that the patients in Phase 2b/3 are all at or above MMSE 20 score. In light of what he said about Phase 2a, those at and above the MMSE score of 20 improved and were rescued whereas those below the score of MMSE 20 were “stopped from declining” (I assume that they were both SIGMAR1 wild type and High Concentration), at least for the first 48 weeks of the Phase 2b/3 the same is expected. The importance of this information cannot be exaggerated, whenever the data is available it will be overwhelming, any doubts of obtaining approval will dissipate. I will later do calculations on the possible Effect Size, preeliminarly I can see it to be between 2 and 1.5 (200% to 150%). Regularly, 50% or .50 is needed for approval. Denozepil was approved on 28% (.28) Effect Size.

The Episodal Memory in Phase 2 Parkinson’s Disease Dementia as the interim results for Phase 2b/3 Alzheimer’s

Selection of patients. In Phase 2b/3 Alzheimer’s patients have MMSE scores above 20 per Dr. Missling. In Phase2 PDD the scores are in another measure, the Montreal Cognitive Assesement (MoCA) scores from 13 to 23 were used to select the volunteers, these correspond to MMSE scores 18 to 28 respectively. Ergo, the patients are similar in their initial scores.

The link to source of info on MoCA vs. MMSE can be found here https://pubmed.ncbi.nlm.nih.gov/26346644/

The duration of Phase 2b/3 Alzheimer’s is 48 weeks. In the first 5-7 weeks Blarcamesine makes the greatest strides against the disease, then for those above MMSE 20, it brings steady but slower improvement. Ergo, 14 weeks might serve as a good indication of progress in next 34 weeks, a good and reasonable interim results could be infered from the Phase 2 PDD trial on basis of duration.

In order to calculate the Effect Size from the Episodic Memory battery of Phase 2 PDD, I made few assumptions. The First Standard Deviations are shown by the red bars. I assume that the extend of SD to be as large as possible as the bars are not symetrical. Upon making the calculation the Effect Size between the Placebo Arm and 50mg Arm might be 1.4. Wikipedia page on Effect Size lists these ranges to describe them qualitatively.

In 70% of cases the ADAS-Cog measure of cognition moves in the same direction with Episodic Memory measurments, taking this as adjustment; In the worst case the Effect Size in ADAS-Cog should be at least ~1.00, reading half way between Large and Very Large. And this is for the first 14 weeks of the trial. Had the data be obtained after additional 34 weeks the gap between the placebo arm and the dosed 50mg/d arm should increase even more creating posibility of even greater Effect Size.

Some time ago, Dr. McFarlane said that Blarcamesine showed 1.10 (110%) Effect Size, unheard of in the realm of Alzheimer’s research. It is hard to ascertain to what particular trial he was referring. Just as a remainder Donezepil was approved with Effect Size 0.28.

Now, with computerized tests subtle differences in your cognition can be detected, in some measures overlapping with MMSE and some not, to indicate mental decline above the age expected decline. With constant testing, let’s say every few months, early detection is possible and patients can be rescued from Alzheimer’s at least for few years. The 20 points on 30 point MMSE scale is quite deep into decline, as it is not a trivial difference, the people with the decline to the 20 points should be easy to detect with a common computerized tests, making Alzheimer’s much less of a death sentence if not at all. Such scenario hinges on the ability of Blarcamesine to rescue those above the MMSE 20 score.

Dr. Missling was explaining that the SIGMAR1 agonist like Blarcamesine has been setting in motion a mechanism of cellular repair so fundamental to cellular physiology that it can only to be best described by evoking the concept of homeostasis. Homeostasis is the concept in molecural biology to address the paradox that the life on basis of sheer probability of errors in its molecular machinery should not function as entropy could over take it and scuttle it. In my thinking Rett Syndrome shows how far the SIGMAR1 agoinist can go into restoring the cellular homeostasis, this I will tackle in the next post.